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Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

ABSTRACT: PURPOSE:Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors. METHODS:We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Unconditional logistic regression models were used to derive adjusted odds ratios (ORs) and 95 % confidence intervals (CIs) to measure the association of breast cancer risk with T2D GRS or T2D-associated genetic risk variants. Meta-analyses were conducted to obtain summary ORs across all studies. RESULTS:The T2D GRS was not found to be associated with breast cancer risk, overall, by menopausal status, or for estrogen receptor positive or negative breast cancer. Three T2D associated risk variants were individually associated with breast cancer risk after adjustment for multiple comparisons using the Bonferroni method (at p < 0.001), rs9939609 (FTO) (OR 0.94, 95 % CI = 0.92-0.95, p = 4.13E-13), rs7903146 (TCF7L2) (OR 1.04, 95 % CI = 1.02-1.06, p = 1.26E-05), and rs8042680 (PRC1) (OR 0.97, 95 % CI = 0.95-0.99, p = 8.05E-04). CONCLUSIONS:We have shown that several genetic risk variants were associated with the risk of both T2D and breast cancer. However, overall genetic susceptibility to T2D may not be related to breast cancer risk.

SUBMITTER: Zhao Z

PROVIDER: S-EPMC5029371 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

Zhao Zhiguo Z Wen Wanqing W Michailidou Kyriaki K Bolla Manjeet K MK Wang Qin Q Zhang Ben B Long Jirong J Shu Xiao-Ou XO Schmidt Marjanka K MK Milne Roger L RL García-Closas Montserrat M Chang-Claude Jenny J Lindstrom Sara S Bojesen Stig E SE Ahsan Habibul H Aittomäki Kristiina K Andrulis Irene L IL Anton-Culver Hoda H Arndt Volker V Beckmann Matthias W MW Beeghly-Fadiel Alicia A Benitez Javier J Blomqvist Carl C Bogdanova Natalia V NV Børresen-Dale Anne-Lise AL Brand Judith J Brauch Hiltrud H Brenner Hermann H Burwinkel Barbara B Cai Qiuyin Q Casey Graham G Chenevix-Trench Georgia G Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Dörk Thilo T Dumont Martine M Fasching Peter A PA Figueroa Jonine J Flesch-Janys Dieter D Fletcher Olivia O Flyger Henrik H Fostira Florentia F Gammon Marilie M Giles Graham G GG Guénel Pascal P Haiman Christopher A CA Hamann Ute U Harrington Patricia P Hartman Mikael M Hooning Maartje J MJ Hopper John L JL Jakubowska Anna A Jasmine Farzana F John Esther M EM Johnson Nichola N Kabisch Maria M Khan Sofia S Kibriya Muhammad M Knight Julia A JA Kosma Veli-Matti VM Kriege Mieke M Kristensen Vessela V Le Marchand Loic L Lee Eunjung E Li Jingmei J Lindblom Annika A Lophatananon Artitaya A Luben Robert R Lubinski Jan J Malone Kathleen E KE Mannermaa Arto A Manoukian Siranoush S Margolin Sara S Marme Frederik F McLean Catriona C Meijers-Heijboer Hanne H Meindl Alfons A Miao Hui H Muir Kenneth K Neuhausen Susan L SL Nevanlinna Heli H Neven Patrick P Olson Janet E JE Perkins Barbara B Peterlongo Paolo P Phillips Kelly-Anne KA Pylkäs Katri K Rudolph Anja A Santella Regina R Sawyer Elinor J EJ Schmutzler Rita K RK Schoemaker Minouk M Shah Mitul M Shrubsole Martha M Southey Melissa C MC Swerdlow Anthony J AJ Toland Amanda E AE Tomlinson Ian I Torres Diana D Truong Thérèse T Ursin Giske G Van Der Luijt Rob B RB Verhoef Senno S Wang-Gohrke Shan S Whittemore Alice S AS Winqvist Robert R Pilar Zamora M M Zhao Hui H Dunning Alison M AM Simard Jacques J Hall Per P Kraft Peter P Pharoah Paul P Hunter David D Easton Douglas F DF Zheng Wei W

Cancer causes & control : CCC 20160406 5

<h4>Purpose</h4>Type 2 diabetes (T2D) has been reported to be associated with an elevated risk of breast cancer. It is unclear, however, whether this association is due to shared genetic factors.<h4>Methods</h4>We constructed a genetic risk score (GRS) using risk variants from 33 known independent T2D susceptibility loci and evaluated its relation to breast cancer risk using the data from two consortia, including 62,328 breast cancer patients and 83,817 controls of European ancestry. Uncondition ...[more]

PMID: 27053251

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Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high mortality, uncertain cause, and few treatment options. Studies have identified a significant genetic risk associated with the development of IPF; however, mechanisms by which genetic risk factors promote IPF remain unclear. We aimed to identify genetic variants associated with IPF susceptibility and provide mechanistic insight using gene and protein expression analyses.MethodsWe used a two-stage approach: a genome-wide association study in patients with IPF of European ancestry recruited from nine different centres in the UK and controls selected from UK Biobank (stage 1) matched for age, sex, and smoking status; and a follow-up of associated genetic variants in independent datasets of patients with IPF and controls from two independent US samples from the Chicago consortium and the Colorado consortium (stage 2). We investigated the effect of novel signals on gene expression in large transcriptomic and genomic data resources, and examined expression using lung tissue samples from patients with IPF and controls.Findings602 patients with IPF and 3366 controls were selected for stage 1. For stage 2, 2158 patients with IPF and 5195 controls were selected. We identified a novel genome-wide significant signal of association with IPF susceptibility near A-kinase anchoring protein 13 (AKAP13; rs62025270, odds ratio [OR] 1·27 [95% CI 1·18-1·37], p=1·32 × 10-9) and confirmed previously reported signals, including in mucin 5B (MUC5B; rs35705950, OR 2·89 [2·56-3·26], p=1·12 × 10-66) and desmoplakin (DSP; rs2076295, OR 1·44 [1·35-1·54], p=7·81 × 10-28). For rs62025270, the allele A associated with increased susceptibility to IPF was also associated with increased expression of AKAP13 mRNA in lung tissue from patients who had lung resection procedures (n=1111). We showed that AKAP13 is expressed in the alveolar epithelium and lymphoid follicles from patients with IPF, and AKAP13 mRNA expression was 1·42-times higher in lung tissue from patients with IPF (n=46) than that in lung tissue from controls (n=51).InterpretationAKAP13 is a Rho guanine nucleotide exchange factor regulating activation of RhoA, which is known to be involved in profibrotic signalling pathways. The identification of AKAP13 as a susceptibility gene for IPF increases the prospect of successfully targeting RhoA pathway inhibitors in patients with IPF.FundingUK Medical Research Council, National Heart, Lung, and Blood Institute of the US National Institutes of Health, Agencia Canaria de Investigación, Innovación y Sociedad de la Información, Spain, UK National Institute for Health Research, and the British Lung Foundation.

Project description:IntroductionNon-Hispanic (nH) Black and Hispanic women are disproportionately affected by early onset disease, later stage, and with more aggressive, higher grade and ER/PR negative breast cancers. The purpose of this analysis was to examine whether genetic ancestry could account for these variation in breast cancer characteristics, once data were stratified by self-reported race/ethnicity and adjusted for potential confounding by social and behavioral factors.MethodsWe used a panel of 100 ancestry informative markers (AIMs) to estimate individual genetic ancestry in 656 women from the "Breast Cancer Care in Chicago" study, a multi-ethnic cohort of breast cancer patients to examine the association between individual genetic ancestry and breast cancer characteristics. In addition we examined the association of individual AIMs and breast cancer to identify genes/regions that may potentially play a role in breast cancer disease disparities.ResultsAs expected, nH Black and Hispanic patients were more likely than nH White patients to be diagnosed at later stages, with higher grade, and with ER/PR negative tumors. Higher European genetic ancestry was protective against later stage at diagnosis (OR 0.7 95%CI: 0.54-0.92) among Hispanic patients, and higher grade (OR 0.73, 95%CI: 0.56-0.95) among nH Black patients. After adjustment for multiple social and behavioral risk factors, the association with later stage remained, while the association with grade was not significant. We also found that the AIM SNP rs10954631 on chromosome 7 was associated with later stage (p = 0.02) and higher grade (p = 0.012) in nH Whites and later stage (p = 0.03) in nH Blacks.ConclusionNon-European genetic ancestry was associated with later stage at diagnosis in ethnic minorities. The relation between genetic ancestry and stage at diagnosis may be due to genetic factors and/or unmeasured environmental factors that are overrepresented within certain racial/ethnic groups.

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Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

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Association of genetic susceptibility variants for type 2 diabetes with breast cancer risk in women of European ancestry.

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