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Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

ABSTRACT: BACKGROUND:Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors. METHODS:We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases? = ?46,325, controls? = ?42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively. RESULTS:In the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]? = ?0.65 per 5 kg/m2 increase, 95% confidence interval [CI]: 0.56-0.75, p = 3.32?×?10-10). The associations were similar for both premenopausal (OR?? = ??0.44, 95% CI:0.31-0.62, p? = ?9.91?×?10-8) and postmenopausal breast cancer (OR? = ?0.57, 95%?CI: 0.46-0.71, p? = ?1.88?×?10-8). This association was replicated in the data from the DRIVE consortium (OR? = ?0.72, 95%?CI: 0.60-0.84, p?? = ??1.64?×?10-7). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p?

SUBMITTER: Guo Y

PROVIDER: S-EPMC4995025 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Guo Yan Y Warren Andersen Shaneda S Shu Xiao-Ou XO Michailidou Kyriaki K Bolla Manjeet K MK Wang Qin Q Garcia-Closas Montserrat M Milne Roger L RL Schmidt Marjanka K MK Chang-Claude Jenny J Dunning Allison A 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 Bogdanova Natalia V NV Bonanni Bernardo B Børresen-Dale Anne-Lise AL Brand Judith J Brauch Hiltrud H Brenner Hermann H Brüning Thomas T Burwinkel Barbara B Casey Graham G Chenevix-Trench Georgia G Couch Fergus J FJ Cox Angela A Cross Simon S SS Czene Kamila K Devilee Peter P 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 Hooning Maartje J MJ Hopper John L JL Jakubowska Anna A Jasmine Farzana F Jenkins Mark M John Esther M EM Johnson Nichola N Jones Michael E ME Kabisch Maria M Kibriya Muhammad M Knight Julia A JA Koppert Linetta B LB Kosma Veli-Matti VM Kristensen Vessela V Le Marchand Loic L Lee Eunjung E Li Jingmei J Lindblom Annika A Luben Robert R Lubinski Jan J Malone Kathi E KE Mannermaa Arto A Margolin Sara S Marme Frederik F McLean Catriona C Meijers-Heijboer Hanne H Meindl Alfons A Neuhausen Susan L SL Nevanlinna Heli H Neven Patrick P Olson Janet E JE Perez Jose I A JI 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 Seynaeve Caroline C Shah Mitul M Shrubsole Martha J MJ 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 Whittemore Alice S AS Winqvist Robert R Zhao Hui H Zhao Shilin S Hall Per P Simard Jacques J Kraft Peter P Pharoah Paul P Hunter David D Easton Douglas F DF Zheng Wei W

PLoS medicine 20160823 8

<h4>Background</h4>Observational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.<h4>Methods</h4>We applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. W ...[more]

PMID: 27551723

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Project description:BackgroundThe literature on associations of circulating concentrations of minerals and vitamins with risk of colorectal cancer is limited and inconsistent. Evidence from randomized controlled trials (RCTs) to support the efficacy of dietary modification or nutrient supplementation for colorectal cancer prevention is also limited.ObjectivesTo complement observational and RCT findings, we investigated associations of genetically predicted concentrations of 11 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, and zinc) with colorectal cancer risk using Mendelian randomization (MR).MethodsTwo-sample MR was conducted using 58,221 individuals with colorectal cancer and 67,694 controls from the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions.ResultsNominally significant associations were noted for genetically predicted iron concentration and higher risk of colon cancer [ORs per SD (ORSD): 1.08; 95% CI: 1.00, 1.17; P value = 0.05] and similarly for proximal colon cancer, and for vitamin B-12 concentration and higher risk of colorectal cancer (ORSD: 1.12; 95% CI: 1.03, 1.21; P value = 0.01) and similarly for colon cancer. A nominally significant association was also noted for genetically predicted selenium concentration and lower risk of colon cancer (ORSD: 0.98; 95% CI: 0.96, 1.00; P value = 0.05) and similarly for distal colon cancer. These associations were robust to sensitivity analyses. Nominally significant inverse associations were observed for zinc and risk of colorectal and distal colon cancers, but sensitivity analyses could not be performed. None of these findings survived correction for multiple testing. Genetically predicted concentrations of β-carotene, calcium, copper, folate, magnesium, phosphorus, and vitamin B-6 were not associated with disease risk.ConclusionsThese results suggest possible causal associations of circulating iron and vitamin B-12 (positively) and selenium (inversely) with risk of colon cancer.

Dataset Information

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

Publications

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent.

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