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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Guo Yan, Warren Andersen Shaneda, Shu Xiao-Ou, Michailidou Kyriaki, Bolla Manjeet K, Wang Qin, Garcia-Closas Montserrat, Milne Roger L, Schmidt Marjanka K, Chang-Claude Jenny, Dunning Allison, Bojesen Stig E, Ahsan Habibul, Aittomäki Kristiina, Andrulis Irene L, Anton-Culver Hoda, Arndt Volker, Beckmann Matthias W, Beeghly-Fadiel Alicia, Benitez Javier, Bogdanova Natalia V, Bonanni Bernardo, Børresen-Dale Anne-Lise, Brand Judith, Brauch Hiltrud, Brenner Hermann, Brüning Thomas, Burwinkel Barbara, Casey Graham, Chenevix-Trench Georgia, Couch Fergus J, Cox Angela, Cross Simon S, Czene Kamila, Devilee Peter, Dörk Thilo, Dumont Martine, Fasching Peter A, Figueroa Jonine, Flesch-Janys Dieter, Fletcher Olivia, Flyger Henrik, Fostira Florentia, Gammon Marilie, Giles Graham G, Guénel Pascal, Haiman Christopher A, Hamann Ute, Hooning Maartje J, Hopper John L, Jakubowska Anna, Jasmine Farzana, Jenkins Mark, John Esther M, Johnson Nichola, Jones Michael E, Kabisch Maria, Kibriya Muhammad, Knight Julia A, Koppert Linetta B, Kosma Veli-Matti, Kristensen Vessela, Le Marchand Loic, Lee Eunjung, Li Jingmei, Lindblom Annika, Luben Robert, Lubinski Jan, Malone Kathi E, Mannermaa Arto, Margolin Sara, Marme Frederik, McLean Catriona, Meijers-Heijboer Hanne, Meindl Alfons, Neuhausen Susan L, Nevanlinna Heli, Neven Patrick, Olson Janet E, Perez Jose I A, Perkins Barbara, Peterlongo Paolo, Phillips Kelly-Anne, Pylkäs Katri, Rudolph Anja, Santella Regina, Sawyer Elinor J, Schmutzler Rita K, Seynaeve Caroline, Shah Mitul, Shrubsole Martha J, Southey Melissa C, Swerdlow Anthony J, Toland Amanda E, Tomlinson Ian, Torres Diana, Truong Thérèse, Ursin Giske, Van Der Luijt Rob B, Verhoef Senno, Whittemore Alice S, Winqvist Robert, Zhao Hui, Zhao Shilin, Hall Per, Simard Jacques, Kraft Peter, Pharoah Paul, Hunter David, Easton Douglas F, Zheng Wei
Аннотация
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 < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.
CONCLUSIONS: BMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.