ORCID Profile
0000-0001-6099-7066
Current Organisation
Friedrich-Alexander-Universität Erlangen-Nürnberg
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Publisher: Oxford University Press (OUP)
Date: 07-2009
DOI: 10.1093/JNCI/DJP167
Publisher: Oxford University Press (OUP)
Date: 05-05-2010
DOI: 10.1093/JNCI/DJQ057
Publisher: Springer Science and Business Media LLC
Date: 26-10-2011
Publisher: Elsevier BV
Date: 2016
Publisher: BMJ
Date: 19-09-2011
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1053/J.GASTRO.2018.11.029
Abstract: Intestinal fibrosis is a long-term complication in inflammatory bowel diseases (IBD) that frequently results in functional damage, bowel obstruction, and surgery. Interleukin (IL) 36 is a group of cytokines in the IL1 family with inflammatory effects. We studied the expression of IL36 and its receptor, interleukin 1 receptor like 2 (IL1RL2 or IL36R) in the development of intestinal fibrosis in human tissues and mice. We obtained intestinal tissues from 92 patients with Crohn's disease (CD), 48 patients with ulcerative colitis, and 26 patients without inflammatory bowel diseases (control in iduals). Tissues were analyzed by histology to detect fibrosis and by immunohistochemistry to determine the distribution of fibroblasts and levels of IL36R ligands. Human and mouse fibroblasts were incubated with IL36 or control medium, and transcriptome-wide RNA sequences were analyzed. Mice were given neutralizing antibodies against IL36R, and we studied intestinal tissues from Il1rl2 Mucosal and submucosal tissue from patients with CD or ulcerative colitis had higher levels of collagens, including type VI collagen, compared with tissue from control in iduals. In tissues from patients with fibrostenotic CD, significantly higher levels of IL36A were noted, which correlated with high numbers of activated fibroblasts that expressed α-smooth muscle actin. IL36R activation of mouse and human fibroblasts resulted in expression of genes that regulate fibrosis and tissue remodeling, as well as expression of collagen type VI. Il1rl2 We found higher levels of IL36A in fibrotic intestinal tissues from patients with IBD compared with control in iduals. IL36 induced expression of genes that regulate fibrogenesis in fibroblasts. Inhibition or knockout of the IL36R gene in mice reduces chronic colitis and intestinal fibrosis. Agents designed to block IL36R signaling could be developed for prevention and treatment of intestinal fibrosis in patients with IBD.
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
DOI: 10.1038/S41467-021-27198-4
Abstract: Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant ( p 1.1E–7) CpGs explain 11.6% of the serum urate variance. At SLC2A9 , the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH , 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.
Publisher: Springer Science and Business Media LLC
Date: 11-2019
DOI: 10.1038/S41523-019-0127-5
Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1 , BRCA2 , PALB2 , ATM , and CHEK2 are associated with breast cancer risk. FANCM , which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM :p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2 . These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM −/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM :p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79 P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM :p.Arg658* and found that also FANCM :p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96 P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM :p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM -associated tumors.
Publisher: Springer Science and Business Media LLC
Date: 20-01-2020
Publisher: Springer Science and Business Media LLC
Date: 17-06-2014
DOI: 10.1038/NCOMMS5051
Publisher: Springer Science and Business Media LLC
Date: 18-05-2020
Publisher: Springer Science and Business Media LLC
Date: 30-01-2019
Publisher: Elsevier BV
Date: 07-2021
Publisher: American Society for Clinical Investigation
Date: 09-2011
DOI: 10.1172/JCI43428
Publisher: Oxford University Press (OUP)
Date: 02-05-2020
DOI: 10.1093/JNCI/DJAA056
Abstract: We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by in idual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2015
DOI: 10.1038/NG.3336
Publisher: Impact Journals, LLC
Date: 31-01-2016
Publisher: Springer Science and Business Media LLC
Date: 16-08-2015
Publisher: Springer Science and Business Media LLC
Date: 19-09-2010
DOI: 10.1038/NG.666
Publisher: Springer Science and Business Media LLC
Date: 02-08-2009
DOI: 10.1038/NG.424
Publisher: Springer Science and Business Media LLC
Date: 26-10-2018
DOI: 10.1038/S41467-018-06356-1
Abstract: Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 in iduals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
Publisher: Springer Science and Business Media LLC
Date: 19-09-2010
DOI: 10.1038/NG.668
Publisher: American Association for Cancer Research (AACR)
Date: 06-2011
DOI: 10.1158/1078-0432.CCR-10-3405
Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res 17(11) 3742–50. ©2011 AACR.
Publisher: Elsevier BV
Date: 10-2013
Publisher: Wiley
Date: 07-08-2020
DOI: 10.1002/IJC.33206
Publisher: Oxford University Press (OUP)
Date: 23-06-2014
DOI: 10.1093/JNCI/DJU149
Publisher: Public Library of Science (PLoS)
Date: 06-06-2011
Publisher: American Association for Cancer Research (AACR)
Date: 2021
DOI: 10.1158/1055-9965.EPI-20-0739
Abstract: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni & 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P & 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger s le sets are required to confirm our findings.
Publisher: Oxford University Press (OUP)
Date: 24-03-2015
DOI: 10.1093/HMG/DDV101
Publisher: Springer Science and Business Media LLC
Date: 18-08-2021
DOI: 10.1186/S13058-021-01450-7
Abstract: Given the high heterogeneity among breast tumors, associations between common germline genetic variants and survival that may exist within specific subgroups could go undetected in an unstratified set of breast cancer patients. We performed genome-wide association analyses within 15 subgroups of breast cancer patients based on prognostic factors, including hormone receptors, tumor grade, age, and type of systemic treatment. Analyses were based on 91,686 female patients of European ancestry from the Breast Cancer Association Consortium, including 7531 breast cancer-specific deaths over a median follow-up of 8.1 years. Cox regression was used to assess associations of common germline variants with 15-year and 5-year breast cancer-specific survival. We assessed the probability of these associations being true positives via the Bayesian false discovery probability (BFDP 0.15). Evidence of associations with breast cancer-specific survival was observed in three patient subgroups, with variant rs5934618 in patients with grade 3 tumors (15-year-hazard ratio (HR) [95% confidence interval (CI)] 1.32 [1.20, 1.45], P = 1.4E−08, BFDP = 0.01, per G allele) variant rs4679741 in patients with ER-positive tumors treated with endocrine therapy (15-year-HR [95% CI] 1.18 [1.11, 1.26], P = 1.6E−07, BFDP = 0.09, per G allele) variants rs1106333 (15-year-HR [95% CI] 1.68 [1.39,2.03], P = 5.6E−08, BFDP = 0.12, per A allele) and rs78754389 (5-year-HR [95% CI] 1.79 [1.46,2.20], P = 1.7E−08, BFDP = 0.07, per A allele), in patients with ER-negative tumors treated with chemotherapy. We found evidence of four loci associated with breast cancer-specific survival within three patient subgroups. There was limited evidence for the existence of associations in other patient subgroups. However, the power for many subgroups is limited due to the low number of events. Even so, our results suggest that the impact of common germline genetic variants on breast cancer-specific survival might be limited.
Publisher: Elsevier BV
Date: 02-2012
DOI: 10.1016/J.JAD.2011.11.042
Abstract: Maternal depression during the peripartum period has an incidence of about 13%. In iduals with specific genetic predispositions are more vulnerable to stressful life events suggesting that exploration of gene-environmental pathways might facilitate the identification of risk factors for peripartum depression. The aim of this study was to evaluate the influence of stressful life events in combination with the serotonin transporter gene 5-HTTLPR polymorphism on peripartum depressive symptoms. In a non-psychiatric cohort of 419 Caucasians, the severity of depression was assessed prospectively during pregnancy (3rd trimester) and the postpartum period (2-3 days and 6-8 months) using the Edinburgh Postnatal Depression Scale. Satisfaction with the partner and exposure to negative life events were evaluated using self-report questionnaires and the genotype of the 5-HTTLPR was assessed. Repeated measures generalized linear models were used to investigate the gene-environment interaction on depressive symptoms across late pregnancy and the postpartum period. The 5-HTTLPR S-allele carrier status predicted late postpartum depressive symptom severity only in the presence of negative life events. This interaction was not observed for depressive symptoms during the 3rd trimester or the early postpartum. In addition, S-allele carrier status increased the negative effects of dissatisfaction with the current partner on depressive symptoms in the late postpartum period. In this non-psychiatric cohort, the 5-HTTLPR interacts with both lifetime and current stressors to influence depressive symptoms in the late post partum period. These findings could have clinical implications by allowing identification of women at higher risk for developing postpartum depressive symptoms.
Publisher: Springer Science and Business Media LLC
Date: 02-05-2016
DOI: 10.1038/NG.3562
Publisher: American Association for Cancer Research (AACR)
Date: 05-2009
DOI: 10.1158/1055-9965.EPI-08-0745
Abstract: Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small s le size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5% TNF 1.00 (0.95-1.06), 5.0% CASP10 1.02 (0.98-1.07), 6.5% PGR 1.02 (0.99-1.06), 15.3% and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009 (5):1610–6)
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2015
DOI: 10.1158/1078-0432.CCR-15-0632
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res 21(23) 5264–76. ©2015 AACR.
Publisher: Oxford University Press (OUP)
Date: 19-05-2011
DOI: 10.1093/HMG/DDR228
Publisher: Wiley
Date: 02-04-2018
DOI: 10.1002/CAM4.1445
Abstract: Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation ( r g = 0.23, P = 9.3 × 10 −3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy ( P = 6.0 × 10 −3 ) and concordance in effect direction ( P = 2.0 × 10 −3 ) between the two diseases. Cross‐disease GWAS meta‐analysis highlighted 13 distinct loci associated at P ≤ 10 −5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level ( P = 4.9 × 10 −8 , OR = 1.11, 95% CI = 1.07–1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross‐disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases.
Publisher: Springer Science and Business Media LLC
Date: 06-2023
DOI: 10.1038/S41588-023-01409-8
Abstract: The kidneys operate at the interface of plasma and urine by clearing molecular waste products while retaining valuable solutes. Genetic studies of paired plasma and urine metabolomes may identify underlying processes. We conducted genome-wide studies of 1,916 plasma and urine metabolites and detected 1,299 significant associations. Associations with 40% of implicated metabolites would have been missed by studying plasma alone. We detected urine-specific findings that provide information about metabolite reabsorption in the kidney, such as aquaporin (AQP)-7-mediated glycerol transport, and different metabolomic footprints of kidney-expressed proteins in plasma and urine that are consistent with their localization and function, including the transporters NaDC3 ( SLC13A3 ) and ASBT ( SLC10A2 ). Shared genetic determinants of 7,073 metabolite–disease combinations represent a resource to better understand metabolic diseases and revealed connections of dipeptidase 1 with circulating digestive enzymes and with hypertension. Extending genetic studies of the metabolome beyond plasma yields unique insights into processes at the interface of body compartments.
Publisher: Springer Science and Business Media LLC
Date: 17-04-2011
DOI: 10.1038/NG.812
Publisher: Wiley
Date: 08-03-2011
DOI: 10.1002/IJC.25554
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/NG.3826
Publisher: Springer Science and Business Media LLC
Date: 09-12-2021
DOI: 10.1038/S41467-021-27234-3
Abstract: Chronic kidney disease is a major public health burden. Elevated urinary albumin-to-creatinine ratio is a measure of kidney damage, and used to diagnose and stage chronic kidney disease. To extend the knowledge on regulatory mechanisms related to kidney function and disease, we conducted a blood-based epigenome-wide association study for estimated glomerular filtration rate (n = 33,605) and urinary albumin-to-creatinine ratio (n = 15,068) and detected 69 and seven CpG sites where DNA methylation was associated with the respective trait. The majority of these findings showed directionally consistent associations with the respective clinical outcomes chronic kidney disease and moderately increased albuminuria. Associations of DNA methylation with kidney function, such as CpGs at JAZF1 , PELI1 and CHD2 were validated in kidney tissue. Methylation at PHRF1 , LDB2 , CSRNP1 and IRF5 indicated causal effects on kidney function. Enrichment analyses revealed pathways related to hemostasis and blood cell migration for estimated glomerular filtration rate, and immune cell activation and response for urinary albumin-to-creatinineratio-associated CpGs.
Publisher: American Association for Cancer Research (AACR)
Date: 31-10-2016
DOI: 10.1158/1055-9965.EPI-16-0147
Abstract: Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) in idual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22 95% CI, 1.10–1.39 P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P & 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with in idual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev 25(11) 1503–10. ©2016 AACR.
Publisher: Elsevier BV
Date: 06-2018
Publisher: Oxford University Press (OUP)
Date: 13-06-2014
DOI: 10.1093/HMG/DDU300
Publisher: Bioscientifica
Date: 10-2015
DOI: 10.1530/ERC-15-0319
Abstract: Excessive exposure to estrogen is a well-established risk factor for endometrial cancer (EC), particularly for cancers of endometrioid histology. The physiological function of estrogen is primarily mediated by estrogen receptor alpha, encoded by ESR1 . Consequently, several studies have investigated whether variation at the ESR1 locus is associated with risk of EC, with conflicting results. We performed comprehensive fine-mapping analyses of 3633 genotyped and imputed single nucleotide polymorphisms (SNPs) in 6607 EC cases and 37 925 controls. There was evidence of an EC risk signal located at a potential alternative promoter of the ESR1 gene (lead SNP rs79575945, P =1.86×10 −5 ), which was stronger for cancers of endometrioid subtype ( P =3.76×10 −6 ). Bioinformatic analysis suggests that this risk signal is in a functionally important region targeting ESR1 , and eQTL analysis found that rs79575945 was associated with expression of SYNE1 , a neighbouring gene. In summary, we have identified a single EC risk signal located at ESR1 , at study-wide significance. Given SNPs located at this locus have been associated with risk for breast cancer, also a hormonally driven cancer, this study adds weight to the rationale for performing informed candidate fine-scale genetic studies across cancer types.
Publisher: Springer Science and Business Media LLC
Date: 27-04-2016
DOI: 10.1038/NCOMMS11375
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations ( P × 10 −8 ) with oestrogen receptor (ER)-negative breast cancer and BRCA1 -associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5 , a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations ( P .05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Publisher: Springer Science and Business Media LLC
Date: 09-08-2018
DOI: 10.1038/S41467-018-05427-7
Abstract: Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins ( SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2019
DOI: 10.1158/0008-5472.CAN-17-3864
Abstract: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene. See related commentary by Choi and Brown, p. 439
Publisher: American Association for Cancer Research (AACR)
Date: 09-2010
DOI: 10.1158/1055-9965.EPI-10-0374
Abstract: Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23 Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 19(9) 2143–51. ©2010 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2012
DOI: 10.1158/1055-9965.EPI-11-1160
Abstract: Background: Genome-wide association studies (GWAS) have identified more than 100 genetic loci for various cancers. However, only one is for endometrial cancer. Methods: We conducted a three-stage GWAS including 8,492 endometrial cancer cases and 16,596 controls. After analyzing 585,963 single-nucleotide polymorphisms (SNP) in 832 cases and 2,682 controls (stage I) from the Shanghai Endometrial Cancer Genetics Study, we selected the top 106 SNPs for in silico replication among 1,265 cases and 5,190 controls from the Australian/British Endometrial Cancer GWAS (stage II). Nine SNPs showed results consistent in direction with stage I with P & 0.1. These nine SNPs were investigated among 459 cases and 558 controls (stage IIIa) and six SNPs showed a direction of association consistent with stages I and II. These six SNPs, plus two additional SNPs selected on the basis of linkage disequilibrium and P values in stage II, were investigated among 5,936 cases and 8,166 controls from an additional 11 studies (stage IIIb). Results: SNP rs1202524, near the CAPN9 gene on chromosome 1q42.2, showed a consistent association with endometrial cancer risk across all three stages, with ORs of 1.09 [95% confidence interval (CI), 1.03–1.16] for the A/G genotype and 1.17 (95% CI, 1.05–1.30) for the G/G genotype (P = 1.6 × 10−4 in combined analyses of all s les). The association was stronger when limited to the endometrioid subtype, with ORs (95% CI) of 1.11 (1.04–1.18) and 1.21 (1.08–1.35), respectively (P = 2.4 × 10−5). Conclusions: Chromosome 1q42.2 may host an endometrial cancer susceptibility locus. Impact: This study identified a potential genetic locus for endometrial cancer risk. Cancer Epidemiol Biomarkers Prev 21(6) 980–7. ©2012 AACR.
Publisher: Public Library of Science (PLoS)
Date: 19-06-2015
Publisher: Oxford University Press (OUP)
Date: 09-10-2017
DOI: 10.1093/IJE/DYX131
Publisher: Public Library of Science (PLoS)
Date: 06-07-2018
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-03-2018
Abstract: Background The kidneys have a central role in the generation, turnover, transport, and excretion of metabolites, and these functions can be altered in CKD. Genetic studies of metabolite concentrations can identify proteins performing these functions. Methods We conducted genome-wide association studies and aggregate rare variant tests of the concentrations of 139 serum metabolites and 41 urine metabolites, as well as their pairwise ratios and fractional excretions in up to 1168 patients with CKD. Results After correction for multiple testing, genome-wide significant associations were detected for 25 serum metabolites, two urine metabolites, and 259 serum and 14 urinary metabolite ratios. These included associations already known from population-based studies. Additional findings included an association for the uremic toxin putrescine and variants upstream of an enzyme catalyzing the oxidative deamination of polyamines ( AOC1 , P -min=2.4×10 −12 ), a relatively high carrier frequency (2%) for rare deleterious missense variants in ACADM that are collectively associated with serum ratios of medium-chain acylcarnitines ( P -burden=6.6×10 −16 ), and associations of a common variant in SLC7A9 with several ratios of lysine to neutral amino acids in urine, including the lysine/glutamine ratio ( P =2.2×10 −23 ). The associations of this SLC7A9 variant with ratios of lysine to specific neutral amino acids were much stronger than the association with lysine concentration alone. This finding is consistent with SLC7A9 functioning as an exchanger of urinary cationic amino acids against specific intracellular neutral amino acids at the apical membrane of proximal tubular cells. Conclusions Metabolomic indices of specific kidney functions in genetic studies may provide insight into human renal physiology.
Publisher: Springer Science and Business Media LLC
Date: 2016
DOI: 10.1038/NG0116-101B
Publisher: American Association for Cancer Research (AACR)
Date: 02-2013
DOI: 10.1158/1055-9965.EPI-12-0903
Abstract: Background: Experimental and epidemiologic evidence have suggested that chronic inflammation may play a critical role in endometrial carcinogenesis. Methods: To investigate this hypothesis, a two-stage study was carried out to evaluate single-nucleotide polymorphisms (SNP) in inflammatory pathway genes in association with endometrial cancer risk. In stage I, 64 candidate pathway genes were identified and 4,542 directly genotyped or imputed SNPs were analyzed among 832 endometrial cancer cases and 2,049 controls, using data from the Shanghai Endometrial Cancer Genetics Study. Linkage disequilibrium of stage I SNPs significantly associated with endometrial cancer (P & 0.05) indicated that the majority of associations could be linked to one of 24 distinct loci. One SNP from each of the 24 loci was then selected for follow-up genotyping. Of these, 21 SNPs were successfully designed and genotyped in stage II, which consisted of 10 additional studies including 6,604 endometrial cancer cases and 8,511 controls. Results: Five of the 21 SNPs had significant allelic odds ratios (ORs) and 95% confidence intervals (CI) as follows: FABP1, 0.92 (0.85–0.99) CXCL3, 1.16 (1.05–1.29) IL6, 1.08 (1.00–1.17) MSR1, 0.90 (0.82–0.98) and MMP9, 0.91 (0.87–0.97). Two of these polymorphisms were independently significant in the replication s le (rs352038 in CXCL3 and rs3918249 in MMP9). The association for the MMP9 polymorphism remained significant after Bonferroni correction and showed a significant association with endometrial cancer in both Asian- and European-ancestry s les. Conclusions: These findings lend support to the hypothesis that genetic polymorphisms in genes involved in the inflammatory pathway may contribute to genetic susceptibility to endometrial cancer. Impact statement: This study adds to the growing evidence that inflammation plays an important role in endometrial carcinogenesis. Cancer Epidemiol Biomarkers Prev 22(2) 216–23. ©2012 AACR.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
DOI: 10.1038/NATURE24284
Publisher: Oxford University Press (OUP)
Date: 18-06-2014
DOI: 10.1093/HMG/DDU311
Publisher: Elsevier BV
Date: 07-2020
Publisher: Springer Science and Business Media LLC
Date: 12-01-2015
DOI: 10.1038/NG.3185
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41598-019-48804-Y
Abstract: Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC , has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44–1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1 , BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.
Publisher: Springer Science and Business Media LLC
Date: 21-02-2019
Publisher: Bioscientifica
Date: 16-11-2015
DOI: 10.1530/ERC-15-0386
Abstract: Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E 2 ) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P =4.8×10 −11 ). SNP rs727479 was also among those most strongly associated with circulating E 2 concentrations in 2767 post-menopausal controls ( P =7.4×10 −8 ). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11–1.21) is compatible with that predicted by the observed effect on E 2 concentrations (1.09, CI=1.03–1.21), consistent with the hypothesis that endometrial cancer risk is driven by E 2 . From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI ( P interaction =0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
DOI: 10.1038/NG.3785
Publisher: Elsevier BV
Date: 07-2013
No related grants have been discovered for Arif Ekici.