ORCID Profile
0000-0003-2907-6714
Current Organisation
University of Melbourne
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Publisher: Cold Spring Harbor Laboratory
Date: 02-11-2019
DOI: 10.1101/19010785
Abstract: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of in iduals, we combined 9 PRS gathering genomic variants associated to cardiovascular and renal diseases and their key risk factors into one logistic regression model, to predict micro- and macrovascular endpoints of diabetes. Its clinical utility in predicting complications of diabetes was tested in 4098 participants with diabetes of the ADVANCE trial followed during a period of 10 years and replicated it in three independent non-trial cohorts. The prediction model adjusted for ethnicity, sex, age at onset and diabetes duration, identified the top 30% of ADVANCE participants at 3.1-fold increased risk of major micro- and macrovascular events (p=6.3×10 −21 and p=9.6×10 −31 , respectively) and at 4.4-fold (p=6.8×10 −33 ) increased risk of cardiovascular death compared to the remainder of T2D subjects. While in ADVANCE overall, combined intensive therapy of blood pressure and glycaemia decreased cardiovascular mortality by 24%, the prediction model identified a high-risk group in whom this therapy decreased mortality by 47%, and a low risk group in whom the therapy had no discernable effect. Patients with high PRS had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel polygenic prediction model identified people with diabetes at low and high risk of complications and improved targeting those at greater benefit from intensive therapy while avoiding unnecessary intensification in low-risk subjects.
Publisher: Wiley
Date: 2020
DOI: 10.1111/IMJ.14699
Abstract: Whether part of the blood pressure lowering effects of glyceryl trinitrate (GTN) is the result of centrally mediated reduction in sympathetic activity is debated. In humans, baroreflex activity potentially obscures the central sympatholytic effects of GTN. We examined this in a routine clinical tilt test in a patient with baroreflex failure secondary to previous neck radiotherapy. With reduced baroreflex function we observed an exaggerated fall in blood pressure and reduced sympathetic activity with GTN, supporting a peripheral vasodilation and central sympatholytic effect.
Publisher: Wiley
Date: 11-06-2013
DOI: 10.1111/DOM.12122
Abstract: There is limited evidence regarding the association between physical activity and vascular complications, particularly microvascular disease, in patients with type 2 diabetes. From the 11 140 patients in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modified release Controlled Evaluation) trial, the effect of physical activity, categorized as none, mild, moderate or vigorous, and the number of sessions within a week, was examined in multivariable regression models adjusted for potential confounders. The study end-points were major cardiovascular events, microvascular complications and all-cause mortality. Forty-six percent of participants reported undertaking moderate to vigorous physical activity for >15 min at least once in the previous week. During a median of 5 years of follow-up, 1031 patients died, 1147 experienced a major cardiovascular event and 1136 a microvascular event. Compared to patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a decreased risk of cardiovascular events (HR: 0.78, 95% CI: 0.69-0.88, p < 0.0001), microvascular events (HR: 0.85, 95% CI: 0.76-0.96, p = 0.010) and all-cause mortality (HR: 0.83, 95% CI: 0.73-0.94, p = 0.0044). Moderate to vigorous, but not mild, physical activity is associated with a reduced incidence of cardiovascular events, microvascular complications and all-cause mortality in patients with type 2 diabetes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2014
Publisher: Oxford University Press (OUP)
Date: 04-11-2013
DOI: 10.1093/AJH/HPT193
Publisher: American Diabetes Association
Date: 12-07-2014
DOI: 10.2337/DC13-2625
Abstract: We investigated microvascular event risk in people with type 2 diabetes and assessed whether N-terminal pro–B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) improved prediction. We performed a case-cohort study, including 439 incident cases of microvascular events (new or worsening nephropathy or retinopathy) and 2,946 noncase subjects identified from participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. NT-proBNP and hsTnT were measured in stored plasma s les using automated commercial assays. After adjustment for age, sex, and randomized treatment, the hazard ratios for microvascular events per 1-SD increase in the log-transformed hsTnT and NT-proBNP were 1.67 (95% CI 1.51–1.85) and 1.63 (1.44–1.84), respectively. After further adjustment for classical and diabetes-related cardiovascular disease risk factors, the hazard ratios attenuated to 1.40 (1.24–1.58) and 1.41 (1.24–1.60), respectively. While the C statistic did not improve on addition of hsTnT or NT-proBNP for the total microvascular end point, a combination of both markers improved the prediction of nephropathy (P = 0.033) but not retinopathy (P = 0.72). The corresponding net reclassification indices in a three–risk category model (& %, 10–15%, and & % 5-year risk) for all microvascular events were 7.31% (95% CI 2.24–12.79) for hsTNT addition, 6.23% (1.74–11.5) for NT-proBNP addition, and 7.1% (1.5–12.9) for both markers together. These data suggest that cardiac biomarkers moderately improve microvascular event risk prediction, in particular the risk of nephropathy. Further studies examining the value of this approach for trial design and clinical use are warranted.
Publisher: Elsevier BV
Date: 04-2012
DOI: 10.1016/J.PREGHY.2011.12.002
Abstract: We have previously demonstrated deterioration in cardiac function at term in human pregnancy. To explore further, we investigated central arterial hemodynamics and association with maternal weight during gestation. Primiparous women (n=32) were recruited in a tertiary referral obstetric hospital and a longitudinal cohort study with analyses at median 16 and 37weeks gestation undertaken. Subgroups of normal body mass index, <25kg/m(2), and overweight, ⩾25kg/m(2), at 16weeks were created. We performed 2D speckle tracking echocardiography strain analysis and tonometric measures of central arterial pressures, waveforms and pulse wave velocity. A reduction in cardiac strain (2P=0.002) from 16 to 37weeks gestation was associated with increased systemic vascular resistance (2P=0.008), reduced arterial compliance (2P=0.004) and increased central arterial pressures (2P<0.001) and augmentation index (2P=0.001). By 37weeks, compared with values in earlier pregnancy, overweight women had higher systemic vascular resistance (2P<0.05). Additionally, their central diastolic pressure was higher (2P<0.05) and their ventricular strain was lower (2P<0.05) than in normal weight pregnant women. An increase in systemic vascular resistance and central arterial pressures by term may contribute to the observed deterioration in cardiac function. This appears more prominent in overweight women.
Publisher: Wiley
Date: 04-2012
DOI: 10.5694/MJA11.10474
Abstract: The recent 100-year anniversary of the Flexner review and the release of the Australian Medical Education Study have stimulated vigorous debate about the role of bioscience knowledge in medical education. Two critical questions define debate in this area: does bioscience learning assist in educating medical students to become competent doctors, and, if so, what are the most effective teaching and learning methods to facilitate this outcome? There is tacit acceptance that specific bioscience knowledge is critical for the development of clinical expertise however, there are few empirical data to support this notion. Two differing theories have been proposed to describe the role of bioscience learning in the development of clinical reasoning skills - the "two-worlds" model and the "encapsulation" model. A series of studies provides support for the encapsulation model. Some medical programs are now integrating bioscience teaching into the clinical years of the course. Evidence of the effectiveness of this on outcomes, such as improved clinical reasoning, is inconclusive.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2011
DOI: 10.1161/HYPERTENSIONAHA.111.176370
Abstract: Variants in the gene encoding the γ-subunit of the epithelial sodium channel ( SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 in iduals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G ( rs13331086 ) was significantly associated with age-, sex-, and body mass index–adjusted blood pressure in each of the 4 populations ( P .05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P =0.002 for systolic blood pressure SE=0.21, P =0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion ( P =0.04), consistent with increased epithelial sodium channel activity. Renal s les from hypertensive subjects showed a nonsignificant ( P =0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-02-2008
DOI: 10.1212/01.WNL.0000308819.43401.87
Abstract: The apolipoprotein E (APOE) polymorphism is an established risk factor for intracerebral hemorrhage (ICH) that is related to cerebral amyloid angiopathy in the white population. Among Asian populations, although ICH represents up to one third of all strokes and has high rates of mortality and morbidity, the role of the APOE polymorphism has not been well studied. The Perindopril Protection Against Recurrent Stroke Study (PROGRESS) was a randomized, double-blind, placebo-controlled trial of a blood pressure lowering regimen in subjects with prior cerebrovascular disease. APOE status was determined for 5,671 patients, including 2,148 Asians (38%). During the 3.9 years of follow-up, ICH occurred in 99 patients. Overall, carrying an epsilon 2 or epsilon 4 allele of the APOE polymorphism was associated with an adjusted hazard ratio (HR(a)) of 1.85 (95% CI = 1.24 to 2.76). In Asian patients the risk of ICH for epsilon 2 or epsilon 4 carriers was 2.11 (95% CI = 1.28 to 3.47) and 1.48 (95% CI = 0.76 to 2.87) in Europeans. Carriers of the epsilon 2 or epsilon 4 allele had an increased risk of both incident and recurrent ICH, and both cortical and deep ICH, and most risk estimates were higher in Asians than in Europeans. For both ethnic groups and for subtypes of ICH active treatment more than halved the risk of ICH and the treatment effects were not different in carriers of the epsilon 2 or epsilon 4 allele and in those with the epsilon 3 epsilon 3 genotype. There is a strong association between APOE genotype and the risk of intracerebral hemorrhage (ICH). In Asian patients the role of APOE polymorphisms in ICH is much broader than was previously supposed.
Publisher: FapUNIFESP (SciELO)
Date: 04-2014
DOI: 10.1590/0004-2730000003019
Abstract: O presente documento foi preparado por um grupo de especialistas, membros das Sociedades de Cardiologia, Endocrinologia, Medicina Interna, Nefrologia e Diabetes dos países da América Latina, para que sirva de diretriz para médicos que cuidam de pacientes com diabetes, hipertensão e fatores de risco concomitantes ou complicações de ambas as condições. Embora o conceito de síndrome metabólica seja atualmente muito discutido, a alta prevalência na América Latina do conjunto de alterações metabólicas que a compõem sugere que a síndrome metabólica é uma entidade nosográfica útil no contexto da medicina latino-americana. Devido a isso, no presente documento presta-se especial atenção a essa síndrome com a finalidade de alertar aos médicos sobre uma população particularmente de alto risco, que, por ser subestimada, não é tratada de forma adequada para os fatores de risco que constituem a síndrome metabólica. As recomendações deste documento são o resultado de apresentações e debates que ocorreram durante um encontro de dois dias em Bucaramanga (Colômbia), em outubro de 2012. Todos os participantes aprovaram as decisões finais. Os autores reconhecem que a publicação e difusão das diretrizes não serão suficientes para alcançar as mudanças recomendadas tanto em estratégias diagnósticas como terapêuticas, por isso programaram intervenções que permitirão identificar as barreiras do conhecimento, as atitudes e comportamento, o que permitirá tanto aos médicos como aos pacientes uma adequada adesão às recomendações sugeridas nestas diretrizes. Arq Bras Endocrinol Metab. 2014 (3):205-25
Publisher: Springer Science and Business Media LLC
Date: 21-12-2011
DOI: 10.1007/S00125-011-2404-1
Abstract: There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA(1c) and the risks of vascular complications and death in such patients. Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA(1c) measurements during follow-up and prior to the first event. Adjusted risks for each HbA(1c) decile were estimated using Cox models. Possible differences in the association between HbA(1c) and risks at different levels of HbA(1c) were explored using linear spline models. There was a non-linear relationship between mean HbA(1c) during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA(1c) studied (5.5-10.5%), there was evidence of 'thresholds', such that below HbA(1c) levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA(1c) level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001). In patients with type 2 diabetes, HbA(1c) levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.
Publisher: Elsevier
Date: 2005
Publisher: Portland Press Ltd.
Date: 09-1999
DOI: 10.1042/CS19990078
Publisher: Springer Science and Business Media LLC
Date: 10-09-2005
DOI: 10.1007/S10038-005-0289-X
Abstract: Androgens determine male secondary sexual characteristics and influence a variety of metabolic pathways. Circulating levels of androgens are highly heritable however, the genes involved are largely unknown. The 5alpha-reductase enzymes types 1 and 2 responsible for converting testosterone to the more potent androgen dihydrotestosterone are encoded by the SRD5A1 and SRD5A2 genes, respectively. We performed indirect genetic association studies of SRD5A1 and SRD5A2 and the dihydrotestosterone/testosterone ratio that reflects the activity of 5alpha-reductase in 57 males with type 2 diabetes. We found evidence of significant association between a single nucleotide polymorphism in SRD5A1 and the dihydrotestosterone/testosterone ratio (median 0.10, interquartile range 0.08 vs. median 0.06, interquartile range 0.04, P = 0.009). The polymorphism was not associated with any diabetic phenotypes. These results suggest that functional genetic variants might exist in or around SRD5A1 that affect the activity of the 5alpha-reductase enzyme type 1 and influence androgen levels.
Publisher: Wiley
Date: 2006
DOI: 10.1002/GEPI.20156
Abstract: Pulse pressure (PP) is an independent risk factor for cardiovascular disease. PP rises with age, more so in women. We examined sex differences in the correlations and variance components of PP in adult subjects from 767 nuclear families, enriched with those containing twins, from the Victorian Family Heart Study. After adjusting for age, we found no significant differences in the means or variances of PP in males and females. Under the assumption of no sex differences, the proportions of variance due to shared genes, shared environment, and in idual-specific environment were 20%, 23% and 57%, respectively. However, same-sex relative pairs had significantly higher correlations than opposite-sex pairs (P = 0.005), implying the existence of sex-dependent effects. Extensions to the simple variance components model suggested three possible explanations for these differences: smaller genetic correlation between opposite-sex pairs (rhoG,MF = 0.45, P = 0.007) smaller environmental correlation between opposite-sex pairs (P = 0.0003) or different environmental and genetic correlations obtained by estimating genetic, environmental, and in idual variance components separately for males and females (not nested, Akaike's Information Criterion (AIC) smaller by 6.69). Under the last model, the genetic component of PP variance is greater for males (1.62 vs 0.33) while the environmental component is greater for females (1.84 vs 0), which would have implications for the planning of gene discovery studies, since heritability would be higher in males. However, the second (environmental) approach best fits the data according to the AIC. Genetic explanations for sex differences in phenotypic correlations may be misleading unless shared environmental factors are also considered. PP illustrates a phenotype in which sex dependency represents an important component of phenotypic determination that can be revealed by detailed variance components modelling.
Publisher: Oxford University Press (OUP)
Date: 24-11-2011
DOI: 10.1111/J.1365-2133.2011.10708.X
Abstract: Male-pattern baldness (androgenetic alopecia, AGA) is the most common form of hair loss among humans. Research has shown that it is caused by genetic factors. Numerous studies have unequivocally identified two major genetic risk loci for AGA: the X-chromosomal AR/EDA2R locus, and the PAX1/FOXA2 locus on chromosome 20. To identify further candidate genes for AGA, and thus gain further insights into this phenotype. A German s le of 581 severely affected cases and 617 controls was used to perform a genome-wide association study. The identified associated locus was further analysed by fine-mapping, and then independently replicated in an Australian s le. Expression and pathway analyses were performed to characterize the susceptibility gene identified. The most significant association signal was obtained for rs756853 (P = 1·64 × 10(-7) ), which is located intronically in the histone deacetylase 9 (HDAC9) gene. Fine-mapping and a family-based analysis revealed that rs756853 and the 6-kb distal rs2249817 were the most highly associated single nucleotide polymorphisms. The association finding was replicated in an independent Australian s le, when the analysis was restricted to severely affected cases and unaffected controls (P = 0·026). Analysis of rs2249817 in a combined s le of severely affected German and Australian cases and unaffected controls revealed a strong association signal (P = 9·09 × 10(-8) ). Tissue expression studies demonstrated HDAC9 expression in various tissues, including tissues of relevance to AGA. No strong genotypic effects were observed in genotype-specific expression or splice studies. Pathway analyses supported the hypothesis that HDAC9 plays a functional role in AGA via interaction with the AR gene. The present study suggests that HDAC9 is the third AGA susceptibility gene.
Publisher: Wiley
Date: 06-12-2001
DOI: 10.1046/J.1440-1681.2001.03579.X
Abstract: 1. Throughout most of life, males have higher average blood pressures than females. This sexual dichotomy may be related to genetic factors including the X and Y sex chromosomes and genes that control sex steroids. Resultant physiological differences between men and women may also be relevant to the quantitative variation of blood pressure within the sexes. 2. The present overview collates our published and novel sex-related genetic data in relation to blood pressure from the Victorian Family Heart Study. These include a multipoint quantitative linkage analysis of the X chromosome and genetic association studies of single nucleotide polymorphisms (SNP) of the Y chromosome and genes encoding the androgen receptor (AR), oestrogen receptor alpha (ERalpha), 5alpha-reductase types I and II (SRD5A1 and SRD5A2) and aromatase (CYP19). 3. Systolic blood pressure (SBP) was linked (Z=3.3, genome-wide P < 0.05) to a region of the X chromosome that encompassed the AR gene and the Y chromosome was associated with diastolic blood pressure (DBP P=0.03). In new analyses, we observed a possible association between a SNP in AR and DBP in 369 males (84.5 vs 82.1 mmHg for genotype A vs genotype B, respectively P=0.06) and a significant association between haplotypes of the Y chromosome and AR SNP in males (P=0.01) with a difference of nearly 6 mmHg DBP between extreme groups. Associations were also observed for polymorphisms of SRD5A1 and ERalpha with DBP and SBP in males, respectively. 4. The findings indicate that genes related to sexual phenotypes may be relevant to the normal variation in blood pressure, even within the sexes. Further genetic and physiological analyses will be required to confirm these observations and to determine the mechanisms of action and the nature of any interactions.
Publisher: Wiley
Date: 14-08-2003
Publisher: American Physiological Society
Date: 04-2008
DOI: 10.1152/AJPHEART.01283.2007
Abstract: Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia-reperfusion (I/R) damage have not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the hypertrophic heart rat (HHR). In this study the sex differences in HHR cardiac function and responses to I/R [compared to control normal heart rat (NHR)] were investigated ex vivo. The ventricular weight index was markedly increased in HHR female (7.82 ± 0.49 vs. 4.80 ± 0.10 mg/g P 0.05) and male (5.76 ± 0.22 vs. 4.62 ± 0.07 mg/g P 0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males [maximum first derivative of pressure (dP/d t max ): NHR, 4,036 ± 171 vs. 4,258 ± 152 mmHg/s and HHR, 3,974 ± 160 vs. 4,540 ± 259 mmHg/s P 0.05]. HHR hearts were more susceptible to I/R (I = 25 min, and R = 30 min) injury than NHR hearts (decreased functional recovery, and increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/d t max ) post-I/R relative to male NHR (95.0 ± 12.2% vs. 60.5 ± 9.4%), a resistance to postischemic dysfunction not evident in female HHR (29.0 ± 5.6% vs. 25.9 ± 6.3%). Ventricular fibrillation was suppressed, and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to I/R insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection.
Publisher: Springer Science and Business Media LLC
Date: 13-11-2011
DOI: 10.1038/NG.981
Abstract: Kawasaki disease is a systemic vasculitis of unknown etiology, with clinical observations suggesting a substantial genetic contribution to disease susceptibility. We conducted a genome-wide association study and replication analysis in 2,173 in iduals with Kawasaki disease and 9,383 controls from five independent s le collections. Two loci exceeded the formal threshold for genome-wide significance. The first locus is a functional polymorphism in the IgG receptor gene FCGR2A (encoding an H131R substitution) (rs1801274 P = 7.35 × 10(-11), odds ratio (OR) = 1.32), with the A allele (coding for histadine) conferring elevated disease risk. The second locus is at 19q13, (P = 2.51 × 10(-9), OR = 1.42 for the rs2233152 SNP near MIA and RAB4B P = 1.68 × 10(-12), OR = 1.52 for rs28493229 in ITPKC), which confirms previous findings(1). The involvement of the FCGR2A locus may have implications for understanding immune activation in Kawasaki disease pathogenesis and the mechanism of response to intravenous immunoglobulin, the only proven therapy for this disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2003
DOI: 10.1161/01.HYP.0000044938.94050.E3
Abstract: The linkage and association between inherent blood pressure and underlying genotype is potentially confounded by antihypertensive treatment. We estimated blood pressure variance components (genetic, shared environmental, in idual-specific) in 767 adult volunteer families by using a variety of approaches to adjusting blood pressure of the 244 subjects (8.2%) receiving antihypertensive medications. The additive genetic component of variance for systolic pressure was 73.9 mm Hg 2 (SE, 8.8) when measured pressures (adjusted for age by gender within each generation) were used but fell to 61.4 mm Hg 2 (SE, 8.0) when treated subjects were excluded. When the relevant 95th percentile values were substituted for treated systolic pressures, the additive genetic component was 81.9 mm Hg 2 (SE, 9.5), but in idual adjustments in systolic pressure ranged from −53.5 mm Hg to +64.5 mm Hg (mean, +17.2 mm Hg). Instead, when 10 mm Hg was added to treated systolic pressure, the additive genetic component rose to 86.6 mm Hg 2 (SE, 10.1). Similar changes were seen in the shared environment component of variance for systolic pressure and for the combined genetic and shared environmental (ie, familial) components of diastolic pressure. There was little change in the in idual-specific variance component across any of the methods. Therefore, treated subjects contribute important information to the familial components of blood pressure variance. This information is lost if treated subjects are excluded and obscured by treatment effects if unadjusted measured pressures are used. Adding back an appropriate increment of pressure restores familial components, more closely reflects the pretreatment values, and should increase the power of genomic linkage and linkage disequilibrium analyses.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-1996
DOI: 10.1097/00004872-199602000-00007
Abstract: High blood pressure in spontaneously hypertensive rat (SHR) is associated with increased sympathetic innervation of key tissues, possibly as the result of increased nerve growth factor (NGF). The aim of this study was to test for genetic linkage of the NGF gene to high blood pressure. We studied NGF gene expression in young SHR and examined linkage of the NGF locus to mean arterial pressure in genetically segregating crosses of SHR and normotensive Donryu (DRY) rats. NGF mRNA was measured by Northern blot, and a restriction fragment length polymorphism of the NGF gene revealed after digestion with the NsiI restriction enzyme was used to study inheritance. Levels of NGF mRNA were detected easily in the kidneys of 2-, 4- and 10-week-old SHR but not in age-matched DRY rats. In an F2 population, the blood pressure of rats homozygous for the DRY NGF allele was 6 mmHg less than in heterozygotes and 8 mmHg less than in rats homozygous for the SHR NGF allele (analysis of variance, P < 0.004). In backcross rats the blood pressure of NGF heterozygotes was not significantly different from that of SHR homozygotes. These results indicate differences in renal NGF mRNA in SHR during the development of hypertension and suggest that a genetic locus in or near the NGF gene contributes in a Mendelian dominant pattern to a significant increment in blood pressure in SHR.
Publisher: Hindawi Limited
Date: 2010
DOI: 10.4061/2010/951254
Publisher: Oxford University Press (OUP)
Date: 08-2009
DOI: 10.1111/J.1365-2133.2009.09186.X
Abstract: Female pattern hair loss (FPHL) is a common trait in which androgens and oestrogens may have a pathogenic role. The aromatase enzyme converts androgens to oestrogens in scalp hair follicles and is differentially expressed in balding and nonbalding scalps of women. Sequence variation in the gene encoding aromatase, CYP19A1, might influence the risk of developing FPHL. To examine the role of CYP19A1 genetic variation in the heritability of FPHL. We investigated associations between FPHL and 61 tag single nucleotide polymorphisms (SNPs) representing variation in and around CYP19A1 in 484 caucasian women with grades 3-5 FPHL on the Sinclair scale, and 471 caucasian women with no evidence of hair loss. For the tag SNP rs4646 (overall genotype frequencies: CC, 53.6% AC, 39.3% AA, 7.1%), the genotype CC was more frequent in women with FPHL (58.1%) than controls (48.9%) (P = 0.006). Although this result did not achieve experiment-wide significance (P < 0.001 by permutation testing), subanalyses according to sources of recruitment and ages at presentation revealed consistent patterns of association. In particular, young cases (< 40 years) had the highest frequency of the CC genotype (68.2%) among all subgroups. These findings suggest that the common rs4646 C allele, which has been associated previously with higher circulating oestrogen levels, might be associated with predisposition to FPHL.
Publisher: Public Library of Science (PLoS)
Date: 02-04-2009
Publisher: Informa UK Limited
Date: 2004
Abstract: We have previously reported a quantitative trait locus associated with pressure-independent cardiac hypertrophy in the spontaneously hypertensive rat (SHR) of the Okamoto strain. This locus (Lvm1 left ventricular mass locus 1) contains the gene Fgf2 that codes for the potent cardiac growth factor, Fibroblast Growth Factor 2 (FGF2). Given that FGF2 appears essential for the induction of certain forms of cardiac hypertrophy in the rat, we proposed this gene as a candidate for the cardiac enlargement seen in the SHR. Previous reports of elevated FGF2 mRNA levels in the SHR, led us to hypothesise that nucleotide sequence variations occurring in the coding regions or in putative transcriptional factor binding sites within the Fgf2 promoter might play a role in cardiac hypertrophy in this strain. Given that we have also recently derived from the SHR a rat strain that develops spontaneous cardiac hypertrophy in the absence of hypertension (the Hypertrophic Heart Rat HHR), we also took the opportunity to examine the sequence of its Fgf2 promoter and coding region. However, extensive sequence analysis of the promoter and coding regions of the SHR and HHR Fgf2 genes failed to reveal any nucleotide variations between strains. Thus, we conclude that variations in the nucleotide sequence of the promoter and coding region of the SHR Fgf2 gene do not play a role in the cardiac hypertrophy of the SHR and HHR strains.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-1992
DOI: 10.1097/00004872-199205000-00011
Abstract: To assess the feasibility and utility of a new method to identify factors associated with increased predisposition to high blood pressure in young people. Eight hundred and sixty-four people aged 16-24 years and their parents. Ladywell Medical Centre, Edinburgh, Scotland, UK. Blood pressure was measured in 864 young adults and in both of their parents. Four groups of approximately 50 offspring were selected from the corners of a scatter diagram, with offspring blood pressure scores on one axis and combined parental blood pressure scores on the other. Blood and urine s les were taken for biochemical and genetic analyses. Two groups of offspring had parents with high blood pressure and two groups had parents with low blood pressure. When parental blood pressure was low, comparison of offspring with high and low blood pressure revealed significantly higher mean body mass index in offspring with high blood pressure, but no significant elevation of biochemical or hormonal variables. When parental blood pressure was high, comparison of offspring with high and low blood pressure also revealed a significant difference in body mass index, but in addition, offspring with high blood pressure and high parental blood pressure had higher levels of angiotensinogen, cortisol and 18-OH corticosterone. Restriction fragment length polymorphism analysis revealed that 27% of offspring at the greatest genetic risk (high personal and parental blood pressure) were homozygous for the larger allele of the glucocorticoid receptor gene compared with only 9% of those at lowest genetic risk (low personal and parental blood pressure). The combined biochemical and genetic findings suggest that abnormalities of glucocorticoid metabolism and the renin-angiotensin system may help to explain genetic predisposition to high blood pressure. The new s ling method is practicable and could be applied to the investigation of other continuously distributed variables which show familial aggregation.
Publisher: Oxford University Press (OUP)
Date: 24-06-2011
Publisher: Portland Press Ltd.
Date: 06-1999
DOI: 10.1042/CS19990005
Publisher: American Diabetes Association
Date: 12-07-2014
DOI: 10.2337/DC14-0199
Abstract: There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P & 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05–2.55) and 3.31 (1.57–6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P & 0.001 2.70 [1.65–4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P & 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.
Publisher: American Diabetes Association
Date: 10-04-2014
DOI: 10.2337/DC13-2727
Abstract: Moderate alcohol consumption has been associated with a reduced risk of mortality and coronary artery disease. The relationship between cardiovascular health and alcohol use in type 2 diabetes is less clear. The current study assesses the effects of alcohol use among participants in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation (ADVANCE) trial. The effects of alcohol use were explored using Cox regression models, adjusted for potential confounders. The study end points were cardiovascular events (cardiovascular death, myocardial infarction, and stroke), microvascular complications (new or worsening nephropathy or retinopathy), and all-cause mortality. During a median of 5 years of follow-up, 1,031 (9%) patients died, 1,147 (10%) experienced a cardiovascular event, and 1,136 (10%) experienced a microvascular complication. Compared with patients who reported no alcohol consumption, those who reported moderate consumption had fewer cardiovascular events (adjusted hazard ratio [aHR] 0.83 95% CI 0.72–0.95 P = 0.008), less microvascular complications (aHR 0.85 95% CI 0.73–0.99 P = 0.03), and lower all-cause mortality (aHR 0.87 96% CI 0.75–1.00 P = 0.05). The benefits were particularly evident in participants who drank predominantly wine (cardiovascular events aHR 0.78, 95% CI 0.63–0.95, P = 0.01 all-cause mortality aHR 0.77, 95% CI 0.62–0.95, P = 0.02). Compared with patients who reported no alcohol consumption, those who reported heavy consumption had dose-dependent higher risks of cardiovascular events and all-cause mortality. In patients with type 2 diabetes, moderate alcohol use, particularly wine consumption, is associated with reduced risks of cardiovascular events and all-cause mortality.
Publisher: Wiley
Date: 15-01-2014
DOI: 10.1111/JCH.12245
Publisher: Wiley
Date: 27-02-2008
DOI: 10.1111/J.1440-1681.2008.04880.X
Abstract: 1. The search for DNA sequence variants for complex human polygenic conditions has been a strong focus of recent genetic research. While gene loci have been identified, few variants in the coding sequences of these genes have been found, suggesting that non-coding sequence variation may underlie many complex conditions. 2. Non-coding DNA harbours regulatory elements capable of making changes to gene expression. However, regulatory DNA sequences are currently difficult to recognize and their function is poorly understood, complicating the task of assigning potential functional significance to non-coding variation. 3. Comparative genomics, the study of evolutionary DNA conservation, has enabled the emergent field of non-coding DNA identification in human disease analysis. 4. This brief review will focus on the potential of a relatively high throughput technique based on comparative genomics, that may aid in the identification of functionally important non-coding sequence variation in complex diseases.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.ARTERI.2013.11.008
Abstract: The present document has been prepared by a group of experts, members of Cardiology, Endocrinology, Internal Medicine, Nephrology and Diabetes societies of Latin American countries, to serve as a guide to physicians taking care of patients with diabetes, hypertension and comorbidities or complications of both conditions. Although the concept of metabolic syndrome is currently disputed, the higher prevalence in Latin America of that cluster of metabolic alterations has suggested that metabolic syndrome is useful nosography entity in the context of Latin American medicine. Therefore, in the present document, particular attention is paid to this syndrome in order to alert physicians on a particular high- risk population, usually underestimated and undertreated. These recommendations results from presentation and debates by discussion panels during a 2-day conference held in Bucaramanga, in October 2012, and all the participants have approved the final conclusions. The authors acknowledge that the publication and diffusion of guidelines do not suffice to achieve the recommended changes in diagnostic or therapeutic strategies, and plan suitable interventions overcoming both physicians and patients from effectively adhering to guideline recommendations.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1999
DOI: 10.1097/00004872-199917100-00010
Abstract: Endothelial nitric oxide exerts important effects on the regulation of vascular tone and structure. Variants of the endothelial nitric oxide synthase gene (eNOS) have been associated with hypertension and myocardial infarction, although some reports have shown negative linkage with hypertension. To examine whether the region encoding the eNOS gene is linked with physiological blood pressure variation, we undertook a linkage analysis of this region in the general population. In healthy volunteer families, we used two independent quantitative linkage analyses to examine the relationship between genotypes and phenotypes, with both parametric and non-parametric and single-locus and multi-point methods. We selected 260 families comprising mother and father (aged 40-70 years) and two natural offspring (aged 18-30 years) from the Victorian Family Heart Study. After standardized measurement of clinical data and extraction of DNA, all family members were genotyped at five microsatellite loci including the CA repeat in the eNOS gene by a PCR method. The quantitative linkage analyses were conducted according to two different analysis programs, the Genetic Analysis System (GAS) and the MAPMAKER/SIBS. With both linkage analyses, we found no linkage between any of the loci on chromosome 7q35-36 and the phenotypes systolic and diastolic blood pressure, mean arterial pressure, pulse pressure, pulse rate, weight, height and body mass index. Based on these results, we conclude that in this population the eNOS gene is not linked to the physiological variation of blood pressure and other related phenotypes.
Publisher: Elsevier BV
Date: 03-2001
DOI: 10.1046/J.1523-1747.2001.01261.X
Abstract: The common heritable loss of scalp hair known as male pattern baldness or androgenetic alopecia affects up to 80% of males by age 80. A balding scalp is characterized by high levels of the potent androgen dihydrotestosterone and increased expression of the androgen receptor gene. To determine if the androgen receptor gene is associated with male pattern baldness, we compared allele frequencies of the androgen receptor gene polymorphisms (StuI restriction fragment length polymorphism and two triplet repeat polymorphisms) in cases with cosmetically significant baldness (54 young and 392 older men) and controls (107 older men) with no indication of baldness. The androgen receptor gene StuI restriction site was found in all but one (98.1%) of the 54 young bald men (p = 0.0005) and in 92.3% of older balding men (p = 0.000004) but in only 76.6% of nonbald men. The combination of shorter CAG and GGC triplet repeat lengths was also more prevalent in bald men (p = 0.03). The ubiquity of the androgen receptor gene StuI restriction site, and higher incidence of shorter triplet repeat haplotypes in bald men suggests that these markers are very close to a functional variant that is a necessary component of the polygenic determination of male pattern baldness. Functional mutation in or near the androgen receptor gene may explain the reported high levels of expression of this gene in the balding scalp.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 05-2002
DOI: 10.1161/01.ATV.0000016258.40568.F1
Abstract: A positive family history is a recognized cardiovascular risk factor, and genome-wide scans may reveal susceptibility loci for coronary artery disease. The acute coronary syndrome, consisting of myocardial infarction and unstable angina, is the most important manifestation of coronary disease and is characterized by atherosclerotic plaque disruption and coronary thrombosis. From ≈6000 hospital admissions to cardiology units, we identified affected sibling pairs (n=61) who had documented acute coronary syndrome before the age of 70 years. A 10-cM resolution genetic map and MAPMAKER/SIBS were used for genome-wide linkage analysis. One locus on chromosome 2q36-q37.3 showed linkage with a lod score of 2.63 ( P .0001). Separate multipoint fine-mapping of this locus with independent markers replicated the linkage results (lod 2.64). Two other regions on chromosomes 3q26-q27 and 20q11-q13 showed lod scores in excess of 1.5 ( P .005). This genome scan in acute coronary syndrome suggests 1 locus that encompasses the gene encoding the insulin receptor substrate-1 gene. Two other potential loci were identified. These data imply that a limited number of potent susceptibility genes exist for the acute coronary syndrome. Such genes are likely to be relevant to the combined processes of atherosclerosis, plaque instability, and coronary thrombosis.
Publisher: Elsevier BV
Date: 10-2012
DOI: 10.1016/J.DIABRES.2012.05.002
Abstract: To asses differences in treatment effects of a fixed combination of perindopril-indapamide on major clinical outcomes in patients with type 2 diabetes across subgroups of cardiovascular risk. 11,140 participants with type 2 diabetes, from the ADVANCE trial, were randomized to perindopril-indapamide or matching placebo. The Framingham equation was used to calculate 5-year CVD risk and to ide participants into two risk groups, moderate-high risk ( 25% and/or history of macrovascular disease). Endpoints were macrovascular and microvascular events. The mean age of participants was 66 years (42.5% female). 1000 macrovascular and 916 microvascular events were recorded over follow-up of 4.3 years. Relative treatment effects were similar across risk groups, (all P-values for heterogeneity ≥0.38). Hazard ratios for combined macro- and microvascular events were 0.89 (0.77-1.03) for the moderate-high risk and 0.92 (0.81-1.03) for the very high risk. Absolute treatment effects tended to be greater in the high risk groups although differences were not statistically significant (P>0.05). Relative effects of blood pressure lowering with perindopril-indapamide on cardiovascular outcomes were similar across risk groups whilst absolute effects trended to be greater in the high risk group.
Publisher: Wiley
Date: 05-07-2010
DOI: 10.1111/J.1464-5491.2010.03080.X
Abstract: We investigated the association between alcohol consumption and diabetic retinopathy and deterioration of visual acuity in in iduals with Type 2 diabetes. We conducted a cohort analysis of 1239 participants with Type 2 diabetes aged 55-81 years enrolled in the AdRem study, a sub-study of the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial. Current and past consumption of wine, spirits and beer was measured by self-report. Moderate and heavy alcohol consumption was defined as 1-14 and >14 drinks/week, respectively. Diabetic retinopathy, measured by mydriatic stereoscopic seven-field retinal photography, was defined by a 2-step progression in the Early Treatment of Diabetic Retinopathy Study (ETDRS) score or the presence of any retinal vascular lesions. Deterioration of visual acuity was defined by a decrease of two lines in best vision in either eye, measured corrected, or through a pinhole using a Snellen chart. In a mean follow-up of 5.5 years, we identified 182 participants with a 2-step progression in the ETDRS score, 640 participants with the presence of any retinal vascular lesions and 693 participants with a deterioration of visual acuity. Current moderate consumption of alcohol, compared with no current consumption, was not associated with presence or progression of diabetic retinopathy however, it was associated with higher risk of deterioration of visual acuity (multivariable-adjusted OR 1.83 95% CI 1.34-2.48 P<0.001). Alcohol consumption is associated with increased risk of deterioration of visual acuity, but not with retinopathy in in iduals with Type 2 diabetes.
Publisher: Portland Press Ltd.
Date: 12-09-2013
DOI: 10.1042/CS20120269
Abstract: The RAS (renin–angiotensin system) plays an important role in the pathophysiology of CVD (cardiovascular disease), and RAS blockade is an important therapeutic strategy in the management of CVD. A new counterbalancing arm of the RAS is now known to exist in which ACE (angiotensin-converting enzyme) 2 degrades Ang (angiotensin) II, the main effector of the classic RAS, and generates Ang-(1–7). Altered ACE2 expression is associated with cardiac and vascular disease in experimental models of CVD, and ACE2 is increased in failing human hearts and atherosclerotic vessels. In man, circulating ACE2 activity increases with coronary heart disease, as well as heart failure, and a large proportion of the variation in plasma ACE2 levels has been attributed to hereditary factors. The ACE2 gene maps to chromosome Xp22 and this paper reviews the evidence associating ACE2 gene variation with CVD and considers clues to potential functional ACE2 variants that may alter gene expression or transcriptional activity. Studies to date have investigated ACE2 gene associations in hypertension, left ventricular hypertrophy and coronary artery disease, but the results have been inconsistent. The discrepancies may reflect the s le size of the studies, the gender or ethnicity of subjects, the cardiovascular phenotype or the ACE2 SNP investigated. The frequent observation of apparent sex-dependence might be of special importance, if confirmed. As yet, there are no studies to concurrently assess ACE2 gene polymorphisms and circulating ACE2 activity. Large-scale carefully conducted clinical studies are urgently needed to clarify more precisely the potential role of ACE2 in the CVD continuum.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
DOI: 10.1097/00004872-200406000-00013
Abstract: There is mounting physiological evidence for an important role of the oestrogen receptors, ERalpha and ERbeta, in vasodilatation and the response to vascular injury. In addition, genetic studies have suggested that the genes encoding these receptors may be involved in the genetic regulation of blood pressure. The existence of such sex steroid-related genes may help to explain the observed sex differences in blood pressure. To investigate the role of the oestrogen receptor genes (ERalpha and ERbeta) in blood pressure variation in women and in men. We performed a genetic association study of the oestrogen receptor genes in 718 unrelated healthy white in iduals (386 men and 332 women) from the parental generation of the Victorian Family Heart Study, a general population survey of cardiovascular risk. Participants were genotyped for single nucleotide polymorphisms (SNPs) in ERalpha and ERbeta, and blood pressure phenotypes were compared between genotype groups by analysis of variance. When genotype groups were compared, men inheriting the 'a' allele of the ERalpha SNP had significantly higher systolic blood pressure than men with other genotypes [127.7 +/-14.3 mmHg (mean +/- SD) compared with 132.4 +/- 16.1 mmHg P = 0.014)]. In addition, men inheriting the 'b' allele of the ERbeta SNP had significantly higher diastolic blood pressure than men with other genotypes (81.4 +/-8.1 mmHg compared with 84.4 +/- 9.6 mmHg P = 0.004). No significant associations between the oestrogen receptor genes and blood pressure were detected in women. These results suggest that ERalpha and ERbeta may be involved in the genetic regulation of blood pressure in men, that the two genes may have different roles, and that these genes may contribute to the differences in blood pressures between the sexes.
Publisher: Portland Press Ltd.
Date: 04-2001
DOI: 10.1042/CS20000203
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2011
Publisher: Informa UK Limited
Date: 2015
DOI: 10.2147/MDER.S76409
Publisher: Springer Science and Business Media LLC
Date: 10-1997
Abstract: Inflammatory cytokines, cell adhesion molecules, and toll-like receptors (TLRs) play an important role in atherosclerosis. The aim of this study was to further evaluate the role of inflammatory cytokines, cell adhesion molecules, and toll-like receptors in atherosclerosis. Forty local breed domestic male rabbits were ided randomly into 4 groups, 10 rabbits each. Group I was the control group, group II received a high cholesterol diet, group III received the drug solvent dimethyl sulfoxide (DMSO), and group IV received Atorvastatin (3.5 mg/kg/day). Blood s les were collected at 0 times, 5 weeks, and at the end of 10 weeks. TLRs expression on monocyte was measured by flow cytometry, IL-10, IL-17, IL-1β, intracellular adhesion molecule (ICAM), and vascular cell adhesion molecule (VCAM) were measured by ELISA. In group II, a high cholesterol diet led to a statistically significant elevation of lipids profile (TC, TG, and LDL) at both 5 weeks and 10 weeks compared to the control. The expression of TLRs was also increased compared to the control (13.53±2.5 to 25.79±6.5). The intimal thickness increased from 103.46±13.85 to 248.43±11.11. IL-17 increased significantly from 3.4±0.4 to 7.7±1.00, and IL-1β increased from 1.04±0.19 to 9.66±1.4 (P 0.05) at 10 weeks. ICAM and VCAM increased from 1.7±0.16 to 8.2±0.74 and from 0.89±0.07 to 5.2±0.45, respectively. Atorvastatin significantly reduced TLRs at 10 weeks to 21.98±3.4 and intimal thickness to 191.6±15.59. IL-17, IL-1β, ICAM, and VCAM were significantly reduced by Atorvastatin. Cytokines, cellular adhesion molecules, and probably TLRs have a role in the pathogenesis of hyperlipidemia and atherosclerosis.
Publisher: Elsevier BV
Date: 11-2010
Publisher: Portland Press Ltd.
Date: 07-2001
DOI: 10.1042/CS20000294
Publisher: Oxford University Press (OUP)
Date: 15-10-2000
Abstract: The Victorian Family Heart Study was established to address the causes of familial patterns in cardiovascular risk factors. From 1990 to 1996, a representative population s le of 783 adult families (2,959 in iduals), each comprising both parents (40-70 years) and at least one natural adult offspring (18-30 years), was recruited in Melbourne, Australia. Included in both generations were 461 monozygotic and dizygotic twins as pairs or singletons. A multivariate normal model was used for pedigree analysis of height, weight, body mass index, diastolic and systolic blood pressure, pulse rate, and total and high density lipoprotein cholesterol. All traits showed evidence for additive genetic variation, explaining from 55% (height) to 26% (pulse) of age- and sex-adjusted variance. An effect persisting into adulthood of shared family environment during cohabitation explained from 39% (body mass index) to 13% (systolic blood pressure) of variance (not nominally significant for diastolic blood pressure). These shared environmental effects were strongest within twin pairs, less so for sibling pairs, and least for parent-offspring pairs (in which an effect was not observed for weight, diastolic and systolic blood pressure, and total cholesterol). On a background of genetic influences, there are periods in early life during which the family environment cements long-term correlations between adult relatives in cardiovascular risk factors.
Publisher: Massachusetts Medical Society
Date: 09-10-2014
Publisher: Springer Science and Business Media LLC
Date: 20-12-2000
DOI: 10.1007/S00439-006-0305-Z
Abstract: There have been a number of genome-wide linkage studies for adult height in recent years. These studies have yielded few well-replicated loci, and none have been further confirmed by the identification of associated gene variants. The inconsistent results may be attributable to the fact that few studies have combined accurate phenotype measures with informative statistical modelling in healthy populations. We have performed a multi-stage genome-wide linkage analysis for height in 275 adult sibling pairs drawn randomly from the Victorian Family Heart Study (VFHS), a healthy population-based Caucasian cohort. Height was carefully measured in a standardised fashion on regularly calibrated equipment. Following genome-wide identification of a peak Z-score of 3.14 on chromosome 3 at 69 cM, we performed a fine-mapping analysis of this region in an extended s le of 392 two-generation families. We used a number of variance components models that incorporated assortative mating and shared environment effects, and we observed a peak LOD score of approximately 3.5 at 78 cM in four of the five models tested. We also demonstrated that the most prevalent model in the literature gave the worst fit, and the lowest LOD score (2.9) demonstrating the importance of appropriate modelling. The region identified in this study replicates the results of other genome-wide scans of height and bone-related phenotypes, strongly suggesting the presence of a gene important in bone growth on chromosome 3p. Association analyses of relevant candidate genes should identify the genetic variants responsible for the chromosome 3p linkage signal in our population.
Publisher: American Diabetes Association
Date: 13-02-2014
DOI: 10.2337/DB12-1625
Abstract: C-reactive protein (CRP), fibrinogen, and interleukin-6 (IL-6) are associated with cardiovascular disease (CVD) and death in general populations. However, studies of these factors in type 2 diabetes are limited. We studied their associations with the risk of major macrovascular events, microvascular complications, and mortality in patients with type 2 diabetes who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) Study. Plasma CRP, fibrinogen, and IL-6 levels were determined in a case-cohort study (n = 3,865) nested within the 11,140 men and women with type 2 diabetes and baseline CVD or risk factors in the ADVANCE Study. All three biomarkers of inflammation were associated with an increased risk of macrovascular events and death in analyses adjusted for age, sex, and treatment groups. After further adjustment, only IL-6 was an independent predictor of macrovascular events (hazard ratio per SD increase 1.37 [95% CI 1.24–1.51]) and death (1.35 [1.23–1.49]). IL-6 significantly improved the prediction of macrovascular events and death. After adjustment, none of the markers predicted microvascular complications. We conclude that IL-6 levels, but not CRP or fibrinogen levels, add significantly to the prediction of macrovascular events and mortality in in iduals with type 2 diabetes who have baseline CVD or risk factors.
Publisher: Informa UK Limited
Date: 2004
DOI: 10.1080/08037050410029605
Abstract: Analyses of the risks of stroke were conducted for subjects with and without diabetes, participating in a randomized, double-blind, placebo-controlled trial of a perindopril-based blood pressure lowering regimen in 6105 people with prior stroke or transient ischaemic attack (TIA), followed for a median of 3.9 years. Seven hundred and sixty-one patients had diabetes at baseline. Diabetes increased the risk of recurrent stroke by 35% (95% CI 10-65%) principally through an effect on ischaemic stroke (1.53, 95% CI 1.23-1.90). Active treatment reduced blood pressure by 9.5/4.6 mmHg in patients with diabetes and by 8.9/3.9 mmHg in patients without diabetes. The proportional risk reductions achieved for stroke in patients with diabetes, 38% (95% CI 8-58%), and patients without diabetes, 28% (95% CI 16-39%), were not significantly different (p homogeneity = 0.5). The absolute reduction in the risk of recurrent stroke in the patients with diabetes was equivalent to one stroke avoided among every 16 (95% CI 9-111) patients treated for 5 years. Diabetes is an important risk factor for stroke in patients with established cerebrovascular disease. Treatment with the ACE inhibitor perindopril with discretionary use of the diuretic indapamide produced reductions in the risk of recurrent stroke in patients with diabetes that were at least as great as those achieved in patients without diabetes.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.PUPT.2005.02.010
Abstract: We have previously reported a quantitative trait locus (QTL) on rat chromosome 2 that influences heart size independently of blood pressure (Left Ventricular Mass Locus 1 Lvm1). The recent release of the rat genome sequence allowed us to retest and refine this relatively broad QTL with a view to identifying within it candidate genes worthy of structural investigation. We sought to achieve this 'fine mapping' by increasing the marker density within the interval and undertaking a linkage analysis in a previously defined population of F2 hybrids generated from inbred spontaneously hypertensive rats (SHR) of the Okamoto strain and Fischer rat (F344) progenitors. We were able to reconfirm and resolve Lvm1 from its original width of approximately 45 to 15 cM. By reference to the ENSEBL rat genome data bank, we identified within Lvm1 27 known genes, 109 predicted genes and 7 pseudogenes. Of the known genes, candidates include potential regulators of cardiac growth, a sodium channel and calcium channel as well as the fibroblast growth factor 2 gene. Located nearby the Lvm1 locus was the gene for the angiotensin Type 1B receptor. Given the evidence that the ligand for the angiotensin Type 1B receptor-angiotensin II-is a potent cardiotroph, we also consider this gene a potential candidate. The identification of the precise allelic variant(s) within Lvm1 involved in the control of pressure-independent cardiac growth awaits further molecular studies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2008
Publisher: Public Library of Science (PLoS)
Date: 23-02-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-1998
DOI: 10.1097/00004872-199816080-00010
Abstract: To investigate the role of the renin gene in the hypertension of the spontaneously hypertensive rat (SHR) of the Okamoto strain. We determined whether the SHR renin allele was cosegregated with high blood pressure in 137 F2 rats derived from inbred SHR and Wistar-Kyoto rats. Systolic blood pressure in conscious rats was measured by the tail-cuff method, whereas mean arterial pressure was determined from an indwelling catheter in the left carotid artery. Renin genotypes of F2 rats were determined using a SHR-specific Bg/II restriction fragment length polymorphism that we have previously described. The SHR renin allele was cosegregated significantly with higher systolic blood pressure in male F2 rats aged 8-24 weeks and in females aged 12-24 weeks. The greatest differences in blood pressure between SHR renin allele homozygotes and Wistar-Kyoto rat renin allele homozygotes were 35 mmHg for males and 17 mmHg for females aged 24 weeks. The SHR renin allele was also associated with a higher mean arterial pressure in rats aged 24 weeks and cosegregated with higher body weight of male F2 rats aged 12-24 weeks but not with that of the females. In contrast to the relationship with blood pressure, the SHR renin allele was segregated with lower plasma renin concentrations in rats aged 24 weeks. These results are consistent with the SHR renin gene being one of the loci determining high blood pressure in rats of this strain, possibly through action at some extra-renal site subserving control of blood pressure.
Publisher: Japanese Society of Hypertension
Date: 2008
Abstract: The hypertrophic heart rat (HHR) was derived from the spontaneously hypertensive rat of the Okamoto strain and develops cardiac hypertrophy in the absence of hypertension. The genetic basis of this hypertrophy is unknown. Therefore, we compared gene expression profiles in the left ventricular myocardium of young (8-10 weeks of age) and old (38-50 weeks) HHR with rats from an age-matched control strain, the normal heart rat (NHR). cDNA microarrays (National Institute of Aging [NIA], 15,247 clones) were used to evaluate gene expression in cardiac-derived Cy3 and Cy5 labeled cDNA. M values (log2[Cy5/Cy3]) were obtained and significant differential expression was identified using an empirical Bayesian approach with specific results verified using real-time PCR. Compared with NHR, HHR cardiac weight index (heart weight/ body weight) was significantly elevated at both ages (young: 5.5 +/- 0.5 vs. 3.9 +/- 0.2 old: 4.2 +/- 0.3 vs. 3.4 +/- 0.2 mg/g p < 0.05) with no difference in body weight or in tail-cuff blood pressure detected between the strains at either age. Differential expression was observed in 65 and 390 clones in young and old HHR, respectively, with more genes exhibiting down-regulation than up-regulation in both instances (young: down 44 vs. up 21 old: down 292 vs. up 98). Our data suggest a role for the Ras/mitogen-activated protein kinase (MAPK) signaling pathway and the tumor necrosis factor (TNF) receptor-mediated activation of nuclear factor-kappaB (NF-kappaB) in the etiology of cardiac enlargement in the HHR. These findings support the candidature of previously identified cardiotrophic agents in contributing to the cardiac enlargement in the normotensive HHR, and also identify novel genetic factors which may be involved in the genesis of primary cardiac hypertrophy.
Publisher: Elsevier BV
Date: 2001
Publisher: Elsevier BV
Date: 06-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2002
DOI: 10.1161/01.HYP.0000022693.11752.E9
Abstract: The correlations between systolic blood pressure (SBP) and diastolic blood pressure (DBP), and between SBP and body mass index (BMI), might result from genetic or environmental factors that determine variation in 2 or more phenotypes and are shared by family members. In 767 adult nuclear families (n=2912 in iduals, including 66 pairs of monozygotic twins and 84 pairs of dizygotic twins), we used a multivariate normal model and the software FISHER to estimate genetic and environmental components of variation and covariation. Mean phenotypes were adjusted for age, gender, and generation, and for antihypertensive treatment. Genetic and shared family environmental factors accounted for 46% and 31% of total variance in SBP, respectively. Adjustment of SBP for DBP reduced considerably both the additive genetic (86.7 to 21.0) and shared environmental (59.7 to 21.0) components of variance. Smaller reductions in genetic (86.7 to 84.9) and shared environmental (59.7 to 51.1) components were observed after adjustment of SBP for BMI. For SBP and DBP, the correlation between the effects of genes was 1.00 and between shared environmental effects was 0.52. For SBP and BMI the correlations were 0.30 for genetic and 0.22 for shared environmental effects. Our findings suggest that the same genes and many of the same family environmental factors determine variation in both SBP and DBP. In contrast, SBP and BMI share genetic and family environmental determinants to a lesser degree. These observations are relevant to multifactorial cardiovascular risk reduction based on genetic and family environmental approaches.
Publisher: Elsevier BV
Date: 07-1994
Publisher: Elsevier BV
Date: 11-1995
DOI: 10.1016/S0140-6736(95)91863-9
Abstract: Asthma is a manifestation of bronchial hyperreactivity (BHR) and forms part of the spectrum of atopic disease. Some pedigree studies of atopy have suggested linkage with the high-affinity IgE receptor (Fc epsilon RI beta) gene on chromosome 11q13, but others find no linkage. The molecular genetics of asthma and BHR have not been studied in the general population. We examined the genetic linkage of the Fc epsilon RI beta gene with clinical asthma and the underlying phenotypes of BHR (to methacholine) and atopy (defined by skinprick testing) in 123 affected sibling-pairs recruited from the general population. We found evidence of significant linkage of a highly polymorphic microsatellite marker in the fifth intron of the Fc epsilon RI beta gene to a diagnosis of asthma (18.0% excess of shared alleles, p = 0.002) and to BHR (21.7% excess of shared alleles, p = 0.001). Significant linkage was also observed in siblings sharing BHR when those with atopy were excluded (32.8% excess of shared alleles, p = 0.004). Atopy in the absence of BHR did not show significant linkage to the Fc epsilon RI beta gene (7.2% excess of shared alleles, p = 0.124). These findings suggest that mutations in the Fc epsilon RI beta gene or a closely linked gene influence the BHR underlying asthma, even in the absence of atopy.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2014
DOI: 10.1007/S00125-014-3369-7
Abstract: Data are inconsistent regarding the associations between age, age at diagnosis of diabetes, diabetes duration and subsequent vascular complications. The associations between age (or age at diagnosis), diabetes duration and major macrovascular events, all-cause death and major microvascular events were examined in 11,140 patients with type 2 diabetes randomly allocated to intensive or standard glucose control in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Rates were calculated by 5 year baseline age (or age at diagnosis) and diabetes duration strata. Risks were estimated using Cox models adjusted for treatment assignment and HbA1c. The mean age (±SD) was 65.8 ± 6.4 years, age at diagnosis was 57.8 ± 8.7 years and diabetes duration was 7.9 ± 6.4 years. Diabetes duration was associated with the risk of macrovascular events (HR 1.13 [95% CI 1.08, 1.17]), microvascular events (1.28 [1.23, 1.33]) and death (1.15 [1.10, 1.20]) whereas age (or age at diagnosis) was only associated with the risk of macrovascular events (1.33 [1.27, 1.39]) and death (1.56 [1.48, 1.64]). No interaction was observed between diabetes duration, age and the risk of macrovascular events or death (both p > 0.4). However, an interaction was observed between diabetes duration, age and the risk of microvascular events (p = 0.002), such that the effects of increasing diabetes duration were greatest at younger rather than older age. In patients with type 2 diabetes, age or age at diagnosis and diabetes duration are independently associated with macrovascular events and death whereas only diabetes duration is independently associated with microvascular events and this effect is greater in the youngest patients.
Publisher: Portland Press Ltd.
Date: 02-03-2009
DOI: 10.1042/CS20080142
Abstract: The aim of the present study was to undertake a longitudinal study of systolic and diastolic cardiac function during normal pregnancy. At a median of 16 weeks of gestation, 100 primiparous women underwent echocardiography, including tissue Doppler imaging, determining left ventricular mass, cardiac output, systolic and diastolic velocities, and wall stress. A total of 32 were assessed again at a median of 37 weeks of gestation. Non-pregnant control estimates (n=9) were obtained by averaging four separate measures over two menstrual cycles. Initially, the pregnant women had significantly higher pulse rates than controls, associated with greater ventricular wall stress (two-tailed P value=0.015), and systolic (two-tailed P value=0.005) and diastolic (two-tailed P value=0.018) lateral wall myocardial velocities, but no differences in systolic blood pressure, left ventricular mass or cardiac output. By 37 weeks of gestation, increased blood pressure (two-tailed P value & .001) and left ventricular mass (two-tailed P value=0.002) were associated with a significant increase in ventricular wall stress (two-tailed P value & .001), and reductions in septal systolic (two-tailed P value=0.004) and septal and lateral early diastolic (two-tailed P value & .001) myocardial velocities. The diastolic velocities at 37 weeks correlated inversely with maternal weight and age. In conclusion, by term pregnancy, an increase in ventricular wall stress is accompanied by a deterioration in cardiac function.
Publisher: Elsevier BV
Date: 03-2009
Publisher: Oxford University Press (OUP)
Date: 05-03-2012
Publisher: Wiley
Date: 07-09-2010
DOI: 10.1111/J.1600-0625.2010.01132.X
Abstract: The gene encoding the androgen receptor (AR) is associated with male pattern baldness (androgenetic alopecia - AGA). In case-control and family analyses, we mapped AR and the adjacent intergenic regions. We found evidence for association with two independent loci, one upstream and previously described and the other downstream and apparently novel. The haplotype comprising these SNPs was strongly associated with AGA (P = 3.75 × 10(-5)) in 1195 men. We also replicated association with a recently reported non-coding region on chromosome 20 and found that its association with AGA was less strong and independent of that of AR. Our results will help focus future efforts to further define AGA genetic risk.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2003
DOI: 10.1161/01.HYP.0000088322.85804.96
Abstract: The insertion/deletion ( I/D ) polymorphism of the angiotensin-converting enzyme (ACE) gene might have consequences for the risks of vascular diseases. We examined the ACE genotype and the effects of a perindopril-based blood pressure-lowering regimen on macrovascular events, dementia, and cognitive decline among hypertensive and nonhypertensive patients with a history of cerebrovascular disease. ACE I/D genotypes were measured in 5688 of 6105 in iduals with previous stroke or transient ischemic attack who participated in the PROGRESS trial. The DD genotype was significantly ( P .0001) less frequent in Asian subjects (Chinese and Japanese, 14.7%) than in non-Asian subjects (32.0%). Controlling for racial background, there were no associations between ACE genotypes and cerebrovascular disease history or cardiovascular risk factors, including baseline blood pressure. The ACE genotype was not associated with the long-term risks of stroke, cardiac events, mortality, dementia, or cognitive decline neither did the ACE genotype predict the blood pressure reduction associated with the use of the ACE inhibitor perindopril. Similarly, there was no evidence that the ACE genotype modified the relative benefits of ACE inhibitor-based therapy over placebo. This study provides no evidence that in patients with cerebrovascular disease, knowledge of ACE genotype is useful for predicting either the risk of disease or the benefits of perindopril-based blood pressure-lowering treatment.
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1016/J.DIABRES.2010.05.012
Abstract: The aim of these analyses was to examine the efficacy of the intensive gliclazide MR-based glucose lowering regimen used in the ADVANCE trial in lowering the level of glycated haemoglobin (HbA1c). All 11,140 randomised patients were included in analyses of treatment efficacy. Treatment efficacy was also examined in subgroups defined by baseline characteristics and treatments. At the end of 5 years follow-up, the mean HbA1c was reduced from 7.5% at baseline to 6.5% in those on intensive glucose control and to 7.3% in those on standard glucose control. With intensive glucose lowering greater proportions achieved HbA1c levels of < or =7.0%, < or =6.5% and < or =6.0%. With intensive glucose lowering substantial reductions in HbA1c were observed across subgroups defined by baseline age, sex, duration of diabetes, BMI, HbA1c or treatment regimen (p<0.0001). The main independent predictors of reduction in HbA1c during follow-up were baseline HbA1c, duration of diabetes and BMI. There was no weight gain in the intensive glucose control group and severe hypoglycaemia was uncommon, though more frequent than in the standard control group. Intensive glucose control with a gliclazide MR-based regimen was well tolerated and consistently effective in lowering HbA1c across a broad range of patient with type 2 diabetes.
Publisher: Wiley
Date: 17-12-2014
DOI: 10.1111/JCH.12237
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2009
DOI: 10.1161/HYPERTENSIONAHA.108.128488
Abstract: Autophagy has emerged as an important process in the pathogenesis of cardiovascular diseases, but the proximal triggers for autophagy are unknown. Angiotensin II plays a central role in the pathogenesis of cardiac hypertrophy and heart failure. In this study, we used angiotensin II type 1 (AT 1 ) and type 2 (AT 2 ) receptor–expressing adenoviruses in cultured neonatal cardiomyocytes to provide the first demonstration that neonatal cardiomyocyte autophagic activity is differentially modulated by AT 1 and AT 2 receptor subtypes. Angiotensin II stimulation (48 hours) of neonatal cardiomyocytes expressing the AT 1 receptor alone (Ad-AT 1 10 multiplicities of infection) induced a significant increase in the number of HcRed-LC3 autophagosomes per cell (17.3±1.6 versus 33.3±4.1 autophagosomes per cell P .05). Coexpression of a high ratio of AT 2 :AT 1 (Ad-AT 2 :Ad-AT 1 multiplicity of infection ratio: 20:5) receptors completely abrogated the AT 1 -mediated increase in autophagy (9.3±1.4 versus 33.3±4.1 autophagosomes per cell P .05). Treatment with the AT 2 receptor antagonist PD123319 did not reverse the AT 2 -mediated antiautophagic effect. AT 1 - and AT 2 -mediated autophagic responses were also assessed in cardiomyocytes from a genetic model that exhibits neonatal myocardial growth suppression. In these neonate myocyte cultures, AT 1 receptor activation induced a marked increase in the number of myocytes containing cytoplasmic vacuoles compared with the control (22.7±4.1% versus 1.1±0.6% P .001) and was characterized by a nonapoptotic autophagic phenotype. The incidence of cardiomyocyte autophagic vacuolization in this myocyte population decreased dramatically to only 0.4±0.2% in myocytes infected with a high ratio of Ad-AT 2 :Ad-AT 1 . This study provides the first description of reciprocal regulation of cardiomyocyte autophagic induction by the AT 1 and AT 2 receptor subtypes.
Publisher: Springer Science and Business Media LLC
Date: 09-2001
Abstract: Patients with Type II (non-insulin-dependent) diabetes mellitus are at increased risk of macrovascular and microvascular disease, both of which are reduced by controlling raised blood pressure in hypertensive patients. Intensive glycaemic control has also been shown to reduce microvascular disease but the effects on macrovascular disease remain uncertain. This study will examine the hypotheses that lowering blood pressure with an ACE inhibitor-diuretic combination and intensively controlling gylcaemia with a sulphonylurea-based regimen in high-risk patients with Type II diabetes (both hypertensive and non-hypertensive) reduces the incidence of macrovascular and microvascular disease. The study is a 2 x 2 factorial randomised controlled trial that will include 10000 adults with Type II diabetes at high risk of vascular disease. Following 6 weeks on open label perindopril-indapamide combination, eligible patients are randomised to continued perindopril-indapamide or matching placebo, and to an intensive gliclazide MR-based glucose control regimen or usual guidelines-based therapy. Primary outcomes are, first, the composite of nonfatal stroke, non-fatal myocardial infarction or cardiovascular death and, second, the composite of new or worsening nephropathy or diabetic eye disease. The scheduled average duration of treatment and follow-up is 4.5 years. The study will be conducted in approximately 200 centres in Australasia, Asia, Europe and North America. ADVANCE is designed to provide reliable evidence on the balance of benefits and risks conferred by blood pressure lowering therapy and intensive glucose control therapy in high-risk diabetic patients, regardless of initial blood pressure or glucose concentrations.
Publisher: Elsevier BV
Date: 09-2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2009
DOI: 10.1161/HYPERTENSIONAHA.109.133041
Abstract: The relative importance of various blood pressure indices on cardiovascular risk in people with type 2 diabetes mellitus has not been established. This study compares the strengths of the associations between different baseline blood pressure variables (systolic blood pressure [SBP], diastolic blood pressure [DBP], pulse pressure [PP], and mean arterial pressure) and the 4.3-year risk of major cardiovascular events in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. Mean (SD) age for the 11 140 participants was 65.8 years (6.4 years). During follow-up, 1000 major cardiovascular events, 559 major coronary events, and 468 cardiovascular deaths were recorded. After adjustment for age, sex, and treatment allocation, the hazard ratios (95% CIs) associated with 1 increment in SD for the risk of major cardiovascular events were 1.17 (1.10 to 1.24) for SBP 1.20 (1.13 to 1.28) for PP 1.12 (1.05 to 1.19) for mean arterial pressure and 1.04 (0.98 to 1.11) for DBP. The areas under the receiver operating characteristic curve were slightly higher for SBP and PP compared with mean arterial pressure and DBP for major cardiovascular and coronary events. Using achieved instead of baseline blood pressure values marginally improved the effect estimates for SBP, DBP, and mean arterial pressure, with no significant differences in the areas under the receiver operating characteristic curve between models with SBP and those with PP. In conclusion, SBP and PP are the 2 best and DBP is the least effective determinant of the risk of major cardiovascular outcomes in the relatively old patients with type 2 diabetes mellitus participating in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-Modified Release Controlled Evaluation Study. However, SBP may be the simplest and most useful predictor across a wider range of age groups and populations.
Publisher: Oxford University Press (OUP)
Date: 11-03-2009
Abstract: The aim of this study was to investigate serious clinical outcomes associated with atrial fibrillation (AF) and the effects of routine blood pressure lowering on such outcomes in the presence or absence of AF, among in iduals with type 2 diabetes. About 11 140 patients with type 2 diabetes (7.6% of whom had AF at baseline) were randomized to a fixed combination of perindopril and indapamide or placebo in the Action in Diabetes and Vascular Disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE) study. We compared total mortality and cardiovascular disease outcomes and effects of randomized treatment for 4.3 years on such outcomes between patients with and without AF at baseline. After multiple adjustments, AF was associated with a 61% (95% confidence interval 31-96, P < 0.0001) greater risk of all-cause mortality and comparable higher risks of cardiovascular death, stroke, and heart failure (all P < 0.001). Routine treatment with a fixed combination of perindopril and indapamide produced similar relative, but greater absolute, risk reductions for all-cause and cardiovascular mortalities in patients with AF, compared with those without AF. The number of patients needed to be treated with perindopril-indapamide for 5 years to prevent one cardiovascular death was 42 for patients with AF and 120 for patients without AF at baseline. Atrial fibrillation is relatively common in type 2 diabetes and is associated with substantially increased risks of death and cardiovascular events in patients with type 2 diabetes. This arrhythmia identifies in iduals who are likely to obtain greater absolute benefits from blood pressure-lowering treatment. Atrial fibrillation in diabetic patients should be regarded as a marker of particularly adverse outcome and prompt aggressive management of all risk factors.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2014
DOI: 10.1161/HYPERTENSIONAHA.113.02252
Abstract: The objective of the present analysis was to determine the effects of a fixed combination of perindopril and indapamide in combination with calcium channel blockers (CCBs) in patients with type 2 diabetes mellitus. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial was a factorial randomized controlled trial. A total of 11 140 patients with type 2 diabetes mellitus were randomly assigned to fixed combination of perindopril–indapamide (4/1.25 mg) or placebo. Effects of randomized treatment on mortality and major cardiovascular outcomes were examined in subgroups defined by baseline use of CCBs. Patients on CCB at baseline (n=3427) constituted a higher risk group compared with those not on CCB (n=7713), with more extensive use of antihypertensive and other protective therapies. Active treatment reduced the relative risk of death by 28% (95% confidence interval, 10%–43%) among patients with CCB at baseline compared with 5% (−12% to 20%) among those without CCB ( P homogeneity=0.02) and 14% (2%–25%) for the whole population. Similarly, the relative risk reduction for major cardiovascular events was 12% (−8% to 28%) versus 6% (−10% to 19%) for those with and without CCB at baseline although the difference was not statistically significant ( P homogeneity=0.38). There was no detectable increase in adverse effects in those receiving CCB. The combination of perindopril and indapamide with CCBs seems to provide further protection against mortality in patients with type 2 diabetes mellitus.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2011
Publisher: Springer Science and Business Media LLC
Date: 26-01-2007
DOI: 10.1007/S00439-006-0317-8
Abstract: Androgenetic alopecia, or male pattern baldness, is a complex condition with a strong heritable component. In 2001, we published the first significant evidence of a genetic association between baldness and a synonymous coding SNP (rs6152) in the androgen receptor gene, AR. Recently, this finding was replicated in three independent studies, confirming an important role for AR in the baldness phenotype. In one such replication study, it was claimed that the causative variant underlying the association was likely to be the polyglycine (GGN) repeat polymorphism, one of two apparently functional triplet repeat polymorphisms located in the exon 1 transactivating domain of the gene. Here, we extend our original association finding and present comprehensive evidence from approximately 1,200 fathers and sons drawn from 703 families of the Victorian Family Heart Study, a general population Caucasian cohort, that neither exon 1 triplet repeat polymorphism is causative in this condition. Seventy-eight percent of fathers (531/683) and 30% of sons (157/520) were affected to some degree with AGA. We utilised statistical methods appropriate for the categorical nature of the phenotype and familial structure of the cohort, and determined that whilst SNP rs6152 was strongly associated with baldness (P < 0.0001), the GGN triplet repeat was not (P = 0.13). In the absence of any other known common functional coding variants, we argue that the causative variant is likely to be in the non-coding region, and yet to be identified. The identification of functional non-coding variants surrounding AR may have significance not only for baldness, but also for the many other complex conditions that have thus far been linked to AR.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2010
Publisher: Springer Science and Business Media LLC
Date: 06-07-2021
DOI: 10.1007/S00125-021-05491-7
Abstract: Type 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction could lead to timely intervention and better outcomes. Genetic information can be used to enable early detection of risk. We developed a multi-polygenic risk score (multiPRS) that combines ten weighted PRSs (10 wPRS) composed of 598 SNPs associated with main risk factors and outcomes of type 2 diabetes, derived from summary statistics data of genome-wide association studies. The 10 wPRS, first principal component of ethnicity, sex, age at onset and diabetes duration were included into one logistic regression model to predict micro- and macrovascular outcomes in 4098 participants in the ADVANCE study and 17,604 in iduals with type 2 diabetes in the UK Biobank study. The model showed a similar predictive performance for cardiovascular and renal complications in different cohorts. It identified the top 30% of ADVANCE participants with a mean of 3.1-fold increased risk of major micro- and macrovascular events ( p = 6.3 × 10 −21 and p = 9.6 × 10 −31 , respectively) and a 4.4-fold ( p = 6.8 × 10 −33 ) higher risk of cardiovascular death. While in ADVANCE overall, combined intensive blood pressure and glucose control decreased cardiovascular death by 24%, the model identified a high-risk group in whom it decreased the mortality rate by 47%, and a low-risk group in whom it had no discernible effect. High-risk in iduals had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel multiPRS model stratified in iduals with type 2 diabetes according to risk of complications and helped to target earlier those who would receive greater benefit from intensive therapy.
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.JASH.2009.06.001
Abstract: This review briefly charts the recent history of the genetic study of high blood pressure (BP). After an inconsistent start it was hoped that very large genome-wide association studies (GWAS) might be able to provide some reliable answers. The two largest and most recent GWAS: CHARGE and GlobalBPgen were able to identify, despite some significant inconsistencies, genetic loci that accounted for only about 2% of the genetic factors believed to influence BP. The loci were associated with an estimated effect on BP of 1 mm Hg or less. No doubt many other loci exerting even smaller (<0.5 mm Hg) exist. This review contends that it is time to focus on the loci that can be viewed as confirmed, rather than extending the GWAS searches for less significant genetic influences. It is time to identify the precise deoxyribonucleic acid variants affecting BP, understand their mechanisms of action and think of ways in which such knowledge can be used to prevent and treat high BP in novel, effective, and possibly tailored ways.
Publisher: American Physiological Society
Date: 03-2009
DOI: 10.1152/AJPREGU.90919.2008
Abstract: The identification of genetic factors influencing cardiac growth independently of increased load is crucial to an understanding of the molecular and cellular basis of pathological cardiac hypertrophy. The central aim of this investigation was to determine how pathological hypertrophy in the adult can be linked with disturbances in cardiomyocyte growth and viability in early neonatal development. The hypertrophic heart rat (HHR) model is derived from the spontaneously hypertensive rat and exhibits marked cardiac hypertrophy, in the absence of a pressure load at maturity. Hearts were harvested from male HHR, and control strain normal heart rats (NHR), at different stages of postnatal development [neonatal (P2), 4 wk, 6 wk, 8 wk, 12 wk, 20 wk]. Isolated neonatal cardiomyocytes were prepared to evaluate cell size, number, and binucleation. At postnatal day 2, HHR hearts were considerably smaller than control NHR (4.3 ± 0.2 vs. 5.0 ± 0.1 mg/g, P 0.05). Cardiac growth restriction in the neonatal HHR was associated with reduced myocyte size (length and width) and an increased proportion of binucleated cardiomyocytes. Furthermore, the number of cardiomyocytes isolated from HHR neonatal hearts was significantly less (∼29%) than NHR. We also observe that growth stress in the neonate is associated with accentuated PI3K and suppressed MAPK activation, although these signaling pathways are normalized in the adult heart exhibiting established hypertrophy. Thus, using the HHR model, we identified novel molecular and cellular mechanisms involving premature exit from the cell cycle, reduced cardiomyocyte endowment, and dysregulated trophic signaling during early development, which are implicated in the etiology of heritable cardiac hypertrophy in the adult.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: Springer Science and Business Media LLC
Date: 27-08-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2007
DOI: 10.1161/HYPERTENSIONAHA.107.089128
Abstract: Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G , the gene encoding the γ-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we s led unrelated subjects within the upper (mean: 166 mm Hg n=96) and lower (mean: 98 mm Hg n=94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms ( rs13331086 , rs11074553 , and rs4299163 ) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: P =0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10 000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects ( P =0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population.
Publisher: Springer Science and Business Media LLC
Date: 15-07-2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2010
Publisher: Cold Spring Harbor Laboratory
Date: 04-2000
DOI: 10.1101/GR.10.4.473
Abstract: Models of human disease have long been used to understand the basic pathophysiology of disease and to facilitate the discovery of new therapeutics. However, as long as models have been used there have been debates about the utility of these models and their ability to mimic clinical disease at the phenotypic level. The application of genetic studies to both humans and model systems allows for a new paradigm, whereby a novel comparative genomics strategy combined with phenotypic correlates can be used to bridge between clinical relevance and model utility. This study presents a comparative genomic map for “candidate hypertension loci in humans” based on translating QTLs between rat and human, predicting 26 chromosomal regions in the human genome that are very likely to harbor hypertension genes. The predictive power appears robust, as several of these regions have also been implicated in mouse, suggesting that these regions represent primary targets for the development of SNPs for linkage disequilibrium testing in humans and/or provide a means to select specific models for additional functional studies and the development of new therapeutics.
Publisher: BMJ
Date: 14-05-2014
Abstract: There is ongoing controversy regarding a 'J-curve' phenomenon such that low and high blood pressure (BP) levels are associated with increased risks of recurrent stroke. We aimed to determine whether large treatment-related BP reductions are associated with increased risks of recurrent stroke. Data are from the PROGRESS trial, where 6105 patients with cerebrovascular disease were randomly assigned to either active treatment (perindopril ± indapamide) or placebo(s). There were no BP criteria for entry. BP was measured at every visit, and participant groups defined by reduction in systolic BP (SBP) from baseline were used for the analyses. Outcome was recurrent stroke. During a mean follow-up of 3.9 years, 727 recurrent strokes were observed. There were clear associations between the magnitude of SBP reduction and the risk of recurrent stroke. After adjustment for cardiovascular risk factors and randomised treatment, annual incidence was 2.08%, 2.10%, 2.31% and 2.96% for participant groups defined by SBP reductions of ≥ 20, 10-19, 0-9 and <0 mm Hg, respectively (p=0.0006 for trend). The present analysis provided no evidence of an increase in recurrent stroke associated with larger reductions in SBP produced by treatment among patients with cerebrovascular disease.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2012
Publisher: Wiley
Date: 1997
Abstract: There are two key clinical features of asthma: allergy and bronchial hyperreactivity (BHR). Some pedigree studies of atopy have indicated linkage with the high affinity IgE receptor (Fc epsilon RI-beta) gene on chromosome 11q13, but others failed to confirm this linkage. We examined the genetic linkage of three polymorphic microsatellite markers to atopy and BHR in 120 affected sibling pairs recruited from the general community. We found no linkage to atopy at any of the three 11q13 loci studied. Our findings also do not favour linkage between BHR and loci approximately 8-9 cM either side of the Fc epsilon RI-beta gene.
Publisher: Elsevier BV
Date: 06-1998
Publisher: Elsevier BV
Date: 04-1999
Publisher: Elsevier BV
Date: 03-2001
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
DOI: 10.1161/HYPERTENSIONAHA.111.181990
Abstract: Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37–1.73] combined P =2.58 · 10 −13 ). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25–1.44 P =1.032 · 10 −14 ). The quantitative analysis on a population-based s le revealed an effect size of 1.91 (95% CI: 0.16–3.66) for systolic and 1.40 (95% CI: 0.25–2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.
Publisher: Cambridge University Press (CUP)
Date: 02-10-2011
DOI: 10.1016/J.EURPSY.2011.07.005
Abstract: Examine the association of oral disease with future dementia/cognitive decline in a cohort of people with type 2 diabetes. A total of 11,140 men and women aged 55–88 years at study induction with type 2 diabetes participated in a baseline medical examination when they reported the number of natural teeth and days of bleeding gums. Dementia and cognitive decline were ascertained periodically during a 5-year follow-up. Relative to the group with the greatest number of teeth (more than or equal to 22), having no teeth was associated with the highest risk of both dementia (hazard ratio 95% confidence interval: 1.48 1.24, 1.78) and cognitive decline (1.39 1.21, 1.59). Number of days of bleeding gums was unrelated to these outcomes. Tooth loss was associated with an increased risk of both dementia and cognitive decline.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2011
DOI: 10.1161/HYPERTENSIONAHA.111.176180
Abstract: The P2X4 receptor is involved in endothelium-dependent changes in large arterial tone in response to shear stress and is, therefore, potentially relevant to arterial compliance and pulse pressure. Four identified nonsynonymous polymorphisms in P2RX4 were reproduced in recombinantly expressed human P2X4. Electrophysiological studies showed that one of these, the Tyr315 Cys mutation (rs28360472), significantly reduced the peak litude of the ATP-induced inward current to 10.9% of wild-type P2X4 receptors in transfected HEK-293 cells (10 μmol/L of ATP n=4–8 cells P .001). Concentration-response curves for ATP and the partial agonist BzATP demonstrate that the 315Cys-P2X4 mutant had an increased EC 50 value for both ligands. Mutation of Tyr315 Cys likely disrupts the agonist binding site of P2X4 receptors, a finding supported by molecular modeling based on the zebrafish P2X4 receptor crystal structure. We tested inheritance of rs28360472 encoding the Tyr315 Cys mutation in P2RX4 against pulse pressure in 2874 subjects from the Victorian Family Heart Study. The minor allele frequency was 0.014 (1.4%). In a variance components analysis we found significant association with pulse pressure ( P =0.023 for total association) where 1 minor allele increased pulse pressure by 2.84 mm Hg (95% CI: 0.41–5.27). This increase in pulse pressure associated with inheritance of 315Cys-P2X4 receptors might reflect reduced large arterial compliance as a result of impaired endothelium-dependent vasodilation in large arteries.
Publisher: Wiley
Date: 07-10-2015
Abstract: Methods to examine whether genetic and/or environmental sources can account for the residual variation in ordinal family data usually assume proportional odds. However, standard software to fit the non-proportional odds model to ordinal family data is limited because the correlation structure of family data is more complex than for other types of clustered data. To perform these analyses we propose the non-proportional odds multivariate logistic regression model and take a simulation-based approach to model fitting using Markov chain Monte Carlo methods, such as partially collapsed Gibbs s ling and the Metropolis algorithm. We applied the proposed methodology to male pattern baldness data from the Victorian Family Heart Study.
Publisher: American Medical Association (AMA)
Date: 06-2015
DOI: 10.1001/JAMADERMATOL.2014.3593
Abstract: The total cost of psoriasis in the United States is unknown. Defining the US economic burden of psoriasis is needed because it provides the foundation for research, advocacy, and educational efforts. To determine the US economic burden of psoriasis from a societal perspective. PubMed and MEDLINE databases were searched between January 1, 2008, and September 20, 2013, for economic investigations on the direct, indirect, intangible, and comorbidity costs of adult psoriasis in the United States. The base year costs were adjusted to 2013 US dollars using the Consumer Price Index for All Urban Consumers and multiplied by the estimated number of US patients with psoriasis in 2013 to determine the 2013 psoriasis cost burden. Among 100 identified articles, 22 studies were included in the systematic review. The direct psoriasis costs ranged from $51.7 billion to $63.2 billion, the indirect costs ranged from $23.9 billion to $35.4 billion, and medical comorbidities were estimated to contribute $36.4 billion annually in 2013 US dollars. Patients with psoriasis would pay a lifetime cost of $11,498 for relief of physical symptoms and emotional health however, intangible cost data are limited. The annual US cost of psoriasis amounted to approximately $112 billion in 2013. The economic burden of psoriasis is substantial and significant in the United States.
Publisher: American Physiological Society
Date: 02-2010
DOI: 10.1152/PHYSIOLGENOMICS.00173.2009
Abstract: Buffering of blood pressure during change of posture such as standing is controlled largely by the baroreflex. In our population-based Victorian Family Heart Study (VFHS), we previously demonstrated that, on average, systolic blood pressure (SBP) changes very little on standing however, interin idual variation is substantial and shows familial aggregation, with ∼25% of the variance attributable to genetic factors. Our genomewide linkage analysis suggests a region on chromosome 12p that harbors two strong candidate genes, KCNJ8 and ABCC9, encoding the channel-forming inward rectifier subunit Kir6.1 and the ATP-sensitive binding cassette SUR2B, respectively. These are key components of smooth muscle ATP-sensitive potassium (K ATP ) channels, important regulators of arterial tone and blood flow and central to autonomic baroreceptor control of changes in total peripheral resistance. We performed a comprehensive association analysis of 47 tag single nucleotide polymorphisms (SNPs) spanning the KCNJ8 and ABCC9 gene regions with postural change in SBP (ΔSBP). To augment power, we took a selective genotyping approach in which we compared allele and genotype frequencies between 150 unrelated in iduals with high (positive) ΔSBP (≥ 7 mmHg) and 150 unrelated in iduals with low (negative) ΔSBP (≤ −7 mmHg) drawn from the offspring generation (18–30 yr) of the VFHS. Association analyses showed that no SNPs demonstrated statistically significant differences in genotype frequencies between groups, particularly after adjustments for multiple testing. We conclude that sequence variants in KCNJ8 and ABCC9 are unlikely to contribute to variation in ΔSBP. Other genes in the identified chromosome 12p region warrant investigation.
Publisher: Elsevier BV
Date: 11-1990
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2012
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1111/J.1753-6405.2011.00739.X
Abstract: This study investigated the sensitivity and specificity of the national mortality codes in identifying cardiovascular disease (CVD) deaths and documents methods of verification. A 12-year retrospective case ascertainment of all ICD-coded CVD deaths was performed for deaths between 1990 and 2002 in the Melbourne Collaborative Cohort Study, comprising 41,528 subjects. Categories of non-CVD codes were also examined. Stratified s les of 750 deaths were adjudicated from a total of 2,230 deaths. Expert panels of cardiologists and neurologists adjudicated deaths. Of the 750 deaths adjudicated, 582 were verified as CVD [392 coronary heart disease (CHD) and 92 stroke] and 168 non-CVD. Estimated sensitivity and specificity of national mortality codes for identifying specific causes of death were: CHD 74.2% (95% CI: 69.8-78.5%) and 97.6% (96.0-99.2%), respectively myocardial infarction 59.9% (50.9-69.0%) and 94.2% (92.4-96.0%), respectively haemorrhagic stroke 58.9% (46.0-71.7%) and 99.8% (99.4-100.0%), respectively and ischaemic stroke 38.7% (20.5-56.9%) and 99.9% (99.6-100.0%), respectively. Misclassification was most common for deaths with primary ICD codes for endocrine-metabolic and genito-urinary diseases. National mortality coding under-estimated the true proportion of CHD and stroke deaths in the cohort by 13.6% and 50.8%, respectively. Misclassification of cause of death may have implications for conclusions drawn from epidemiological research.
Publisher: Springer Science and Business Media LLC
Date: 29-03-2006
DOI: 10.1007/S00439-006-0167-4
Abstract: Lower plasma levels of high-density lipoprotein cholesterol (HDL-C) are associated with the metabolic syndrome (insulin resistance, obesity, hypertension) and higher cardiovascular risk. Recent association studies have suggested rare alleles responsible for very low HDL-C levels. However, for in idual cardiovascular risk factors, the majority of population-attributable deaths are associated with average rather than extreme levels. Therefore, genetic factors that determine the population variation of HDL-C are particularly relevant. We undertook genome-wide and fine mapping to identify linkage to HDL-C in healthy adult nuclear families from the Victorian Family Heart Study. In 274 adult sibling pairs (average age 24 years, average plasma HDL-C 1.4 mmol/l), genome-wide mapping revealed suggestive evidence for linkage on chromosome 4 (Z score = 3.5, 170 cM) and nominal evidence for linkage on chromosomes 1 (Z = 2.1, 176 cM) and 6 (Z = 2.6, 29 cM). Using genotypes and phenotypes from 932 subjects (233 of the sibling pairs and their parents), finer mapping of the locus on chromosome 4 strengthened our findings with a peak probability (Z score = 3.9) at 169 cM. Our linkage data suggest that chromosome 4q32.3 is linked with normal population variation in HDL-C. This region coincides with previous reports of linkage to apolipoprotein AII (a major component of HDL) and encompasses the gene encoding the carboxypeptidase E, relevant to the metabolic syndrome and HDL-C. These findings are relevant for further understanding of the genetic determinants of cardiovascular risk at a population level.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2004
DOI: 10.1161/01.HYP.0000118044.84189.44
Abstract: The physiological adaptation to the erect posture involves integrated neural and cardiovascular responses that might be determined by genetic factors. We examined the familial- and in idual-specific components of variance for postural changes in systolic and diastolic blood pressure in 767 volunteer nuclear adult families from the Victorian Family Heart Study. In 274 adult sibling pairs, we made a genome-wide scan using 400 markers for quantitative trait loci linked with the postural changes in systolic and diastolic pressures. Overall, systolic pressure did not change on standing, but there was considerable variation in this phenotype (SD=8.1 mm Hg). Familial analyses revealed that 25% of the variance of change in systolic pressure was attributable to genetic factors. In contrast, diastolic pressure increased by 6.3 mm Hg (SD=7.0 mm Hg) on standing and there was no evidence of contributory genetic factors. Multipoint quantitative genome linkage mapping suggested evidence ( Z =3.2) of linkage of the postural change in systolic pressure to chromosome 12 but found no genome-wide evidence of linkage for the change in diastolic pressure. These findings suggest that genetic factors determine whether systolic pressure decreases or increases when one stands, possibly as the result of unidentified alleles on chromosome 12. The genetics of postural changes in systolic blood pressure might reflect the general buffering function of the baroreflex thereby, the predisposition to sudden decreases or increases in systolic pressure might cause postural hypotension or vessel wall disruption, respectively.
Publisher: Elsevier BV
Date: 04-2009
No related grants have been discovered for Stephen Harrap.