Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium.
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Rudolph Anja, Song Minsun, Brook Mark N, Milne Roger L, Mavaddat Nasim, Michailidou Kyriaki, Bolla Manjeet K, Wang Qin, Dennis Joe, Wilcox Amber N, Hopper John L, Southey Melissa C, Keeman Renske, Fasching Peter A, Beckmann Matthias W, Gago-Dominguez Manuela, Castelao Jose E, Guénel Pascal, Truong Thérèse, Bojesen Stig E, Flyger Henrik, Brenner Hermann, Arndt Volker, Brauch Hiltrud, Brüning Thomas, Mannermaa Arto, Kosma Veli-Matti, Lambrechts Diether, Keupers Machteld, Couch Fergus J, Vachon Celine, Giles Graham G, MacInnis Robert J, Figueroa Jonine, Brinton Louise, Czene Kamila, Brand Judith S, Gabrielson Marike, Humphreys Keith, Cox Angela, Cross Simon S, Dunning Alison M, Orr Nick, Swerdlow Anthony, Hall Per, Pharoah Paul D P, Schmidt Marjanka K, Easton Douglas F, Chatterjee Nilanjan, Chang-Claude Jenny, García-Closas Montserrat
Аннотация
METHODS: Analyses were based on data from 20 studies; datasets analysed ranged from 3453 to 23 104 invasive breast cancer cases and similar numbers of controls, depending on the analysed environmental risk factor. We evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS with reproductive history, alcohol consumption, menopausal hormone therapy (MHT), height and body mass index (BMI). We tested the null hypothesis of multiplicative joint associations for PRS and each of the environmental factors, and performed global and tail-based goodness-of-fit tests in logistic regression models. The outcomes were breast cancer overall and by estrogen receptor (ER) status.
RESULTS: The strongest evidence for a non-multiplicative joint associations with the 77-SNP PRS was for alcohol consumption (P-interaction = 0.009), adult height (P-interaction = 0.025) and current use of combined MHT (P-interaction = 0.038) in ER-positive disease. Risk associations for these factors by percentiles of PRS did not follow a clear dose-response. In addition, global and tail-based goodness of fit tests showed little evidence for departures from a multiplicative risk model, with alcohol consumption showing the strongest evidence for ER-positive disease (P = 0.013 for global and 0.18 for tail-based tests).
CONCLUSIONS: The combined effects of the 77-SNP PRS and environmental risk factors for breast cancer are generally well described by a multiplicative model. Larger studies are required to confirm possible departures from the multiplicative model for individual risk factors, and assess models specific for ER-negative disease.