Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium

Rudolph A, Song M, Brook MN, Milne RL, Mavaddat N, Michailidou K, Bolla MK, Wang Q, Dennis J, Wilcox AN, Hopper JL, Southey MC, Keeman R, Fasching P, Beckmann M, Gago-Dominguez M, Castelao JE, Guenel P, Truong T, Bojesen SE, Flyger H, Brenner H, Arndt V, Brauch H, Bruening T, Mannermaa A, Kosma VM, Lambrechts D, Keupers M, Couch FJ, Vachon C, Giles GG, Macinnis RJ, Figueroa J, Brinton L, Czene K, Brand JS, Gabrielson M, Humphreys K, Cox A, Cross SS, Dunning AM, Orr N, Swerdlow A, Hall P, Pharoah PDP, Schmidt MK, Easton DF, Chatterjee N, Chang-Claude J, Garcia-Closas M (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 47

Pages Range: 526-536

Journal Issue: 2

DOI: 10.1093/ije/dyx242

Abstract

Background: Polygenic risk scores (PRS) for breast cancer can be used to stratify the population into groups at substantially different levels of risk. Combining PRS and environmental risk factors will improve risk prediction; however, integrating PRS into risk prediction models requires evaluation of their joint association with known environmental risk factors. 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.

Authors with CRIS profile

Involved external institutions

Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Sookmyung Women's University Korea, Republic of (KR) The Institute of Cancer Research (ICR) United Kingdom (GB) Cancer Council Victoria Australia (AU) University of Cambridge United Kingdom (GB) National Cancer Institute (NCI) United States (USA) (US) The University of Melbourne Australia (AU) Netherlands Cancer Institute (NKI) Netherlands (NL) Complejo Hospitalario Universitario de Santiago de Compostela Spain (ES) Complejo Hospitalario Universitario de Vigo (CHUVI) Spain (ES) University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud France (FR) Copenhagen University Hospital Denmark (DK) Ruhr-Universität Bochum (RUB) Germany (DE) University of Eastern Finland Finland (FI) Flanders Institute for Biotechnology / Vlaams Instituut voor Biotechnologie (VIB) Belgium (BE) Mayo Clinic United States (USA) (US) Karolinska Institute Sweden (SE) University of Sheffield United Kingdom (GB) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE)

How to cite

APA:

Rudolph, A., Song, M., Brook, M.N., Milne, R.L., Mavaddat, N., Michailidou, K.,... Garcia-Closas, M. (2018). Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium. International Journal of Epidemiology, 47(2), 526-536. https://doi.org/10.1093/ije/dyx242

MLA:

Rudolph, Anja, et al. "Joint associations of a polygenic risk score and environmental risk factors for breast cancer in the Breast Cancer Association Consortium." International Journal of Epidemiology 47.2 (2018): 526-536.

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