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Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

ABSTRACT: Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genotyped and imputed SNPs in 6608 Caucasian cases and 37 925 controls, and 895 Asian cases and 1968 controls, revealed the best signal of association for SNP rs11263763 (P = 8.4 × 10(-14), odds ratio = 0.86, 95% confidence interval = 0.82-0.89), located within HNF1B intron 1. Haplotype analysis and conditional analyses provide no evidence of further independent endometrial cancer risk variants at this locus. SNP rs11263763 genotype was associated with HNF1B mRNA expression but not with HNF1B methylation in endometrial tumor samples from The Cancer Genome Atlas. Genetic analyses prioritized rs11263763 and four other SNPs in high-to-moderate linkage disequilibrium as the most likely causal SNPs. Three of these SNPs map to the extended HNF1B promoter based on chromatin marks extending from the minimal promoter region. Reporter assays demonstrated that this extended region reduces activity in combination with the minimal HNF1B promoter, and that the minor alleles of rs11263763 or rs8064454 are associated with decreased HNF1B promoter activity. Our findings provide evidence for a single signal associated with endometrial cancer risk at the HNF1B locus, and that risk is likely mediated via altered HNF1B gene expression.

SUBMITTER: Painter JN

PROVIDER: S-EPMC4321445 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Painter Jodie N JN O'Mara Tracy A TA Batra Jyotsna J Cheng Timothy T Lose Felicity A FA Dennis Joe J Michailidou Kyriaki K Tyrer Jonathan P JP Ahmed Shahana S Ferguson Kaltin K Healey Catherine S CS Kaufmann Susanne S Hillman Kristine M KM Walpole Carina C Moya Leire L Pollock Pamela P Jones Angela A Howarth Kimberley K Martin Lynn L Gorman Maggie M Hodgson Shirley S De Polanco Ma Magdalena Echeverry MM Sans Monica M Carracedo Angel A Castellvi-Bel Sergi S Rojas-Martinez Augusto A Santos Erika E Teixeira Manuel R MR Carvajal-Carmona Luis L Shu Xiao-Ou XO Long Jirong J Zheng Wei W Xiang Yong-Bing YB Montgomery Grant W GW Webb Penelope M PM Scott Rodney J RJ McEvoy Mark M Attia John J Holliday Elizabeth E Martin Nicholas G NG Nyholt Dale R DR Henders Anjali K AK Fasching Peter A PA Hein Alexander A Beckmann Matthias W MW Renner Stefan P SP Dörk Thilo T Hillemanns Peter P Dürst Matthias M Runnebaum Ingo I Lambrechts Diether D Coenegrachts Lieve L Schrauwen Stefanie S Amant Frederic F Winterhoff Boris B Dowdy Sean C SC Goode Ellen L EL Teoman Attila A Salvesen Helga B HB Trovik Jone J Njolstad Tormund S TS Werner Henrica M J HM Ashton Katie K Proietto Tony T Otton Geoffrey G Tzortzatos Gerasimos G Mints Miriam M Tham Emma E Hall Per P Czene Kamila K Liu Jianjun J Li Jingmei J Hopper John L JL Southey Melissa C MC Ekici Arif B AB Ruebner Matthias M Johnson Nicola N Peto Julian J Burwinkel Barbara B Marme Frederik F Brenner Hermann H Dieffenbach Aida K AK Meindl Alfons A Brauch Hiltrud H Lindblom Annika A Depreeuw Jeroen J Moisse Matthieu M Chang-Claude Jenny J Rudolph Anja A Couch Fergus J FJ Olson Janet E JE Giles Graham G GG Bruinsma Fiona F Cunningham Julie M JM Fridley Brooke L BL Børresen-Dale Anne-Lise AL Kristensen Vessela N VN Cox Angela A Swerdlow Anthony J AJ Orr Nicholas N Bolla Manjeet K MK Wang Qin Q Weber Rachel Palmieri RP Chen Zhihua Z Shah Mitul M French Juliet D JD Pharoah Paul D P PD Dunning Alison M AM Tomlinson Ian I Easton Douglas F DF Edwards Stacey L SL Thompson Deborah J DJ Spurdle Amanda B AB

Human molecular genetics 20141106 5

Common variants in the hepatocyte nuclear factor 1 homeobox B (HNF1B) gene are associated with the risk of Type II diabetes and multiple cancers. Evidence to date indicates that cancer risk may be mediated via genetic or epigenetic effects on HNF1B gene expression. We previously found single-nucleotide polymorphisms (SNPs) at the HNF1B locus to be associated with endometrial cancer, and now report extensive fine-mapping and in silico and laboratory analyses of this locus. Analysis of 1184 genoty ...[more]

PMID: 25378557

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Project description:A genome-wide association study (GWAS) reported PLCL2 on chromosome 3p24. 3 (rs4618210:A>G) as a novel susceptibility locus for myocardial infarction in the Japanese population. As the most common pathological process, atherosclerosis leads to metabolic syndrome (MetS)-related ischaemic stroke (IS) and myocardial infarction. Hypothesizing that polymorphisms of the PLCL2 gene might be associated with the onset and prognosis of IS in MetS patients, we performed the following study in a Chinese Han population. A total of 709 cases (patients with MetS plus IS) and 711 controls (patients with MetS) were enrolled. A fine-mapping strategy was adopted to identify tagged single nucleotide polymorphisms (SNPs) of the PLCL2 gene, and improved multiplex ligation detection reaction (iMLDR) technology was used to genotype the selected SNPs. Logistic regression was used to analyse the values of the selected SNPs for the risk of IS between the cases and controls, adjusting for sex, age, hypertension, dyslipidaemia, hyperglycaemia, smoking and drinking. To compare the mean age of IS onset among different risk score groups, a genetic risk score was constructed for each case. The cumulative risk of IS events in the case group was presented using a cumulative incidence curve. All cases were followed up for 3 months, and functional outcomes were recorded prospectively. Two SNPs (rs4685423 and rs4618210) were significantly related to the risk of IS in MetS patients. For rs4685423, patients who were AA homozygotes were less likely to suffer from IS than C-allele carriers (OR 0.718; 95% CI 0.567-0.909; multivariate-adjusted, P = 0.006). For rs4618210, A-allele carriers were less likely to develop IS than patients who were GG homozygotes (OR 0.679; 95% CI 0.548-0.841; multivariate-adjusted, P < 0.001). As the genetic risk score increased, the mean age at IS onset decreased (log-rank P = 0.010). There was no statistically significant difference in the distribution of the 90-day modified Rankin Scale (mRS) outcomes across the rs4685423 (P = 0.319) or rs4618210 polymorphisms (P = 0.148). Our findings suggested that genetic polymorphisms of PLCL2 might be associated with the onset of MetS-related IS. Further studies are warranted to validate our findings in other ethnic populations.

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Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

Publications

Fine-mapping of the HNF1B multicancer locus identifies candidate variants that mediate endometrial cancer risk.

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