ORCID Profile
0000-0001-7781-4465
Current Organisations
University of Western Australia
,
University of Tasmania
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Publisher: Elsevier BV
Date: 08-2019
Publisher: Springer Science and Business Media LLC
Date: 23-02-2011
DOI: 10.1038/EJHG.2011.19
Publisher: Springer New York
Date: 21-09-2018
DOI: 10.1007/978-1-4939-7498-6_5
Abstract: Preecl sia (PE) is a serious hypertensive disorder that affects up to 8% of all pregnancies annually. An established risk factor for PE is family history, clearly demonstrating an underlying genetic component to the disorder. To date, numerous genetic studies, using both the candidate gene and genome-wide approach, have been undertaken to tease out the genetic basis of PE and understand its origins. Such studies have identified some promising candidate genes such as STOX1 and ACVR2A. Nevertheless, researchers face ongoing challenges of replicating these genetic associations in different populations and performing the functional validation of identified genetic variants to determine their causality in the disorder. This chapter will review the genetic approaches used in the study of PE, discuss their limitations and possible confounders, and describe current strategies.
Publisher: American Society for Microbiology
Date: 05-1994
DOI: 10.1128/JB.176.9.2663-2669.1994
Abstract: The recombinant plasmid pJIR318 contains a fragment of the Dichelobacter nodosus genome which is associated with virulence. Sequence analysis of the pJIR318 insert has shown that it contains four vap (virulence-associated protein) genes which are homologous to open reading frames found on the Escherichia coli F plasmid and the Neisseria gonorrhoeae cryptic plasmid (M. E. Katz, R. A. Strugnell, and J. I. Rood, Infect. and Immun. 60:4586-4592, 1992). The plasmid pJIR318 hybridizes to three regions of the D. nodosus genome, each of which has now been isolated. Regions 1 and 3 were found to be adjacent in the genome of D. nodosus A198, and the order of the vap genes in vap regions 1 and 2 were shown to be identical. Partial sequence analysis and Southern blot analysis of the vap regions showed that the three regions probably arose by a duplication event(s) followed by insertions and/or deletions. A recombinant plasmid, pJIR749, was isolated from a library of a benign D. nodosus strain, 305. This plasmid contained sequences from both ends of vap region 2. Analysis of pJIR749 showed that the sequences on either side of vap region 2 were separated by 324 bp in the genome of benign strain 305 and that the orientations of the sequences were different. It is clear that a simple insertion or deletion event did not generate the benign and virulent strains studied. A model which describes the evolution of the duplicated vap regions in D. nodosus A198 is presented.
Publisher: Oxford University Press (OUP)
Date: 12-10-2017
Publisher: Oxford University Press (OUP)
Date: 19-07-2010
Publisher: Elsevier BV
Date: 07-2018
DOI: 10.1016/J.SCHRES.2018.02.034
Abstract: The importance of genomic copy number variants (CNVs) has long been recognized in the etiology of neurodevelopmental diseases. We report here the results from the CNV analysis of whole-genome sequences from 91 multiplex schizophrenia families. Employing four algorithms (CNVnator, Cn.mops, DELLY and LUMPY) to identify CNVs, we find 1231 rare deletions and 287 rare duplications in 300 in iduals (77 with schizophrenia (SZ), 32 with schizoaffective disorder (SAD), 82 with another neuropsychiatric diagnosis and 109 unaffected). The size of the CNVs ranges from a few hundred base-pairs to about 1.3Mb. The total burden of CNVs does not differ significantly between affected (SZ and SAD) and unaffected in iduals. Parent-to-child transmission rate for rare CNVs affecting exonic regions is significantly higher for affected (SZ and SAD) probands as compared to their siblings, but rates for all CNVs is not. We observe heterogeneity between families in terms of genes involved in CNVs, and find several CNVs involving genes previously implicated in either schizophrenia or other neuropsychiatric disorders.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2023
DOI: 10.1007/S12072-022-10469-7
Abstract: Epigenetic modifications are associated with hepatic fat accumulation and non-alcoholic fatty liver disease (NAFLD). However, few epigenetic modifications directly implicated in such processes have been identified during adolescence, a critical developmental window where physiological changes could influence future disease trajectory. To investigate the association between DNA methylation and NAFLD in adolescence, we undertook discovery and validation of novel methylation marks, alongside replication of previously reported marks. We performed a DNA methylation epigenome-wide association study (EWAS) on DNA from whole blood from 707 Raine Study adolescents phenotyped for steatosis score and NAFLD by ultrasound at age 17. Next, we performed pyrosequencing validation of loci within the most 100 strongly associated differentially methylated CpG sites (dmCpGs) for which ≥ 2 probes per gene remained significant across four statistical models with a nominal p value 0.007. EWAS identified dmCpGs related to three genes ( ANK1, MIR10a , PTPRN2 ) that met our criteria for pyrosequencing. Of the dmCpGs and surrounding loci that were pyrosequenced ( ANK1 n = 6, MIR10a n = 7, PTPRN2 n = 3), three dmCpGs in ANK1 and two in MIR10a were significantly associated with NAFLD in adolescence. After adjustment for waist circumference only dmCpGs in ANK1 remained significant. These ANK1 CpGs were also associated with γ-glutamyl transferase and alanine aminotransferase concentrations. Three of twenty-two differentially methylated dmCpGs previously associated with adult NAFLD were associated with NAFLD in adolescence (all adjusted p 2.3 × 10 –3 ). We identified novel DNA methylation loci associated with NAFLD and serum liver biochemistry markers during adolescence, implicating putative dmCpG/gene regulatory pathways and providing insights for future mechanistic studies.
Publisher: MDPI AG
Date: 03-08-2021
Abstract: Mammographic breast density (MBD) is a strong and highly heritable predictor of breast cancer risk and a biomarker for the disease. This study systematically assesses MBD as an endophenotype for breast cancer—a quantitative trait that is heritable and genetically correlated with disease risk. Using data from the family-based kConFab Study and the 1994/1995 cross-sectional Busselton Health Study, participants were ided into three status groups—cases, relatives of cases and controls. Participant’s mammograms were used to measure absolute dense area (DA) and percentage dense area (PDA). To address each endophenotype criterion, linear mixed models and heritability analysis were conducted. Both measures of MBD were significantly associated with breast cancer risk in two independent s les. These measures were also highly heritable. Meta-analyses of both studies showed that MBD measures were higher in cases compared to relatives (β = 0.48, 95% CI = 0.10, 0.86 and β = 0.41, 95% CI = 0.06, 0.78 for DA and PDA, respectively) and in relatives compared to controls (β = 0.16, 95% CI = −0.24, 0.56 and β = 0.16, 95% CI = −0.21, 0.53 for DA and PDA, respectively). This study formally demonstrates, for the first time, that MBD is an endophenotype for breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2014
Publisher: Frontiers Media SA
Date: 2013
Publisher: Springer Science and Business Media LLC
Date: 18-09-2013
Publisher: Elsevier BV
Date: 2012
Publisher: Frontiers Media SA
Date: 2012
Publisher: Elsevier BV
Date: 05-2012
DOI: 10.1111/J.1538-7836.2012.04700.X
Abstract: Plasminogen activator inhibitor type 1 (PAI-1) is an important regulator of fibrinolysis. A common deletion polymorphism that results in a sequence of 4G instead of 5G in the promoter region of the gene is associated with a small increase in the risk of venous thromboembolism. Its potential association with adverse pregnancy events remains controversial. We aimed to assess the impact of the 4G PAI-1 polymorphism on pregnancy outcomes in women who had no prior history of adverse pregnancy outcomes or personal or family history of venous thromboembolism. This study represents a secondary investigation of a prior prospective cohort study investigating the association between inherited thrombophilias and adverse pregnancy events in Australian women. Healthy nulliparous women were recruited to this study prior to 22 weeks gestation. Genotyping for the 4G/5G PAI-1 gene was performed using Taqman assays in an ABI prism 7700 Sequencer several years after the pregnancy was completed. Pregnancy outcome data were extracted from the medical record. The primary outcome was a composite comprising development of severe pre-ecl sia, fetal growth restriction, major placental abruption, stillbirth or neonatal death. Pregnancy outcome data were available in 1733 women who were successfully genotyped for this polymorphism. The primary composite outcome was experienced by 139 women (8% of the cohort). Four hundred and fifty-nine women (26.5%) were homozygous for the 4G deletion polymorphism, while 890 (51.4%) were heterozygous. Neither homozygosity nor heterozygosity for the PAI-1 4G polymorphism was associated with the primary composite outcome (homozygous OR = 1.30, 95% CI = 0.81-2.09, P = 0.28, heterozygous OR = 0.84, 95% CI = 0.53-1.31, P = 0.44) or with the in idual pregnancy complications. The PAI-1 4G polymorphism is not associated with an increase in the risk of serious adverse pregnancy events in asymptomatic nulliparous women.
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.ATHEROSCLEROSIS.2021.11.004
Abstract: Familial hypercholesterolaemia (FH) and elevated plasma lipoprotein(a) [Lp(a)] are inherited conditions independently associated with atherosclerotic cardiovascular disease. This study investigated the detection of new cases of elevated Lp(a) during cascade testing of relatives of probands with a definite diagnosis of FH and elevated Lp(a) (≥50 mg/dL). Relatives from 62 adult probands were tested for FH genetically and for elevated Lp(a) using an immunoassay. The prevalence and yield of new cases of FH with or without elevated Lp(a) among relatives and the association between the detection of elevated Lp(a) and the Lp(a) concentration of the probands were assessed. Among 162 relatives tested (136 adults and 26 children), the prevalence of FH and elevated Lp(a) was 60.5% and 41.4%, respectively: FH alone was detected in 31.5%, elevated Lp(a) alone in 12.3%, FH with elevated Lp(a) in 29.0%, and neither disorder in 27.2% of the relatives. Cascade testing detected a new case of FH, elevated Lp(a) and FH with elevated Lp(a) for every 1.5, 2.1 and 3.0 relatives tested, respectively. The proportion of relatives detected with elevated Lp(a) was significantly higher when tested from probands with Lp(a) ≥100 mg/dL compared with those from probands with Lp(a) between 50 and 99 mg/dL (53% vs 34%, p = 0.018). The concordance between the detection of FH and elevated Lp(a) was 56.2% (kappa statistic 0.154), indicating a poor agreement. A dual approach to cascade testing families for FH and high Lp(a) from appropriate probands can effectively identify not only new cases of FH, but also new cases of elevated Lp(a) with or without FH. The findings accord with the co-dominant and independent heritability of FH and Lp(a).
Publisher: BMJ
Date: 05-05-2011
Abstract: Cystinosis is an autosomal recessive disease characterised by the abnormal accumulation of lysosomal cystine. Mutations in the cystinosin gene (CTNS) represent known causes for the disease. The major cystinosis mutation is a 57 kb deletion on human chromosome 17p13 that removes the majority of CTNS and the entire adjacent gene, CARKL/SHPK. In order to identify other genes that may influence the cystinosis pathobiological pathway, peripheral blood mononuclear cells (PBMC) were collected from cystinosis family members, and DNA and RNA extracted. Using whole genome transcriptional profiling, transient receptor potential vanilloid 1 (TRPV1) was found to be differentially expressed in association with cystinosis. This was verified using TaqMan qRT-PCR. There was a 72% reduction in PBMC TRPV1 mRNA levels in cystinosis in iduals homozygous for the 57 kb deletion (n=6) compared to unaffected in iduals without the deletion (n=6) (p=0.002). TRPV1 is a sensory receptor located on chromosome 17p13, adjacent to CARKL/SHPK. It was ascertained that the 57 kb deletion extends from exon 10 of CTNS, upstream through CARKL/SHPK, to intron 2 of TRPV1, thus deleting the first two non-coding exons. This is the first study to report that the 57 kb deletion extends into the TRPV1 gene causing dysregulation of transcription in PBMC isolated from cystinosis patients.
Publisher: Springer Science and Business Media LLC
Date: 14-11-2018
DOI: 10.1038/S41467-018-06649-5
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, UK, and USA comprising 52,506 in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs in KITLG and a region of 9q32. In a bivariate analysis combining the nevus results with a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A, CYP1B1 , PPARGC1B , HDAC4 , FAM208B, DOCK8 , and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1, reached a suggestive level. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis.
Publisher: Oxford University Press (OUP)
Date: 08-2000
Abstract: Differential display methodology was employed to examine and compare the mRNA species derived from normal endometrial tissue and endometrial carcinoma (grade 3, stage III) tissue biopsies. Two cDNA sequences, one expressed in the tumour group only (T19) and the other expressed only in the normal group (N22), were selected for verification of differential expression by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The expression of N22 was restricted to the normal group, suggesting a possible tumour suppressing function. Sequence analysis of this fragment revealed a high degree of similarity to a human cDNA sequence of unknown function. The expression of T19 mRNA was observed in both normal and neoplastic tissues, however the relative abundance was significantly higher in endometrial carcinomas. Expression of T19 mRNA was further examined in a larger clinical s le set and was significantly increased in the tumours (n = 16), with a three-fold increase when compared with the normal endometria, n = 5 (Kruskal-Wallis analysis of variance, P<0.05). Subsequent sequence analysis of T19 revealed a high degree of similarity to the 3' untranslated region of a rat growth factor responsive gene, SM-20. Further characterization of these mRNA transcripts may lead to the identification of novel genes involved in endometrial tumourogenesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
Publisher: Public Library of Science (PLoS)
Date: 26-05-2015
Publisher: Elsevier BV
Date: 1998
DOI: 10.1016/S0143-4004(98)90096-0
Abstract: Recently, a model has been proposed for the involvement of secretory phospholipase A2 (sPLA2) in the onset of and/or progression of human labour via the metabolism of cell membrane glycerophospholipids to generate biologically active, phospholipid-derived mediators. The recent molecular cloning and characterization of a cell-surface receptor for sPLA2 raise the possibility that sPLA2 enzymes may also affect cell function in intrauterine tissues via a receptor-mediated pathway. The aim of this study was to determine the expression profile of the PLA2 receptor messenger RNA in human gestational tissues at term. Messenger RNA for the PLA2 receptor was detected in amnion, choriodecidua and placenta by RT-PCR and transcripts of similar size to the 6.5- and 5.4-kb transcripts previously reported in various other human tissues were detected in choriodecidua by Northern blot analysis. However, smaller transcripts of approximately 4, 2.3 and 1 kb were also detected in choriodecidua by Northern blot analysis and the 2.3-kb transcript and the 1-kb transcript were the only major transcripts detected in amnion and placenta, respectively. The presence of PLA2 receptor mRNA in human gestational tissues indicates that an alternative non-catalytic pathway may contribute to the regulatory effects of sPLA2 isozymes in these tissues. While the specificity and affinity of the various transcripts identified in this study have yet to be determined, PLA2 isozymes released from human gestational tissues during pregnancy and at the time of labour may function as paracrine or autocrine mediators to affect cell function.
Publisher: Springer Science and Business Media LLC
Date: 06-06-2022
DOI: 10.1038/S41467-022-30875-7
Abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species putatively in the mechanistic pathway for coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 in iduals from the Busselton Health Study. The discovery GWAS identified 3,361 independent lipid-loci associations, involving 667 genomic regions (479 previously unreported), with validation in two independent cohorts. A meta-analysis revealed an additional 70 independent genomic regions associated with lipid species. We identified 134 lipid endophenotypes for CAD associated with 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 in iduals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association ( P 1 × 10 −3 ), 43 loci were associated with at least one lipid endophenotype. These findings illustrate the value of integrative biology to investigate the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
Publisher: Elsevier BV
Date: 04-2003
Publisher: Cold Spring Harbor Laboratory
Date: 07-08-2017
DOI: 10.1101/173112
Abstract: The total number of acquired melanocytic nevi on the skin is strongly correlated with melanoma risk. Here we report a meta-analysis of 11 nevus GWAS from Australia, Netherlands, United Kingdom, and United States, comprising a total of 52,506 phenotyped in iduals. We confirm known loci including MTAP , PLA2G6 , and IRF4 , and detect novel SNPs at a genome-wide level of significance in KITLG , DOCK8 , and a broad region of 9q32. In a bivariate analysis combining the nevus results with those from a recent melanoma GWAS meta-analysis (12,874 cases, 23,203 controls), SNPs near GPRC5A , CYP1B1 , PPARGC1B , HDAC4 , FAM208B and SYNE2 reached global significance, and other loci, including MIR146A and OBFC1 , reached a suggestive level of significance. Overall, we conclude that most nevus genes affect melanoma risk ( KITLG an exception), while many melanoma risk loci do not alter nevus count. For ex le, variants in TERC and OBFC1 affect both traits, but other telomere length maintenance genes seem to affect melanoma risk only. Our findings implicate multiple pathways in nevogenesis via genes we can show to be expressed under control of the MITF melanocytic cell lineage regulator.
Publisher: Research Square Platform LLC
Date: 21-04-2023
DOI: 10.21203/RS.3.RS-2809465/V1
Abstract: Obesity is a risk factor for type 2 diabetes and cardiovascular disease. However, a substantial proportion of patients with these conditions have a seemingly normal body mass index (BMI). Conversely, not all obese in iduals present with metabolic disorders giving rise to the concept of “metabolically healthy obese”. Using comprehensive lipidomic datasets from two large independent population cohorts in Australia (n = 14,831), we developed models that predicted BMI and calculated a metabolic BMI score (mBMI) as a measure of metabolic dysregulation associated with obesity. We postulated that the mBMI score would be an independent metric for defining obesity and help identify a hidden risk for metabolic disorders regardless of the measured BMI. Based on the difference between mBMI and BMI (mBMI delta “mBMIΔ”), we identified in iduals with a similar BMI but differing in their metabolic health profiles. Participants in the top quintile of mBMIΔ (Q5) were more than four times more likely to be newly diagnosed with T2DM (OR = 4.5 95% CI = 3.1–6.6), more than two times more likely to develop T2DM over a five year follow up period (OR = 2.5 CI = 1.5–4.1) and had higher odds of cardiovascular disease (heart attack or stroke) (OR = 2.1 95% CI = 1.5–3.1) relative to those in the bottom quintile (Q1). Exercise and diet were associated with mBMIΔ suggesting the ability to modify mBMI with lifestyle intervention. In conclusion, our findings show that, the mBMI score captures information on metabolic dysregulation that is independent of the measured BMI and so provides an opportunity to assess metabolic health to identify in iduals at risk for targeted intervention and monitoring.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2020
Publisher: MDPI AG
Date: 10-02-2022
DOI: 10.3390/IJMS23041966
Abstract: Utero-placental development in pregnancy depends on direct maternal–fetal interaction in the uterine wall decidua. Abnormal uterine vascular remodeling preceding placental oxidative stress and placental dysfunction are associated with preecl sia and fetal growth restriction (FGR). Oxidative stress is counteracted by antioxidants and oxidative repair mechanisms regulated by the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2). We aimed to determine the decidual regulation of the oxidative-stress response by NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) in normal pregnancies and preecl tic pregnancies with and without FGR. Decidual tissue from 145 pregnancies at delivery was assessed for oxidative stress, non-enzymatic antioxidant capacity, cellular NRF2- and KEAP1-protein expression, and NRF2-regulated transcriptional activation. Preecl sia combined with FGR was associated with an increased oxidative-stress level and NRF2-regulated gene expression in the decidua, while decidual NRF2- and KEAP1-protein expression was unaffected. Although preecl sia with normal fetal growth also showed increased decidual oxidative stress, NRF2-regulated gene expression was reduced, and KEAP1-protein expression was increased in areas of high trophoblast density. The trophoblast-dependent KEAP1-protein expression in preecl sia with normal fetal growth indicates control of decidual oxidative stress by maternal–fetal interaction and underscores the importance of discriminating between preecl sia with and without FGR.
Publisher: Springer Science and Business Media LLC
Date: 30-04-2008
DOI: 10.1038/HDY.2008.28
Abstract: Resistin has been associated with inflammation and risk for cardiovascular disease. We previously reported evidence of a QTL on chromosome 19p13 affecting the abundance of resistin (RETN) mRNA in the omental adipose tissue of baboons (L0D score 3.8). In this study, whole genome transcription levels were assessed in human lymphocyte s les from 1240 adults participating in the San Antonio Family Heart Study, using the Sentrix Human-6 Expression Beadchip. Lymphocytes were surveyed, as it has been proposed that their expression levels may reflect those in harder to ascertain tissues, such as adipose tissue, that are thought to be more directly relevant to disease procesn was conducted to detect loci affecting RETN mRNA levels. We obtained significant evidence for a QTL influencing the RETN expression (LOD score 10.7) on chromosome 19p. This region is orthologous/homologous to the region previously localized on baboon chromosome 19. The strongest positional candidate gene in this region is the structural gene for resistin, itself. We also found evidence for a QTL influencing resistin protein levels (LOD score 5.3) on chromosome 14q. This differs from our previously reported QTL on chromosome 18 in baboons. The different QTLs for circulating protein suggests that post-translational processing and turnover may be influenced by different or multiple genes in baboons and humans. The parallel findings of a cis-eQTL for RETN mRNA in baboon omental tissue and human lymphocytes lends support to the strategy of using lymphocyte gene expression levels as a surrogate for gene expression levels in other tissues.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
Publisher: Oxford University Press (OUP)
Date: 29-06-2006
Abstract: Pre-ecl sia/ecl sia (PE/E) is a common, serious medical disorder of human pregnancy. Familial association of PE/E has been recognized for decades, but the genetics are complex and poorly understood. In an attempt to identify PE/E susceptibility genes, we embarked on a positional cloning strategy using 34 Australian and New Zealand PE/E pedigrees. An initial 10-cM resolution genome scan revealed a putative susceptibility locus spanning a broad region on chromosome 2 that overlaps an independently determined linkage signal seen in Icelandic PE pedigrees. Subsequent fine mapping using 25 additional short tandem repeat (STR) markers in this region and non-parametric multipoint linkage analysis did not change the overall position. Under a strict diagnosis of PE, we obtained significant evidence of linkage on 2q with a peak log-of-odds ratio score (LOD) of 3.43 near marker D2S151 at 155 cM. To prioritize positional candidate genes at the 2q locus for detailed analysis, we applied an objective prioritization strategy that integrates quantitative bioinformatics, assessment of differential gene expression and association analysis of single-nucleotide polymorphisms (SNPs). Highest priority was assigned to the activin receptor gene ACVR2. This gene also showed >10-fold differential gene expression in human decidual tissue from normotensive and PE in iduals. We genotyped five known SNPs in this gene in our pedigrees and performed tests for association and linkage disequilibrium. One SNP (rs1424954) showed strong preliminary evidence of association with PE (P = 0.007), whereas two others (rs1364658 and rs1895694) exhibited nominal evidence (P < 0.05). Haplotype analysis revealed no additional association information. There was evidence of weak linkage disequilibrium among these SNPs. The highest observed LD occurred between the two strongest associated SNPs, suggesting that the observed signals may be the signature of an observed functional variant.
Publisher: The Endocrine Society
Date: 09-2014
DOI: 10.1210/JC.2013-4475
Publisher: Springer Science and Business Media LLC
Date: 16-11-1999
Abstract: Pre-ecl sia is the most common serious medical disorder of human pregnancy. The human endothelial cell nitric oxide synthase (eNOS) gene is a candidate for pre-ecl sia/ecl sia (PE/E) susceptibility. A linkage study was performed on Australian PE/E families using 25 microsatellite markers from chromosome 7, one of which (eNOS-CA) resides within the eNOS gene. No significant linkage was found for the eNOS-CA marker using either parametric or non-parametric analysis. However, D7S 1805 from the eNOS gene region on 7q36, gave a suggestion of linkage using parametric analysis (maximum LOD score =2.143 at theta=0.14) and non-parametric APM analysis (T1/sqrt(p)=3.53 P=0.002). Further, an association study was performed on unrelated PE/E cases and controls from both Chinese and Australian populations to test for a relationship between the eNOS gene and PE/E. No association was found between the eNOS-CA marker and PE/E in either population. However, there was a significant difference in the allelic distribution of eNOS-CA between the two ethnic groups. The linkage results support the possibility that a susceptibility locus for pre-ecl sia resides in the 7q36 region, however, there is no definitive evidence to support the notion that the eNOS gene itself is responsible for susceptibility to pre-ecl sia.
Publisher: Informa UK Limited
Date: 03-04-2019
DOI: 10.1080/14779072.2019.1596799
Abstract: Lipoprotein(a) [Lp(a)] is a potent, highly heritable and common risk factor for atherosclerotic cardiovascular disease (ASCVD). Evidence for a causal association between elevated Lp(a) and ASCVD has been provided by large epidemiological investigations that have demonstrated a curvilinear association with increased risk, as well as from genetic examinations and cellular and transgenic animal studies. Although there are several therapies available for lowering Lp(a), none are selective for Lp(a) and there is no clinical trial data that has specifically shown that lowering Lp(a) reduces the risk of ASCVD. Hence, screening for elevated Lp(a) is not routinely incorporated into clinical practice. Areas covered: This paper reviews the current evidence supporting the causal role of Lp(a) in the primary and secondary prevention of ASCVD, screening approaches for high Lp(a), current guidelines on testing Lp(a), and barriers to the routine screening of elevated Lp(a) in clinical practice. Expert opinion: At present, there is a moderate level of evidence supporting the routine screening of elevated Lp(a). Current guidelines recommend testing for elevated Lp(a) in in iduals at intermediate or high risk of ASCVD.
Publisher: Elsevier BV
Date: 04-2012
Publisher: Oxford University Press (OUP)
Date: 20-05-2013
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1194/JLR.M001404
Publisher: Oxford University Press (OUP)
Date: 25-02-2011
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.LUNGCAN.2013.04.018
Abstract: Malignant mesothelioma (MM) is a uniformly fatal tumour of mesothelial cells. MM is caused by exposure to asbestos however most in iduals with documented asbestos exposure do not develop MM. Although MM appears to aggregate within families, the genetics of MM susceptibility is a relatively unexplored area. The aim of the current study was to identify genetic factors that contribute to MM risk. A genome-wide association analysis of 2,508,203 single nucleotide polymorphisms (SNPs) from 428 MM cases and 1269 controls from Western Australia was performed. Additional genotyping was performed on a s le of 778 asbestos-exposed Western Australian controls. Replication of the most strongly associated SNPs was undertaken in an independent case-control study of 392 asbestos-exposed cases and 367 asbestos-exposed controls from Italy. No SNPs achieved formal genome-wide statistical significance in the Western Australian study. However, suggestive results for MM risk were identified in the SDK1, CRTAM and RASGRF2 genes, and in the 2p12 chromosomal region. These findings were not replicated in the Italian study, although there was some evidence of replication in the region of SDK1. These suggestive associations will be further investigated in sequencing and functional studies.
Publisher: Oxford University Press (OUP)
Date: 07-2005
Abstract: Pre-ecl sia/ecl sia is a serious disorder of human pregnancy that has a worldwide incidence of 2-10% and carries a severe morbidity and mortality risk for both mother and child. Its precise cause remains unknown. However, there is increasing evidence of an underlying complex maternal genetic susceptibility. Its high population incidence in the face of strong negative selection pressure suggests that the gene(s) involved have a selective advantage and/or a high mutation rate. One class of genetic diseases that involve a high mutation rate are the trinucleotide repeat expansion diseases. Thus, the aim of this study was to determine whether there is an association between a trinucleotide (CAG) repeat expansion and pre-ecl sia/ecl sia. We have used the repeat expansion detection (RED) method, which was developed to directly identify clinically significant repeat expansions, to analyse genomic DNA from an Australian and New Zealand population. The maximal CAG repeat length for each in idual was recorded and the Mann-Whitney U and Wilcoxon rank sum test for independent s les were used to compare distributions for CAG/CTG repeats between two populations. There were no statistically significant differences between the distribution of CAG repeats in normotensive (n = 59) and severe pre-ecl sia (n = 69) (Mann-Whitney U = 1732 P = 0.14), and normotensive (n = 59) and ecl tic (n = 15) populations (Mann-Whitney U = 417, P = 0.726). Therefore, these RED results do not support a role for a large CAG expansion in pre-ecl sia/ecl sia. However, these data do not preclude the possibility that a small CAG expansion is associated with the disorder nor do they negate the hypothesis that a highly mutable gene contributes to the genetic component of pre-ecl sia/ecl sia.
Publisher: Oxford University Press (OUP)
Date: 10-1999
Abstract: The aim of this study was to identify genes involved in human placentation. To do this, differential gene expression was assessed in the decidua (placental bed) from pre-ecl tic and normotensive pregnancies using the polymerase chain reaction (PCR)-based subtractive technique of representational difference analysis. A novel aspartyl protease (cathepsin D-like) cDNA sequence was isolated by virtue of its over-expression in the pre-ecl tic decidual s le tested. It was designated DAP-1 (for Decidual Aspartyl Protease 1). Using DAP-1 primer sequences a second cDNA (DAP-2) was subsequently isolated from decidual RNA by reverse transcription (RT)-PCR and found to be identical to DAP-1 apart from 80 additional and consecutive base pairs in the N-terminal coding region. In DAP-2, a stop codon within the unique 80 bp sequence was predicted to terminate translation immediately before the consensus active site residues. While Southern blotting was used to show that there are two loci with homology to DAP-1 in the human genome, it is postulated that alternative pre-mRNA splicing of the 80 bp exon is involved in the regulated expression of active (DAP-1) and inactive (DAP-2) forms of this novel protease a mechanism similar to that involved in the regulated expression of Caspase-2, a protease involved in apoptosis. In other systems the regulation of alternative splicing is indicated by tissue specificity and developmental stage specificity of the various spliced products. In this context it was demonstrated that whereas DAP-1 was the major transcript expressed in decidua, the pattern was reversed in the adjacent placental tissue. It is proposed that tissue and developmental stage-specific expression of the DAP protease are important for the normal development and function of the uteroplacental tissues and that dysregulation of the control of DAP gene splicing may play a role in abnormal placentation, like that seen in pre-ecl sia.
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1086/316888
Publisher: MDPI AG
Date: 03-07-2202
DOI: 10.3390/BIOMEDICINES8070181
Abstract: As a part of an abnormal healing process of dermal injuries and irritation, keloid scars arise on the skin as benign fibroproliferative tumors. Although the etiology of keloid scarring remains unsettled, considerable recent evidence suggested that keloidogenesis may be driven by epigenetic changes, particularly, DNA methylation. Therefore, genome-wide scanning of methylated cytosine-phosphoguanine (CpG) sites in extracted DNA from 12 keloid scar fibroblasts (KF) and 12 control skin fibroblasts (CF) (six normal skin fibroblasts and six normotrophic fibroblasts) was conducted using the Illumina Human Methylation 450K BeadChip in two replicates for each s le. Comparing KF and CF used a Linear Models for Microarray Data (Limma) model revealed 100,000 differentially methylated (DM) CpG sites, 20,695 of which were found to be hypomethylated and 79,305 were hypermethylated. The top DM CpG sites were associated with TNKS2, FAM45B, LOC723972, GAS7, RHBDD2 and CAMKK1. Subsequently, the most functionally enriched genes with the top 100 DM CpG sites were significantly (p ≤ 0.05) associated with SH2 domain binding, regulation of transcription, DNA-templated, nucleus, positive regulation of protein targeting to mitochondrion, nucleoplasm, Swr1 complex, histone exchange, and cellular response to organic substance. In addition, NLK, CAMKK1, LPAR2, CASP1, and NHS showed to be the most common regulators in the signaling network analysis. Taken together, these findings shed light on the methylation status of keloids that could be implicated in the underlying mechanism of keloid scars formation and remission.
Publisher: S. Karger AG
Date: 2002
DOI: 10.1159/000064696
Abstract: Thrombomodulin plays an important role in thromboresistance. A common mutation of the gene at amino acid 455 producing valine instead of alanine has been implicated as being a risk factor in myocardial infarction and chronic heart disease. However, its link with pre-ecl sia remains controversial. This report explores the Ala455Val point mutation in 280 women as a predictor of pre-ecl sia with the conclusion that in this regard, the dimorphism is essentially neutral.
Publisher: Elsevier BV
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 30-08-2019
DOI: 10.1007/S00384-019-03380-5
Abstract: Survival following colorectal cancer (CRC) survival may be influenced by a number of factors including family history, in idual medical history, and comorbidities. The impact of these factors may vary based on the patient's age. The study cohort consisted of in iduals born in Western Australia between 1945 and 1996, who had been diagnosed with CRC prior to 2015 (n = 3220). Hospital, cancer, and mortality data were extracted for each patient from state health records and were used to identify potential risk factors associated with CRC survival. Family linkage data, in combination with cancer registry data, were used to identify first-degree family members with a history of CRC. The association between survival following CRC diagnosis and identified risk factors was examined using Cox proportional hazard models. Age and sex were not significantly associated with survival in young patients. However, in middle-aged patients increasing age (HR 1.03, 95% CI 1.01-1.05, p = 0.003) and being male (HR 0.72, 95% CI 0.60-0.87, p < 0.001) were associated with reduced survival. Being diagnosed with polyps and having a colonoscopy prior to CRC diagnosis were associated with improved survival in both young and middle-aged patients, while a history of non-CRC and liver disease was associated with reduced survival. In middle-aged patients, having diabetes-related hospital admissions (HR 1.53, 95% CI 1.15-2.03, p = 0.004) was associated with reduced survival. In both young and middle-aged patients with CRC, factors associated with early screening and detection were associated with increased CRC survival while a history of liver disease and non-CRC was associated with decreased CRC survival.
Publisher: Bioscientifica
Date: 06-2005
DOI: 10.1530/REP.1.00524
Abstract: Elucidation of underlying cellular and molecular mechanisms is pivotal to the comprehension of biological systems. The successful progression of processes such as pregnancy and parturition depends on the complex interactions between numerous biological molecules especially within the uterine microenvironment. The tissue- and stage-specific expression of these bio-molecules is intricately linked to and modulated by several endogenous and exogenous factors. Malfunctions may manifest as pregnancy disorders such as preterm labour, pre-ecl sia and fetal growth restriction that are major contributors to maternal and perinatal morbidity and mortality. Despite the immense amount of information available, our understanding of several aspects of these physiological processes remains incomplete. This translates into significant difficulties in the timely diagnosis and effective treatment of pregnancy-related complications. However, the emergence of powerful mass spectrometry-based proteomic techniques capable of identifying and characterizing multiple proteins simultaneously has added a new dimension to the field of biomedical research. Application of these high throughput methodologies with more conventional techniques in pregnancy-related research has begun to provide a novel perspective on the biochemical blueprint of pregnancy and its related disorders. Further, by enabling the identification of proteins specific to a disease process, proteomics is likely to contribute, not only to the comprehension of the underlying pathophysiologies, but also to the clinical diagnosis of multifactorial pregnancy disorders. Although the application of this technology to pregnancy research is in its infancy, characterization of the cellular proteome, unearthing of functional networks and the identification of disease biomarkers can be expected to significantly improve maternal healthcare in the future.
Publisher: Springer Science and Business Media LLC
Date: 24-07-0031
DOI: 10.1038/S41598-017-06791-Y
Abstract: The prevalence of asthma and allergic diseases is disproportionately distributed among different populations, with an increasing trend observed in Western countries. Here we investigated how the environment affected genotype-phenotype association in a genetically homogeneous, but geographically separated population. We evaluated 18 single nucleotide polymorphisms (SNPs) corresponding to 8 genes ( ADAM33 , ALOX5 , LT-α, LTC4S , NOS1, ORMDL3, TBXA2R and TNF-α ), the lung function and five respiratory/allergic conditions (ever asthma, bronchitis, rhinitis, dermatitis and atopy) in two populations of Inuit residing either in the westernized environment of Denmark or in the rural area of Greenland. Our results showed that lung function was associated with genetic variants in ORMDL3 , with polymorphisms having a significant interaction with place of residence. LT-α SNP rs909253 and rs1041981 were significantly associated with bronchitis risk. LT-α SNP rs2844484 was related to dermatitis susceptibility and was significantly influenced by the place of residence. The observed gene-phenotype relationships were exclusively present in one population and absent in the other population. We conclude that the genotype-phenotype associations relating to bronchitis and allergy susceptibility are dependent on the environment and that environmental factors/lifestyles modify genetic predisposition and change the genetic effects on diseases.
Publisher: Public Library of Science (PLoS)
Date: 31-07-2013
Publisher: Proceedings of the National Academy of Sciences
Date: 17-02-2005
Abstract: HLA-G is a nonclassical major histocompatibility complex class I (MHC-I) molecule that is primarily expressed at the fetal–maternal interface, where it is thought to play a role in protecting the fetus from the maternal immune response. HLA-G binds a limited repertoire of peptides and interacts with the inhibitory leukocyte Ig-like receptors LIR-1 and LIR-2 and possibly with certain natural killer cell receptors. To gain further insights into HLA-G function, we determined the 1.9-Å structure of a monomeric HLA-G complexed to a natural endogenous peptide ligand from histone H2A (RIIPRHLQL). An extensive network of contacts between the peptide and the antigen-binding cleft reveal a constrained mode of binding reminiscent of the nonclassical HLA-E molecule, thereby providing a structural basis for the limited peptide repertoire of HLA-G. The α3 domain of HLA-G, a candidate binding site for the LIR-1 and -2 inhibitory receptors, is structurally distinct from the α3 domains of classical MHC-I molecules, providing a rationale for the observed affinity differences for these ligands. The structural data suggest a head-to-tail mode of dimerization, mediated by an intermolecular disulfide bond, that is consistent with the observation of HLA-G dimers on the cell surface.
Publisher: Bioscientifica
Date: 07-1997
Abstract: Parathyroid hormone-related protein (PTHrP) gene expression and/or immunoreactive protein have previously been identified in the uterus and intrauterine gestational tissues. The putative roles of PTHrP during pregnancy include vasodilatation, regulation of placental calcium transfer, uterine smooth muscle relaxation and normal fetal development. The aims of this study were 1) to determine the tissue-specific and temporal expression of PTHrP mRNA and immunoreactive protein in human gestational tissues collected at preterm and term and 2) to determine the effect of labour on PTHrP expression by collecting these tissues from women undergoing elective caesarean section (before labour), intra-partum caesarean section during spontaneous-onset labour (during labour), and women with spontaneous labour and normal vaginal delivery (after labour). Total RNA and protein were extracted from placenta, amnion (over placenta and reflected) and choriodecidua for analysis by Northern blot (using a specific human PTHrP cDNA probe), and by N-terminal PTHrP RIA respectively. In amnion over placenta, reflected amnion and choriodecidua both PTHrP mRNA relative abundance and immunoreactive protein were significantly elevated at term compared with preterm ( P ·01). At term, both PTHrP and its mRNA were significantly greater in amnion than in placenta and choriodecidua ( P ·05). Also, both PTHrP and its mRNA were significantly elevated in amnion over placenta compared with reflected amnion ( P ·05). The expression of PTHrP and its mRNA did not change in association with term labour or rupture of the fetal membranes, therefore this study provides no evidence for a specific PTHrP role in the onset and/or maintenance of term labour. However, the significant up-regulation of PTHrP mRNA and protein in the fetal membranes at term compared with preterm suggests an important role in late human pregnancy. Journal of Endocrinology (1997) 154, 103–112
Publisher: Springer Science and Business Media LLC
Date: 31-01-2022
DOI: 10.1038/S41598-022-05744-4
Abstract: Advanced biological aging, as assessed through DNA methylation markers, is associated with several complex diseases. The associations between maternal DNA methylation age and preecl sia (PE) have not been fully assessed. The aim of this study was to examine if increased maternal DNA methylation age ( DNAm Age) was shown to be accelerated in women with PE when compared to women who had normotensive pregnancies. The case/control cohort available for study consisted of 166 women (89 with normotensive pregnancy, 77 with PE) recruited previously at the Royal Women’s Hospital in Melbourne, Australia. DNA methylation profiles were obtained using the Illumina EPIC Infinium array for analysis of genomic DNA isolated from whole blood. These profiles were used to calculate seven estimates of DNAm Age and included (1) Horvath, (2) Hannum, (3) Horvath Skin and Blood, (4) Wu, (5) PhenoAge, (6) telomere length and (7) GrimAge and its surrogate measures. Three measures of DNA methylation age acceleration were calculated for all seven measures using linear regression. Pearson's correlation was performed to investigate associations between chronological age and DNAm Age. Differences between chronological age and DNAm Age and epigenetic age acceleration were investigated using t-tests. No significant difference was observed for chronological age between women with PE (age = 30.53 ± 5.68) and women who had normotensive pregnancies (age = 31.76 ± 4.76). All seven DNAm Age measures were significantly correlated ( p 0.001) with chronological age. After accounting for multiple testing and investigating differences in DNAm Age between normotensive women and women with PE, only Wu DNAm Age was significant ( p = 0.001). When examining differences for epigenetic age acceleration between PE and normotensive women Hannum, Wu, and PhenoAge DNAm Age estimates ( p 0.001) were significant for both epigenetic age acceleration and intrinsic acceleration models. We found that accelerated maternal DNAm Age is increased in women with PE in some models of epigenetic aging. This research underlines the importance for further investigation into the potential changes of differential DNA methylation in PE.
Publisher: Public Library of Science (PLoS)
Date: 29-09-2010
Publisher: Elsevier BV
Date: 03-1997
DOI: 10.1016/S0378-1135(96)01284-9
Abstract: An antigen extracted from Dichelobacter nodosus with potassium thiocyanate (KSCN) is currently used in enzyme-linked immunosorbent assay (ELISA) for serological diagnosis of ovine footrot, but the test lacks specificity in mature sheep. Other antigens were therefore evaluated for use in this test. Structural components of the cell envelope of D. nodosus including outer membrane, cytoplasmic membrane, lipopolysaccharide and pilus and extracellular proteases were purified from cultured D. nodosus while recombinant membrane proteins, protease and pilus antigens were also evaluated. Many antigenic components of D. nodosus participated in reactions in ELISA that were not specific for infection with D. nodosus and apart from pilus, none of the antigens resulted in improved specificity of the ELISA. Using a positive-negative cut-off to yield sensitivity of 70%, ELISA using pili from cultured D. nodosus serogroup A had a specificity of 98.3% compared with 89.7% for the ELISA with KSCN-extract as antigen (P < 0.001). Recombinant pili morphogenetically expressed in Pseudomonas aeruginosa were unsuitable for use in ELISA due to copurification of Pseudomonas antigens to which apparently healthy sheep directed antibodies. The application of ELISA with D. nodosus pilus as antigen in footrot control programs is discussed.
Publisher: Elsevier BV
Date: 07-2015
Publisher: Elsevier BV
Date: 02-2017
Publisher: Oxford University Press (OUP)
Date: 22-11-2017
DOI: 10.1093/BIOINFORMATICS/BTW675
Abstract: The Ark is an open-source web-based tool that allows researchers to manage health and medical research data for humans and animals without specialized database skills or programming expertise. The system provides data management for core research information including demographic, phenotype, biospecimen and pedigree data, in addition to supporting typical investigator requirements such as tracking participant consent and correspondence, whilst also being able to generate custom data exports and reports. The Ark is ‘study generic’ by design and highly configurable via its web interface, allowing researchers to tailor the system to the specific data management requirements of their study. Source code for The Ark can be obtained freely from the website github.com/The-Ark-Informatics/ark/. The source code can be modified and redistributed under the terms of the GNU GPL v3 license. Documentation and a pre-configured virtual appliance can be found at the website sphinx.org.au/the-ark/. Supplementary data are available at Bioinformatics online.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2017
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.AJOG.2007.09.024
Abstract: The objective of the study was to test for a genetic association between the G-105A promoter polymorphism of the inflammatory mediator Selenoprotein S (SEPS1) and preecl sia. A retrospective study in a large Norwegian case-control cohort compared maternal genotype and allele frequencies of the SEPS1 g.-105G>A polymorphism genotyped by SNPlex assay in preecl tic (n = 1139) and control (n = 2269) women. Statistical significance was determined by chi2 and multivariate regression analyses. Women with preecl sia were 1.34 times more likely to have the GA or AA genotype (P = .0039 95% confidence interval [CI] 1.09 to 1.64) and 1.22 times more likely to carry the A allele (P = .023 odds ratio, 1.22 95% CI, 1.02 to 1.46). The A allele of the SEPS1-105G>A polymorphism is a significant risk factor for preecl sia in this population.
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/0378-1119(96)00032-7
Abstract: Studies on the role of various virulence factors of the ovine pathogen, Dichelobacter nodosus, have suffered from the absence of a mechanism for the introduction of DNA into this organism. As an initial step in the development of genetic methods, we have identified and cloned a native 10-kb plasmid, pJIR896, from a clinical isolate. This plasmid was found to be a circular form of vap region 1/3 that is found in the reference strain, A198. However, pJIR896 lacked the duplicated region present in the A198 sequence and instead contained a 1.7-kb putative insertion sequence, IS1253, which shared similarity to a number of unusual IS elements. A model is proposed for the evolution of vap region 1/3 which involves the integration of a plasmid, such as pJIR896, and subsequent rearrangements resulting from the deletion or transposition of IS1253.
Publisher: Springer Science and Business Media LLC
Date: 04-07-2009
Publisher: Springer Science and Business Media LLC
Date: 10-2016
Publisher: Elsevier BV
Date: 02-2014
Publisher: Oxford University Press (OUP)
Date: 06-01-2009
Publisher: Elsevier BV
Date: 11-2000
Publisher: Wiley
Date: 09-10-2019
DOI: 10.1111/CGE.13648
Abstract: Familial hypercholesterolaemia (FH) is associated with increased risk of coronary artery disease (CAD) however, risk prediction and stratification remain a challenge. Genetic risk scores (GRS) may have utility in identifying FH patients at high CAD risk. The study included 811 patients attending the lipid disorders clinic at Royal Perth Hospital with mutation-positive (n = 251) and mutation-negative (n = 560) FH. Patients were genotyped for a GRS previously associated with CAD. Associations between the GRS, clinical characteristics, and CAD were assessed using regression analyses. The average age of patients was 49.6 years, and 44.1% were male. The GRS was associated with increased odds of a CAD event in mutation-positive [odds ratio (OR) = 3.3 95% confidence interval (CI) = 1.3-8.2 P = .009] and mutation-negative FH patients (OR = 1.8 95% CI = 1.0-3.3 P = .039) after adjusting for established predictors of CAD risk. The GRS was associated with greater subclinical atherosclerosis as assessed by coronary artery calcium score (P = .039). A high GRS was associated with CAD defined clinically and angiographically in FH patients. High GRS patients may benefit from more intensive management including lifestyle modification and aggressive lipid-lowering therapy. Further assessment of the utility of the GRS requires investigation in prospective cohorts, including its role in influencing the management of FH patients in the clinic.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2014
Publisher: Wiley
Date: 12-2008
Publisher: Springer Science and Business Media LLC
Date: 28-10-2010
Publisher: Elsevier BV
Date: 2015
Publisher: Springer Science and Business Media LLC
Date: 03-1983
DOI: 10.1007/BF00965726
Abstract: Neural circuits are responsible for the brain's ability to process and store information. Reductionist approaches to understanding the brain include isolation of in idual neurons for detailed characterization. When maintained in vitro for several days or weeks, dissociated neurons self-assemble into randomly connected networks that produce synchronized activity and are capable of learning. This review focuses on efforts to control neuronal connectivity in vitro and construct living neural circuits of increasing complexity and precision. Microfabrication-based methods have been developed to guide network self-assembly, accomplishing control over in vitro circuit size and connectivity. The ability to control neural connectivity and synchronized activity led to the implementation of logic functions using living neurons. Techniques to construct and control three-dimensional circuits have also been established. Advances in multiple electrode arrays as well as genetically encoded, optical activity sensors and transducers enabled highly specific interfaces to circuits composed of thousands of neurons. Further advances in on-chip neural circuits may lead to better understanding of the brain.
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/189681
Abstract: The high-density-lipoprotein-(HDL-) associated esterase paraoxonase 1 (PON1) is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1 , have been associated with variation in activity levels, but substantial interin idual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates—organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin—in 767 Mexican American in iduals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs) while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.
Publisher: Portland Press Ltd.
Date: 24-02-2000
DOI: 10.1042/CS0980375
Abstract: Apoptosis (programmed cell death) in the human placenta is likely to play a major role in determining the structure and function of that organ. Fetal growth restriction (FGR) has been shown to be associated with increased levels of placental apoptosis. Altered regulation of apoptosis may play an important pathophysiological role in FGR. As reduced placental perfusion and reduced oxygenation are features of FGR, one aim of this study was to determine the effects of hypoxia on apoptotic activity, as assessed by DNA laddering, of placental tissue in vitro. In addition, levels of placental apoptosis may be affected by pharmacological agents routinely used in obstetric patient management. Thus an additional aim of this study was to determine the effects of several relevant pharmacological agents on the levels of DNA laddering during in vitro incubation of human placentae under hypoxic conditions. Incubation of normal placental explant tissue at 37 °C for 1–2 h under hypoxic conditions significantly increased placental DNA laddering compared with that in non-incubated tissue, whereas levels of DNA laddering during incubation for up to 2 h under normoxic conditions were not significantly higher than those in non-incubated tissue. The DNA laddering activity of placental explants after 2 h of incubation under hypoxic conditions was significantly increased with increased concentrations of magnesium, but remained unchanged by the inclusion of pethidine, aspirin, nifedipine, dexamethasone, heparin or indomethacin in the incubation mixture. These results suggest that hypoxia may stimulate apoptotic activity in cultured human placental tissues, and that hypoxia-stimulated placental apoptosis may be further increased by increasing the extracellular magnesium concentration.
Publisher: Elsevier BV
Date: 06-2012
Publisher: American Academy of Sleep Medicine (AASM)
Date: 06-2022
DOI: 10.5664/JCSM.9886
Publisher: Oxford University Press (OUP)
Date: 03-07-2010
DOI: 10.1093/HMG/DDQ274
Publisher: Springer Science and Business Media LLC
Date: 10-09-2009
Publisher: Elsevier BV
Date: 04-1989
DOI: 10.1016/0378-1119(89)90070-X
Abstract: The aim of these studies was to examine the organization of the Bacteroides nodosus protease-encoding gene(s). The extracellular serine proteases (38 kDa) from the prototype virulent strain of B. nodosus were purified and used to raise a specific antiserum in rabbits. This antiserum was used in a colony immunoassay to screen a genomic DNA library constructed in Escherichia coli using BamHI-digested B. nodosus DNA and the plasmid pBR322. An E. coli clone expressing a 50-kDa immunoreactive polypeptide was identified. No protease activity was detected in the culture media, or in crude soluble and membrane fractions prepared from this clone. Restriction mapping and deletion analysis of the recombinant plasmid, pEKM2, was used to locate the coding region to a 1.4-kb EcoRI-BamHI fragment which was subsequently sequenced. A large open reading frame was found to extend through the BamHI site from a putative start codon just downstream from the EcoRI site, which indicated that the complete gene was not isolated. Southern blotting demonstrated that there were at least three B. nodosus BamHI fragments which were homologous to the 0.4-kb PstI-BamHI fragment of pEKM2. Based on these results the existence of multiple protease genes in B. nodosus was postulated.
Publisher: Oxford University Press (OUP)
Date: 26-06-2017
Publisher: Springer Science and Business Media LLC
Date: 15-09-2013
DOI: 10.1038/NM.3270
Publisher: Elsevier BV
Date: 04-2020
Publisher: Public Library of Science (PLoS)
Date: 10-01-2013
Publisher: Public Library of Science (PLoS)
Date: 14-03-2012
Publisher: Elsevier BV
Date: 2019
Publisher: American Association for Cancer Research (AACR)
Date: 11-2020
DOI: 10.1158/1055-9965.EPI-20-0595
Abstract: Scalp and neck (SN) melanoma confers a worse prognosis than melanoma of other sites but little is known about its determinants. We aimed to identify associations between SN melanoma and known risk genes, phenotypic traits, and sun exposure patterns. Participants were cases from the Western Australian Melanoma Health Study (n = 1,200) and the Genes, Environment, and Melanoma Study (n = 3,280). Associations between risk factors and SN melanoma, compared with truncal and arm/leg melanoma, were investigated using binomial logistic regression. Facial melanoma was also compared with the trunk and extremities, to evaluate whether associations were subregion specific, or reflective of the whole head/neck region. Compared with other sites, increased odds of SN and facial melanoma were observed in older in iduals [SN: OR = 1.28, 95% confidence interval (CI) = 0.92–1.80, Ptrend = 0.016 Face: OR = 4.57, 95% CI = 3.34–6.35, Ptrend & 0.001] and those carrying IRF4-rs12203592*T (SN: OR = 1.35, 95% CI = 1.12–1.63, Ptrend = 0.002 Face: OR = 1.29, 95% CI = 1.10–1.50, Ptrend = 0.001). Decreased odds were observed for females (SN: OR = 0.49, 95% CI = 0.37–0.64, P & 0.001 Face: OR = 0.66, 95% CI = 0.53–0.82, P & 0.001) and the presence of nevi (SN: OR = 0.66, 95% CI = 0.49–0.89, P = 0.006 Face: OR = 0.65, 95% CI = 0.52–0.83, P & 0.001). Differences observed between SN melanoma and other sites were also observed for facial melanoma. Factors previously associated with the broader head and neck region, notably older age, may be driven by the facial subregion. A novel finding was the association of IRF4-rs12203592 with both SN and facial melanoma. Understanding the epidemiology of site-specific melanoma will enable tailored strategies for risk factor reduction and site-specific screening c aigns.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2019
DOI: 10.1038/S41467-018-08078-W
Abstract: The original version of this Article contained errors in the spelling of the authors Fan Liu and M. Arfan Ikram, which were incorrectly given as Fan Lui and Arfan M. Ikram. In addition, the original version of this Article also contained errors in the author affiliations which are detailed in the associated Publisher Correction.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Wiley
Date: 03-02-2011
DOI: 10.1002/AJHB.21153
Publisher: Hindawi Limited
Date: 2017
DOI: 10.1155/2017/7281986
Abstract: Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF- α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF- α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.
Publisher: Springer Science and Business Media LLC
Date: 16-09-2007
DOI: 10.1038/NG2119
Abstract: Quantitative differences in gene expression are thought to contribute to phenotypic differences between in iduals. We generated genome-wide transcriptional profiles of lymphocyte s les from 1,240 participants in the San Antonio Family Heart Study. The expression levels of 85% of the 19,648 detected autosomal transcripts were significantly heritable. Linkage analysis uncovered >1,000 cis-regulated transcripts at a false discovery rate of 5% and showed that the expression quantitative trait loci with the most significant linkage evidence are often located at the structural locus of a given transcript. To highlight the usefulness of this much-enlarged map of cis-regulated transcripts for the discovery of genes that influence complex traits in humans, as an ex le we selected high-density lipoprotein cholesterol concentration as a phenotype of clinical importance, and identified the cis-regulated vanin 1 (VNN1) gene as harboring sequence variants that influence high-density lipoprotein cholesterol concentrations.
Publisher: Informa UK Limited
Date: 2006
DOI: 10.1080/10641950500543780
Abstract: Decreased HLA-G expression has been linked to a number of pregnancy disorders, including preecl sia, and a genetic basis for HLA-G regulation has yet to be found. The aim of this study was to determine whether a C-to-T base substitution 56 base pairs (bp) upstream from the HLA-G transcription start site is associated with preecl sia. 277 nulliparous women consisting of 113 normotensive, 118 preecl tic, and 46 ecl tic patients were typed for the -56T polymorphism using restriction fragment length polymorphism and allelic discrimination analysis. -56T allele frequencies for ecl tic, preecl tic, and normotensive women were 0.053, 0.030, and 0.035, respectively. A chi2 test indicated that there was no significant association with the polymorphism in preecl tic or ecl tic women with p > 0.05. The -56T HLA-G polymorphism is not associated with preecl sia or ecl sia in our population.
Publisher: S. Karger AG
Date: 2000
DOI: 10.1159/000010291
Abstract: In European and Japanese but not in Australian, American, and South African women, the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism has been reported to be a genetic risk factor pre-ecl sia/ecl sia (PE/E). The recently described A1298C MTHFR gene polymorphism also results in reduced MTHFR enzyme activity, although to a lesser extent than the previously described C677T polymorphism. Heterozygotes for both polymorphisms are reported to have an even lower MTHFR enzymatic activity than seen in homozygotes for the C677T genotype. In this current study we determined the allele frequency of the A1298C MTHFR gene polymorphism in an Australian population and examined this polymorphism alone and in combination with the C677T MTHFR polymorphism for an association with PE/E. Neither the A1298C polymorphism alone nor a combination of both polymorphisms showed an association with PE/E in our population of Australian women.
Publisher: S. Karger AG
Date: 30-10-2001
DOI: 10.1159/000022954
Abstract: The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism results in reduced MTHFR enzymatic activity. This in turn results in increased levels of homocysteine. It has been suggested that increased levels of homocysteine cause vascular disease, which is known to increase the risk of developing pre-ecl sia (PE) during pregnancy. However, recent studies on Japanese, Italian and American populations have failed to reach agreement on an association between the C677T polymorphism and PE. In this study, 156 cases of ecl sia (E)/PE and 79 normal pregnant control cases from an Australian population were genotyped for this mutation. No significant difference could be found in the incidence of the homozygote mutation or in the allele frequency. We conclude from this study that the C677T mutation in our population is not associated with the development of PE/E.
Publisher: Oxford University Press (OUP)
Date: 18-02-2013
Publisher: Oxford University Press (OUP)
Date: 04-11-2007
Abstract: Pre-ecl sia/ecl sia (PE/E) is a common and serious disorder of human pregnancy that is associated with substantial maternal and perinatal morbidity and mortality. The suspected aetiology of PE/E is complex, with susceptibility being attributable to multiple environmental factors and a large genetic component. By assuming that the underlying liability towards PE/E susceptibility is inherently quantitative, any PE/E susceptibility gene would represent a quantitative trait locus (QTL). This assumption enables a more refined and powerful variance components procedure using a threshold model for our PE/E statistical analysis. Using this more efficient linkage approach, we have now re-analysed our previously completed Australian/New Zealand genome scan data to identify two novel PE/E susceptibility QTLs on chromosomes 5q and 13q. We have obtained strong evidence of linkage on 5q with a peak logarithm-of-odds (LOD) score of 3.12 between D5S644 and D5S433 [at approximately 121 centimorgan (cM)] and strong evidence of linkage on 13q with a peak LOD score of 3.10 between D13S1265 and D13S173 (at approximately 123 cM). Objective identification and prioritization of positional candidate genes using the quantitative bioinformatics program GeneSniffer revealed highly plausible PE/E candidate genes encoding aminopeptidase enzymes and a placental peptide hormone on the 5q QTL and two type IV collagens on the 13q QTL regions, respectively.
Publisher: Elsevier BV
Date: 05-2015
DOI: 10.1016/J.GENE.2015.03.031
Abstract: Malignant mesothelioma (MM) is a uniformly fatal tumour caused predominantly by exposure to asbestos. It is not known why some exposed in iduals get mesothelioma and others do not. There is some epidemiological evidence of host susceptibility. BAP1 gene somatic mutations and allelic loss are common in mesothelioma and recently a BAP1 cancer syndrome was described in which affected in iduals and families had an increased risk of cancer of multiple types, including MM. To determine if BAP1 mutations could underlie any of the sporadic mesothelioma cases in our cohort of patients, we performed targeted deep sequencing of the BAP1 exome on the IonTorrent Proton sequencer in 115 unrelated MM cases. No exonic germline BAP1 mutations of known functional significance were observed, further supporting the notion that sporadic germline BAP1 mutations are not relevant to the genetic susceptibility of MM.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2010
Publisher: Wiley
Date: 07-1995
DOI: 10.1111/J.1365-2958.1995.MMI_17010183.X
Abstract: The molecular cloning and sequence analysis of four structurally variant linked genes (omp1A,B,C,D) that encode the major outer membrane protein of Dichelobacter nodosus strain VCS1001 are described. The isolation of rearranged copies of omp1A and omp1B, and the identification in the 5' regions of all four genes of short cross-over-site sequences that were similar to the Din family of cross-over-site sequences, suggested that site-specific DNA inversion was involved in omp1 rearrangement. Evidence for site-specific inversion of the 497 bp DNA fragment, which was located between the ergently orientated omp1A and omp1B genes, and which contained the promoter and 5' coding sequence of Omp1, was obtained by polymerase chain reaction-mediated lification of inverted forms of these genes. However, to account for all of the omp1 gene copies cloned in this study, a more widespread inversion phenomenon must be involved in the rearrangement of these genes and a model for multiple site-specific DNA inversions at the omp1 locus is described. In this model the four structurally variant omp1 genes can be assembled from one of four structurally variant C-terminal coding regions and a conserved N-terminal coding region and can be expressed from a single promoter. It is postulated that this genetic capability endows D. nodosus with the ability to switch the antigenic specificity of one of its major surface proteins.
Publisher: Elsevier BV
Date: 04-2014
DOI: 10.1016/J.PREGHY.2014.03.005
Abstract: Four putative single nucleotide polymorphism (SNP) risk variants at the preecl sia susceptibility locus on chromosome 2q22 rs2322659 (LCT), rs35821928 (LRP1B), rs115015150 (RND3) and rs17783344 (GCA), were recently shown to associate with known cardiovascular risk factors in a Mexican American cohort. This study aimed to further evaluate the pleiotropic effects of these preecl sia risk variants in an independent Australian population-based cohort. The four SNPs were genotyped in the Western Australian Pregnancy Cohort (Raine) Study that included DNA, clinical and biochemical data from 1246 mothers and 1404 of their now adolescent offspring. Genotype association analyses were undertaken using the SOLAR software. Nominal associations (P<0.05) with cardiovascular risk factors were detected for all four SNPs. The LCT SNP was associated with decreased maternal height (P=0.005) and decreased blood glucose levels in adolescents (P=0.022). The LRP1B SNP was associated with increased maternal height (P=0.026) and decreased maternal weight (P=0.044). The RND3 SNP was associated with decreased triglycerides in adolescents (P=0.001). The GCA SNP was associated with lower risk in adolescents to be born of a preecl tic pregnancy (P=0.003) and having a mother with prior preecl tic pregnancy (P=0.033). Our collective findings support the hypothesis that genetic mechanisms for preecl sia and CVD are, at least in part, shared, but need to be interpreted with some caution as a Bonferroni correction for multiple testing adjusted the statistical significance threshold (adjusted P<0.001).
Publisher: Wiley
Date: 09-11-2012
DOI: 10.1111/J.1600-0412.2011.01293.X
Abstract: The primary aim of this study was to examine the association between inherited thrombophilias and adverse pregnancy outcomes in an Australian population. Case-control study. Two Australian tertiary level maternity hospitals. One hundred and fifteen cases with adverse pregnancy outcomes, comprising severe pre-ecl sia (n=45), fetal growth restriction (n=44), placental abruption (n=16) or stillbirth (n=10), and 115 controls matched for ethnicity, parity and maternal age. Genotyping for factor V Leiden, prothrombin gene mutation, methylenetetrahydrofolate reductase 677 and 1298 and thrombomodulin polymorphism was performed using Taqman assays in an ABI prism 7700 Sequencer. Pregnancy outcome data were extracted from the medical record at the time of recruitment. Prevalence of inherited thrombophilias in women with adverse pregnancy outcomes and matched control women. There were no differences in baseline characteristics between cases and control women, apart from duration of gestation and neonatal birthweight. Overall, there was no significant difference in the prevalence of these inherited thrombophilia polymorphisms between cases and control women. Heterozygosity for the factor V Leiden mutation, however, was significantly associated with an increased risk of both stillbirth (odds ratio 9.33, 95% confidence interval 1.36-64.15, p=0.02) and placental abruption (odds ratio 8.62, 95% confidence interval 1.57-47.17, p=0.01). Overall, this study does not support a significant association between inherited thrombophilia polymorphisms and adverse pregnancy outcomes. Our two statistically significant findings should be interpreted with caution given the small number of patients in these subgroups (10 stillbirths and 16 placental abruption cases) and the wide confidence intervals.
Publisher: Elsevier BV
Date: 07-2010
Publisher: Oxford University Press (OUP)
Date: 07-2005
Abstract: The role of progesterone withdrawal in human parturition continues to provoke controversy. One possible mechanism by which functional progesterone withdrawal may be achieved is by a decrease in the circulating concentration of its bioactive metabolites. The progesterone metabolite 5beta-dihydroprogesterone (5betaDHP) has been shown to be a potent tocolytic in vitro. We quantified plasma concentrations of 5betaDHP in association with the onset of spontaneous labour in women at term and steroid 5beta-reductase mRNA expression in placenta, myometrium, chorion and amnion in relation to parturition, using real time RT-PCR. Serial blood s les were obtained from patients late in pregnancy, before term labour, during term labour and within the first 24 h postpartum. Following organic solvent extraction, steroids including 5betaDHP were separated by high-performance liquid chromatography (HPLC) and then quantified by radioimmunoassay (RIA). 5betaDHP concentration decreased two-fold (P = 0.00001, n = 25) from 0.317 +/- 0.039 nmol/ml to 0.178 +/- 0.017 nmol/ml in association with active labour. Tissue 5beta-reductase mRNA-relative abundance was determined in placenta, myometrium, chorion and amnion obtained from labouring and non-labouring women. In placenta and myometrium, relative expression decreased significantly in association with labour, by about two-fold and 10-fold, respectively. These data are consistent with a possible role for 5betaDHP in the onset of spontaneous human labour. Further studies exploring this hitherto unrecognized endocrinological pathway are indicated.
Publisher: Springer Science and Business Media LLC
Date: 22-10-2015
DOI: 10.1038/NCOMMS9570
Abstract: Disease incidences increase with age, but the molecular characteristics of ageing that lead to increased disease susceptibility remain inadequately understood. Here we perform a whole-blood gene expression meta-analysis in 14,983 in iduals of European ancestry (including replication) and identify 1,497 genes that are differentially expressed with chronological age. The age-associated genes do not harbor more age-associated CpG-methylation sites than other genes, but are instead enriched for the presence of potentially functional CpG-methylation sites in enhancer and insulator regions that associate with both chronological age and gene expression levels. We further used the gene expression profiles to calculate the ‘transcriptomic age’ of an in idual, and show that differences between transcriptomic age and chronological age are associated with biological features linked to ageing, such as blood pressure, cholesterol levels, fasting glucose, and body mass index. The transcriptomic prediction model adds biological relevance and complements existing epigenetic prediction models, and can be used by others to calculate transcriptomic age in external cohorts.
Publisher: Springer Science and Business Media LLC
Date: 03-08-2015
DOI: 10.1038/NG.3373
Publisher: American Physiological Society
Date: 07-2010
DOI: 10.1152/PHYSIOLGENOMICS.00038.2010
Abstract: Neurotransmitters such as serotonin (5-hydroxytryptamine, 5-HT) work closely with leptin and insulin to fine-tune the metabolic and neuroendocrine responses to dietary intake. Losing the sensitivity to excess food intake can lead to obesity, diabetes, and a multitude of behavioral disorders. It is largely unclear how different serotonin receptor subtypes respond to and integrate metabolic signals and which genetic variations in these receptor genes lead to in idual differences in susceptibility to metabolic disorders. In an obese cohort of families of Northern European descent ( n = 2,209), the serotonin type 5A receptor gene, HTR5A, was identified as a prominent factor affecting plasma levels of triglycerides (TG), supported by our data from both genome-wide linkage and targeted association analyses using 28 publicly available and 12 newly discovered single nucleotide polymorphisms (SNPs), of which 3 were strongly associated with plasma TG levels ( P 0.00125). Bayesian quantitative trait nucleotide (BQTN) analysis identified a putative causal promoter SNP (rs3734967) with substantial posterior probability ( P = 0.59). Functional analysis of rs3734967 by electrophoretic mobility shift assay (EMSA) showed distinct binding patterns of the two alleles of this SNP with nuclear proteins from glioma cell lines. In conclusion, sequence variants in HTR5A are strongly associated with high plasma levels of TG in a Northern European population, suggesting a novel role of the serotonin receptor system in humans. This suggests a potential brain-specific regulation of plasma TG levels, possibly by alteration of the expression of HTR5A.
Publisher: Springer Science and Business Media LLC
Date: 27-02-2018
Publisher: Springer Science and Business Media LLC
Date: 12-04-2011
DOI: 10.1038/MP.2011.37
Publisher: Elsevier BV
Date: 07-2022
DOI: 10.1016/J.JACL.2022.05.065
Abstract: Increased risk of coronary artery disease (CAD) in familial hypercholesterolaemia (FH) is modified by factors beyond defects in the low-density lipoprotein receptor pathway. The rs1250229-T single nucleotide polymorphism (SNP) in the FN1 gene is associated with CAD in genome-wide association studies and is in linkage disequilibrium with another SNP (rs1250259-T) in FN1 that is associated with decrease fibronectin secretion. We investigated whether rs1250229-T was also associated with prevalent CAD in patients with genetically confirmed FH. We collected clinical data from 256 patients with genetically confirmed FH. The FN1 rs1250229 SNP was genotyped on a SEQUENOM platform. The association between rs1250229-T and prevalent CAD was assessed using simple and multiple regression analyses. In patients with FH, the FN1 rs1250229-T (minor) allele was a significant negative predictor of prevalent CAD (odds ratio [OR] 0.353 95% confidence interval [CI] 0.193 - 0.647 P = 0.001). FN1 rs1250229-T remained a significant predictor of prevalent CAD after adjusting for age, sex, obesity, hypertension, smoking status and lipoprotein(a) concentration (OR 0.200 95% CI 0.091 - 0.441 P < 0.001). The FN1 rs1250229-T allele is inversely associated with CAD in patients with genetically confirmed FH, independently of traditional risk factors. While this finding requires replication, it suggests that the biology of fibronectin may contribute to variation in the risk of CAD in FH.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2013
DOI: 10.1161/CIRCGENETICS.113.000079
Abstract: Intima-media thickness (IMT) of the common and internal carotid arteries is an established surrogate for atherosclerosis and predicts risk of stroke and myocardial infarction. Often IMT is measured as the average of these 2 arteries yet, they are believed to result from separate biological mechanisms. The aim of this study was to conduct a family-based genome-wide association study (GWAS) for IMT to identify polymorphisms influencing IMT and to determine if distinct carotid artery segments are influenced by different genetic components. IMT for the common and internal carotid arteries was determined through B-mode ultrasound in 772 Mexican Americans from the San Antonio Family Heart Study. A GWAS using 931219 single-nucleotide polymorphisms was undertaken with 6 internal and common carotid artery IMT phenotypes using an additive measured genotype model. The most robust association detected was for 2 single-nucleotide polymorphisms (rs16983261, rs6113474 P =1.60e −7 ) in complete linkage disequilibrium on chromosome 20p11 for the internal carotid artery near wall, next to the gene PAX1 . We also replicated previously reported GWAS regions on chromosomes 19q13 and 7q22. We found no overlapping associations between internal and common carotid artery phenotypes at P .0e −6 . The genetic correlation between the 2 carotid IMT arterial segments was 0.51. This study represents the first large-scale GWAS of carotid IMT in a non–European population and identified several novel loci. We do not detect any shared GWAS signals between common and internal carotid arterial segments, but the moderate genetic correlation implies both common and unique genetic components.
Publisher: Oxford University Press (OUP)
Date: 1998
Abstract: The plasminogen activation cascade is thought to play a critical role in labour-associated remodelling events, such as fetal membrane rupture and placental separation. The aim of this study was to quantify, by Northern analysis, the gene expression of urokinase plasminogen activator (UPA), urokinase receptor (UPAR) and plasminogen activator inhibitor type-2 (PAI-2) in human gestational tissues. Amnion, choriodecidua and placenta were collected from women before, during and after spontaneous-onset labour at term. The expression of UPAR mRNA was significantly (P < 0.05) increased in amnion tissue during and after labour and delivery, compared with the before-labour group. In contrast, UPAR gene expression in choriodecidua and placenta was not significantly altered in association with labour onset. PAI-2 mRNA expression was also significantly (P < 0.05) increased in amnion after labour. No statistically significant differences were observed in choriodecidua or placenta PAI-2 mRNA with labour onset. Neither was any significant effect of labour status on UPA mRNA identified in any of the tissues examined. This study is the first to describe a significant increase in UPAR and PAI-2 gene expression in human amnion tissue with labour. These data are consistent with the hypothesis that, during labour, up-regulation of UPAR expression in amnion serves to localize active UPA at the cell surface, thereby increasing proteolytic activity in fetal membranes. Increased PAI-2 in amnion after labour may provide a regulatory 'switch' to cease further proteolysis in this tissue type. In conclusion, the data obtained support the proposal that the plasminogen activation cascade contributes to the rupture of fetal membranes during active labour.
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 08-10-2011
Publisher: Springer Science and Business Media LLC
Date: 03-05-2019
Publisher: Oxford University Press (OUP)
Date: 27-04-2007
DOI: 10.1093/HMG/DDM101
Abstract: The mitochondria are the major cellular site of energy production and respiration. Recent research has focused on investigating the role of mitochondria in disease development and it has become increasingly evident that mitochondrial dysfunction contributes to a variety of human diseases. Mitochondrial DNA (mtDNA) quantity is very important for maintaining mitochondrial function and meeting the energy needs of the body. We have measured mitochondrial content in 1259 Mexican American in iduals (from 42 extended families) and have shown that mtDNA quantity (a surrogate measure of mitochondrial integrity) has a large genetic component. We performed a genome scan and a genome-wide quantitative transcriptomic scan to identify QTLs influencing mitochondrial content. A variance components linkage-based genome scan utilizing 439 STR markers was used to localize a QTL for mitochondrial content on chromosome 10q (LOD = 3.83). Significant linkage to the mitochondrial genome was also detected for mitochondrial transmission (LOD = 3.39). For replication, we measured mitochondrial content in an independent Caucasian population (1088 in iduals) finding evidence for linkage in these same regions. As part of the San Antonio Family Heart Study, we obtained genome-wide quantitative transcriptional profiles from 1240 in iduals. Using lymphocyte s les, we quantitated 20 413 transcripts and examined correlations between the expression levels of these transcripts and mitochondrial content using the variance components method. Using regression analysis allowing for residual genetic components, we identified 829 transcripts (including many novel genes) influencing mitochondrial content that vary in their general biological actions, from cell signaling to cell trafficking and ion binding.
Publisher: Microbiology Society
Date: 08-1998
DOI: 10.1099/00221287-144-8-2073
Abstract: Proliferative enteropathy (PE) is a complex of diseases of commercial importance to the pig industry. The obligate intracellular bacterium Lawsonia intracellularis is consistently associated with PE and pure cultures of this bacterium have been used to reproduce PE in pigs. In this study L. intracellularis bacteria were purified directly from PE-affected tissue. DNA extracted from purified bacteria was used to construct a partial genomic library which was screened using sera from L. intracellularis -immunized rabbits. Two seroreactive recombinant clones were identified, one of which expressed proteins of 10 and 60 kDa. The sequence of the insert from this clone, plSI-2, revealed ORFs with sequence similarity to the groES/EL operon of Escherichia coli , the 50S ribosomal proteins L21 and L27 of E. coli , a GTP-binding protein of Bacillus subtilis and a possible protoporphyrinogen oxidase, HemK, of E. coli. Primers designed from unique sequences from the plSI-2 insert lified DNA from infected, but not non-infected, porcine ilea the licon sequence obtained from tissue-cultured L. intracellularis was identical to the corresponding sequence in plSI-2, confirming the origin of the clone. The sequence of L. intracellularis GroEL and other GroEL sequences in the databases were used to construct a partial phylogenetic tree. Analysis of the GroEL sequence relationship suggested that L. intracellularis is not significantly related to other organisms whose GroEL sequences are held in the databases and supports previous data from 16S sequence analyses suggesting that L. intracellularis is a member of a novel group of enteric pathogens.
Publisher: Springer Science and Business Media LLC
Date: 27-11-2017
DOI: 10.1007/S00439-017-1856-X
Abstract: Over two billion adults are overweight or obese and therefore at an increased risk of cardiometabolic syndrome (CMS). Obesity-related anthropometric traits genetically correlated with CMS may provide insight into CMS aetiology. The aim of this study was to utilise an empirically derived genetic relatedness matrix to calculate heritabilities and genetic correlations between CMS and anthropometric traits to determine whether they share genetic risk factors (pleiotropy). We used genome-wide single nucleotide polymorphism (SNP) data on 4671 Busselton Health Study participants. Exploiting both known and unknown relatedness, empirical kinship probabilities were estimated using these SNP data. General linear mixed models implemented in SOLAR were used to estimate narrow-sense heritabilities (h
Publisher: Springer Science and Business Media LLC
Date: 11-03-2015
DOI: 10.1038/EJHG.2015.24
Publisher: Springer Science and Business Media LLC
Date: 16-12-2020
Publisher: Oxford University Press (OUP)
Date: 04-2014
DOI: 10.1111/BJD.12829
Abstract: Breslow thickness is the most important predictor of survival in localized malignant melanoma. A number of melanoma risk factors have been shown to be associated with Breslow thickness however, the role of genetic loci has been little investigated to date. To investigate the association of known melanoma susceptibility genetic loci with Breslow thickness. Participants were 800 in iduals from the Western Australian Melanoma Health Study who completed a questionnaire and provided a DNA s le. Genetic association analyses between single-nucleotide polymorphisms (SNPs) from 15 candidate melanoma susceptibility genes and Breslow thickness were performed, controlling for relevant covariates. Older age at diagnosis and absence of naevi were associated with increased Breslow thickness. Following adjustment for multiple testing, no SNPs were significantly associated with Breslow thickness. Associations observed between Breslow thickness and age and naevi reinforce current knowledge. Some evidence of shared genetic determinants between melanoma risk and Breslow thickness was found. Further studies are required to confirm this finding.
Publisher: Springer Science and Business Media LLC
Date: 27-05-2009
DOI: 10.1038/EJHG.2009.80
Publisher: Springer Science and Business Media LLC
Date: 14-01-2015
Publisher: Elsevier BV
Date: 11-2011
Publisher: Springer Science and Business Media LLC
Date: 07-10-2023
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.1016/J.PLACENTA.2021.04.008
Abstract: The placenta is a short-lived organ, yet it shows signs of progressive ageing in the third trimester. Studies of ageing chorionic placental tissue have recently flourished, providing evidence of advanced ageing of tissues in the late ost-term (L/PT) period of gestation. However, ageing of the maternal aspect of the maternal-fetal interface, specifically the decidua basalis, is poorly understood. Here, we investigated whether the L/PT period was associated with advanced ageing and exhaustion of important decidua basalis mesenchymal stem/stromal cells (DMSCs) functions. In this study, DMSCs were isolated and characterised from early term (ET) and L/PT placental tissue and they were then investigated by employing various MSC potency and ageing assays. RNA sequencing was also performed to screen for specific microRNAs that are associated with stem cell exhaustion and ageing between ET- and L/PT-DMSCs. L/PT-DMSCs, when compared to ET-DMSCs, showed significantly lower cell proliferation and a significant higher level of cell apoptosis. L/PT-DMSCs showed significantly lower resistance to oxidative stress and a significant decrease in antioxidant capacity compared with ET-DMSCs. Western blot analysis revealed increased expression of the stress-mediated P-p38MAPK protein in L/PT-DMSCs. RNA Sequencing showed microRNA (miR) miR-516b-5p, was present at significantly lower levels in L/PT-DMSCs. Inhibition of miR-516b-5p in ET-DMSCs revealed a decline in the ability of the inhibited cells to survive in extended cell culture. These data provide the first evidence of advanced ageing and exhaustion of important stem cell functions in L/PT-DMSCs, and the involvement of specific miRs in the DMSC ageing process.
Publisher: Frontiers Media SA
Date: 19-03-2019
Publisher: S. Karger AG
Date: 2000
DOI: 10.1159/000010326
Abstract: i Objective: /i A strong independent association between the prothrombin G20210A gene mutation and pre-ecl sia has been reported in an Italian population. This result was not confirmed in a subsequent study in a Dutch population. The objective of this study was to further test the hypothesis that the prothrombin G20210A mutation is associated with pre-ecl sia/ecl sia. i Methods: /i Seventeen ecl tics and 67 pre-ecl tics were recruited from 34 multicase Australian/New Zealand families. An additional 105 unrelated pre-ecl tic/ecl tic women and 119 parous women were recruited as controls. i Results: /i The overall incidence for the prothrombin G20210A gene mutation in the pre-ecl tic group was 3.6% (95% CI 1.2–8.2%) which was not significantly different from the control group 2.5% (95% CI 0.5–7.2%) (p = 0.73, OR 1.44, 95% CI 0.34–6.17). i Conclusion: /i This study provides little evidence of a significant relationship between the prothrombin G20210A gene mutation and pre-ecl sia. Based on our results, we do not recommend testing for the prothrombin G20210A mutation in the routine investigation of women with pre-ecl sia.
Publisher: Wiley
Date: 25-09-2012
DOI: 10.1038/ICB.2012.44
Publisher: Elsevier BV
Date: 11-2013
Publisher: American Diabetes Association
Date: 15-12-2010
DOI: 10.2337/DB09-1277
Abstract: Genome-wide association studies that compare the statistical association between thousands of DNA variations and a human trait have detected 958 loci across 127 different diseases and traits. However, these statistical associations only provide evidence for genomic regions likely to harbor a causal gene(s) and do not directly identify such genes. We combined gene variation and expression data in a human cohort to identify causal genes. Global gene transcription activity was obtained for each in idual in a large human cohort (n = 1,240). These quantitative transcript data were tested for correlation with genotype data generated from the same in iduals to identify gene expression patterns influenced by the variants. Variant rs8050136 lies within intron 1 of the FTO gene on chromosome 16 and marks a locus strongly associated with type 2 diabetes and obesity and widely replicated across many populations. We report that genetic variation at this locus does not influence FTO gene expression levels (P = 0.38), but is strongly correlated with expression of RBL2 (P = 2.7 × 10−5), ∼270,000 base pairs distant to FTO. These data suggest that variants at FTO influence RBL2 gene expression at large genetic distances. This observation underscores the complexity of human transcriptional regulation and highlights the utility of large human cohorts in which both genetic variation and global gene expression data are available to identify disease genes. Expedient identification of genes mediating the effects of genome-wide association study–identified loci will enable mechanism-of-action studies and accelerate understanding of human disease processes under genetic influence.
Publisher: Wiley
Date: 06-1989
DOI: 10.1111/J.1471-4159.1989.TB07247.X
Abstract: The incorporation of radioactive phosphate into proteins of both normal and regenerating ganglia of the sympathetic nervous system of the rat is reported. The incorporation reactions were carried out in vitro by incubating homogenates of excised ganglia with [gamma-32P]ATP under various conditions. It was found that incorporation of phosphate into proteins of regenerating ganglia in the molecular mass range 10,000-100,000 daltons increased up to 40% over incorporation into proteins from control ganglia during the first 3 days following injury and returned to control levels after 14 days. Analysis of the proteins by two-dimensional electrophoresis revealed that only few, i.e., less than 20, became radioactively labelled in homogenates of superior cervical ganglia in the presence of Ca2+, and even fewer in the presence of cyclic AMP. Furthermore, all these proteins fell within a narrow pI range of 4-6. The growth-associated protein, variously designated GAP-43, B-50, F-1, and pp46, has an enhanced level of expression and phosphorylation in regenerating ganglia compared with controls at day 3. Injury also caused consistently higher levels of incorporation into two other proteins with molecular masses at positions 55,000 and 85,000 and pI values of 5.1 and 4.5, respectively the former protein most probably is beta-tubulin. The fact that both proteins are found in the 15,000 g pellet after the tissue has been solubilized in 0.5% nonionic detergent indicates that they may indeed by components of filament assemblies. Thus, the results suggest that protein phosphorylation is a mechanism involved in cytoskeletal function in regenerating nerve.
Publisher: Elsevier BV
Date: 08-2011
Publisher: Elsevier BV
Date: 2017
Publisher: Frontiers Media SA
Date: 2013
Publisher: Wiley
Date: 25-01-2022
DOI: 10.1002/ALZ.12538
Abstract: The apolipoprotein E ( APOE ) genotype is the strongest genetic risk factor for late‐onset Alzheimer's disease. However, its effect on lipid metabolic pathways, and their mediating effect on disease risk, is poorly understood. We performed lipidomic analysis on three independent cohorts (the Australian Imaging, Biomarkers and Lifestyle [AIBL] flagship study, n = 1087 the Alzheimer's Disease Neuroimaging Initiative [ADNI] 1 study, n = 819 and the Busselton Health Study [BHS], n = 4384), and we defined associations between APOE ε2 and ε4 and 569 plasma/serum lipid species. Mediation analysis defined the proportion of the treatment effect of the APOE genotype mediated by plasma/serum lipid species. A total of 237 and 104 lipid species were associated with APOE ε2 and ε4, respectively. Of these 68 (ε2) and 24 (ε4) were associated with prevalent Alzheimer's disease. In idual lipid species or lipidomic models of APOE genotypes mediated up to 30% and 10% of APOE ε2 and ε4 treatment effect, respectively. Plasma lipid species mediate the treatment effect of APOE genotypes on Alzheimer's disease and as such represent a potential therapeutic target.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2016
Publisher: Cold Spring Harbor Laboratory
Date: 17-10-2018
Abstract: Most expression quantitative trait locus (eQTL) studies to date have been performed in heterogeneous tissues as opposed to specific cell types. To better understand the cell-type–specific regulatory landscape of human melanocytes, which give rise to melanoma but account for % of typical human skin biopsies, we performed an eQTL analysis in primary melanocyte cultures from 106 newborn males. We identified 597,335 cis -eQTL SNPs prior to linkage disequilibrium (LD) pruning and 4997 eGenes (FDR 0.05). Melanocyte eQTLs differed considerably from those identified in the 44 GTEx tissue types, including skin. Over a third of melanocyte eGenes, including key genes in melanin synthesis pathways, were unique to melanocytes compared to those of GTEx skin tissues or TCGA melanomas. The melanocyte data set also identified trans -eQTLs, including those connecting a pigmentation-associated functional SNP with four genes, likely through cis -regulation of IRF4 . Melanocyte eQTLs are enriched in cis -regulatory signatures found in melanocytes as well as in melanoma-associated variants identified through genome-wide association studies. Melanocyte eQTLs also colocalized with melanoma GWAS variants in five known loci. Finally, a transcriptome-wide association study using melanocyte eQTLs uncovered four novel susceptibility loci, where imputed expression levels of five genes ( ZFP90 , HEBP1 , MSC , CBWD1 , and RP11-383H13.1 ) were associated with melanoma at genome-wide significant P -values. Our data highlight the utility of lineage-specific eQTL resources for annotating GWAS findings, and present a robust database for genomic research of melanoma risk and melanocyte biology.
Publisher: Wiley
Date: 22-06-2004
Abstract: To date, the quest to develop a noninvasive diagnostic test for endometriosis has mostly concentrated on the levels of cytokines and growth factors that are involved in inflammation, angioneogenesis and tissue remodeling, present in serum, peritoneal fluid, endometrium and endometriotic lesions. As this has not yet translated into the development of such a diagnostic test, proteomic techniques are now being employed to identify proteins that are potential biomarkers for the disease. As proteomics allows the comprehensive analysis of complex fluid and tissue s les with good sensitivity and resolution, it has promise in delivering markers associated with endometriosis. Once identified, the challenge will be in translating these markers into a clinically useful test for endometriosis, as the pathophysiology of this disease is unknown and likely to be complex and multifactorial. Also, with variation between in iduals and the influences of steroid hormones during the menstrual cycle, it could be difficult to validate findings relating to a single protein or small groups of proteins differentially expressed in the disease state. Proteomic profiling, using mass spectrometry in combination with sophisticated bioinformatics software to identify protein patterns, may be where a significant clinical diagnostic contribution can be made.
Publisher: The Endocrine Society
Date: 05-2010
DOI: 10.1210/JC.2010-0042
Publisher: Wiley
Date: 22-06-2004
Abstract: Maternal and perinatal morbidity and mortality rates are significantly higher in pregnancies complicated by preterm labor, pre-ecl sia and fetal growth restriction. Decades of research have not translated into a clear understanding of the underlying pathophysiologies or effective identification of women who are at high risk of developing these complications. Often the severity of these diseases does not correlate with the clinical symptoms, and current diagnostic methods are unable to accurately predict the conditions prior to clinical presentation. Though several potential markers have been proposed for each of these disorders, to date none have proven clinical utility. Emerging proteomic technology is only beginning to be employed in pregnancy research. A comprehensive analysis of gestational tissues can be expected to contribute to the elucidation of the complex molecular mechanisms of pregnancy and related complications. Comparison of the expression profiles of normal and pathogenic tissues and biofluids may also highlight novel candidate marker proteins that have so far remained undetected. More interestingly, rapidly evolving technologies using sophisticated bioinformatic tools are demonstrating their potential in disease diagnostics by using overall protein profiles to detect diseases. The clinical significance of these methodological advances is enormous. Early diagnosis together with improved understanding of underlying molecular mechanisms can enhance outcomes and increase effective management and therapeutic options.
Publisher: Springer Science and Business Media LLC
Date: 04-2023
DOI: 10.1038/S41591-023-02271-1
Abstract: Autism omics research has historically been reductionist and diagnosis centric, with little attention paid to common co-occurring conditions (for ex le, sleep and feeding disorders) and the complex interplay between molecular profiles and neurodevelopment, genetics, environmental factors and health. Here we explored the plasma lipidome (783 lipid species) in 765 children (485 diagnosed with autism spectrum disorder (ASD)) within the Australian Autism Biobank. We identified lipids associated with ASD diagnosis ( n = 8), sleep disturbances ( n = 20) and cognitive function ( n = 8) and found that long-chain polyunsaturated fatty acids may causally contribute to sleep disturbances mediated by the FADS gene cluster. We explored the interplay of environmental factors with neurodevelopment and the lipidome, finding that sleep disturbances and unhealthy diet have a convergent lipidome profile (with potential mediation by the microbiome) that is also independently associated with poorer adaptive function. In contrast, ASD lipidome differences were accounted for by dietary differences and sleep disturbances. We identified a large chr19p13.2 copy number variant genetic deletion spanning the LDLR gene and two high-confidence ASD genes ( ELAVL3 and SMARCA4 ) in one child with an ASD diagnosis and widespread low-density lipoprotein-related lipidome derangements. Lipidomics captures the complexity of neurodevelopment, as well as the biological effects of conditions that commonly affect quality of life among autistic people.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2019
Publisher: Wiley
Date: 12-2021
DOI: 10.1002/ALZ.056703
Abstract: The apolipoprotein E gene (APOE) genotype is the first and strongest genetic risk factor for late‐onset Alzheimer’s disease and has emerged as a novel therapeutic target for AD. The encoded protein (Apolipoprotein E, APOE) is well‐known to be involved in lipoprotein transport and metabolism, but its effect on lipid metabolic pathways and the potential mediating effect of these on disease risk have not been fully defined. We performed lipidomic analysis on three independent cohorts (AIBL, n = 693 ADNI, n=207 BHS, n=4,384) and defined the association between APOE polymorphisms (ε4 and ε2) and plasma lipid species. To identify associations independent of lipoprotein metabolism, the analyses was performed with adjustment for clinical lipids (total cholesterol, HDL‐C and triglycerides). Causal mediation analysis was performed to estimate the proportion of risk in the outcome model explained by a direct effect of APOE genotype on prevalent AD — the average direct effect (ADE) — and the proportion that was mediated by lipid species or lipidomic risk models — the average causal mediation effect (ACME). We identified multiple associations of species from lipid classes such as ceramide, hexosylceramide, sphingomyelin, plasmalogens, alkyldiacylglycerol and cholesteryl esters with APOE polymorphisms (ε4 and ε2) that were independent of clinical lipoprotein measurements. There were 104 and 237 lipid species associated with APOE ε4 and ε2 respectively which were largely discordant. Of these 116 were also associated with Alzheimer’s disease. In idual lipid species (notably the alkyldiacylglycerol subspecies) or lipidomic risk models of APOE genotypes mediated up to 10% and 30% of APOE ε4 and ε2 treatment effect on AD risks respectively. We demonstrate a strong relationship between APOE polymorphisms and peripheral lipid species. Lipids species mediate a proportion of the effects of APOE genotypes in risk of AD, particularly resilience with e2. Our results highlight the involvement of lipids in how APOE e2 mediates its resilience to AD and solidify their involvement with the disease pathway.
Publisher: Frontiers Media SA
Date: 2012
Publisher: S. Karger AG
Date: 2004
DOI: 10.1159/000076689
Abstract: The genetic background predisposing pregnant women to the disorder pre-ecl sia/ecl sia (PE/E) is still unknown. There is compelling evidence to suspect involvement of the immune system in the development of PE/E. The aim of this current study was to investigate whether there is an association between the tumor necrosis factor (TNF)-α –307 polymorphism and PE or ecl sia. In this study, 51 cases of ecl sia, 122 cases of PE and 100 normotensive control cases were genotyped for the TNF-α –307 polymorphism. We found a significant difference between the TNF2 allele frequencies of ecl tic and normotensive controls (χ sup /sup = 6.3 and p = 0.025), but not of pre-ecl tic and normotensive controls (χ sup /sup = 0.5 and p = 1.0). We conclude from this study that the TNF2 allele contributes to the occurrence of ecl sia in our population.
Publisher: Cold Spring Harbor Laboratory
Date: 25-08-2021
DOI: 10.1101/2021.08.20.21261814
Abstract: We integrated lipidomics and genomics to unravel the genetic architecture of lipid metabolism and identify genetic variants associated with lipid species that are putatively in the mechanistic pathway to coronary artery disease (CAD). We quantified 596 lipid species in serum from 4,492 phenotyped in iduals from the Busselton Health Study. In our discovery GWAS we identified 667 independent loci associations with these lipid species (479 novel), followed by meta-analysis and validation in two independent cohorts. Lipid endophenotypes (134) identified for CAD were associated with variation at 186 genomic loci. Associations between independent lipid-loci with coronary atherosclerosis were assessed in ∼456,000 in iduals from the UK Biobank. Of the 53 lipid-loci that showed evidence of association (P ×10 −3 ), 43 loci were associated with at least one of the 134 lipid endophenotypes. The findings of this study illustrate the value of integrative biology to investigate the genetics and lipid metabolism in the aetiology of atherosclerosis and CAD, with implications for other complex diseases.
Publisher: Elsevier BV
Date: 10-2019
DOI: 10.1016/J.CANEP.2019.101591
Abstract: The aim of this study was to examine factors including family history, medical history and comorbidities associated with the risk of colorectal cancer (CRC) in young (18-49 years) and middle-age (50-69 years) in iduals. State records were used to identify in iduals born in Western Australia between 1945 and 1996, and their first-degree relatives. In iduals in the cohort and their relatives were linked to State cancer registry, hospital and mortality data to identify diagnoses of CRC and other risk factors. The associations between CRC and identified risk factors were examined using multivariable logistic regression. For both young and middle-aged patients, family history of CRC, and a history of smoking, inflammatory bowel disease, liver disease and non-CRC cancer were associated with a significant increase in odds of CRC. In middle-aged patients, having a colonoscopy in the previous 10 years was associated with a reduced odds of CRC regardless of the detection of polyps. However, in young patients only the absence of polyps as confirmed by colonoscopy was associated with a decreased risk of CRC (OR: 0.38, 95%CI: 0.26 - 0.54, p < 0.001). Many of the risk factors associated with CRC were similar in young and middle-aged persons, and should be used to identify high risk young patients for screening. The association between colonoscopy and polyps with CRC was modified by age, likely as the result of routine screening in middle-aged patients.
Publisher: Elsevier BV
Date: 12-2005
DOI: 10.1016/J.JRI.2005.07.005
Abstract: An aberrant interaction at the maternal/fetal interface between the genetically distinct fetal trophoblast cells and cells of the maternal decidua has been proposed as an initiating factor in one of the major complications of human pregnancy, preecl sia. Biochemical and epidemiological studies suggest that the immune system plays an important role in preecl sia. Thus, the aim of this study was to determine the decidual gene expression status in preecl sia of one of the key components of the adaptive immune system. Total RNA was extracted from decidua collected from women with normal pregnancies and those complicated by preecl sia. Reverse Northern analysis was performed on 72 cDNAs from human decidua and differentially expressed genes identified were analysed further using semi-quantitative RT-PCR and Northern blot analysis. Expression of the gene encoding the constant region of the heavy chain of immunoglobulin G (IgG CRHC) was shown to be down-regulated in association with preecl sia. These data support the hypothesis that immune maladaptation may play an important role in the pathogenesis of preecl sia.
Publisher: Elsevier BV
Date: 2015
Publisher: Informa UK Limited
Date: 1999
DOI: 10.3109/10641959909009613
Abstract: To investigate the endothelial cell nitric oxide synthase (eNOS) gene as a candidate for susceptibility to preecl sia. Twenty-six Australian families containing 11 ecl tics, 59 severe preecl tics, and 27 mild preecl tics were used to test for linkage between the eNOS gene region and preecl sia. Two microsatellite markers (D7S483 and D7S505) in the proximity of the eNOS gene were used. Logarithm of odds (LOD) scores were used to examine the cosegregation of alleles with the disease under a variety of inheritance models. Model-independent analysis, affected pedigree member method (AFFPED), and pairwise haplotype sharing between affected sibs were also used. Two-point LOD score analysis gave no evidence of linkage between preecl sia and two markers in close proximity to the eNOS gene (LOD scores 0.05). This study provides no evidence for linkage between two markers in close proximity to the eNOS gene and preecl sia in these families. These results do not support the recent suggestion that eNOS could be a familial pregnancy-induced hypertension gene (Arngrimsson R, et al., Am J Hum Genet 1997 :354-62). Distinguishing preecl sia from other hypertensive disorders in pregnancy is difficult. Hypertension appears to be a consequence, rather than a primary cause of preecl sia. Given the vasodilatory role of the eNOS gene product, it is possible that the linkage recently reported for eNOS reflects its relationship with hypertension rather than preecl sia.
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 05-2022
DOI: 10.1016/J.JID.2021.08.445
Abstract: Scars are maintained for life and increase in size during periods of growth such as puberty. Epigenetic changes in fibroblasts after injury may underpin the maintenance and growth of scars. In this study, we combined methylome and transcriptome data from normotrophic mature scar and contralateral uninjured normal skin fibroblasts to identify potential regulators of scar maintenance. In total, 219 significantly differentially expressed and 1,199 significantly differentially methylated promoters were identified, of which there were 12 genes both significantly differentially methylated and expressed. Of these, the two transcription factors, FOXF2 and MKX, were selected for further analysis. Immunocytochemistry and qPCR suggested that FOXF2 but not MKX had elevated expression in scar fibroblasts. Using RNA sequencing, FOXF2 knockdown was shown to significantly reduce the expression of extracellular matrix‒related genes, whereas MKX did not appear to affect similar pathways. Finally, FOXF2 knockdown was also shown to significantly decrease collagen I production in scar and keloid fibroblasts. This study provides insights into the maintenance of normotrophic scar, suggesting that FOXF2 is an important regulator of this process. Targeting genes responsible for maintenance of scar phenotype may ameliorate scar appearance and improve patient outcomes in the future.
Publisher: Elsevier BV
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 15-04-2012
DOI: 10.1038/NG.2250
Publisher: Informa UK Limited
Date: 25-04-2016
DOI: 10.1080/07853890.2016.1174877
Abstract: Preecl sia is a common and partially genetic pregnancy complication characterized by hypertension and proteinuria. Association with cardiovascular disease and type 2 diabetes has been reported in 9p21 by several genome-wide association studies. It has been hypothesized that cardiometabolic diseases may share common etiology with preecl sia. We tested association with the 9p21 region to preecl sia in the Finnish population by genotyping 23 tagging single nucleotide polymorphisms (SNPs) in 15 extended preecl sia families and in a nationwide cohort consisting of 281 cases and 349 matched controls. Replication was conducted in additional datasets. Four SNPs (rs7044859, rs496892, rs564398 and rs7865618) showed nominal association (p ≤ 0.024 uncorrected) with preecl sia in the case-control cohort. To increase power, we genotyped two SNPs in additional 388 cases and 341 controls from the Finnish Genetics of Preecl sia Consortium (FINNPEC) cohort. Partial replication was also attempted in a UK cohort (237 cases and 199 controls) and in 74 preecl tic families from Australia/New Zealand. We were unable to replicate the initial association in the extended Finnish dataset or in the two international cohorts. Our study did not find evidence for the involvement of the 9p21 region in the risk of preecl sia. Key Message Chromosome 9p21 is not associated with preecl sia.
Publisher: Springer Science and Business Media LLC
Date: 14-03-2020
Publisher: Springer Science and Business Media LLC
Date: 03-2010
Publisher: Elsevier BV
Date: 2019
Publisher: Wiley
Date: 24-06-2014
DOI: 10.1002/GEPI.21817
Publisher: Public Library of Science (PLoS)
Date: 09-12-2020
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1086/521151
Publisher: Public Library of Science (PLoS)
Date: 28-09-2020
No related grants have been discovered for Eric Moses.