Reproductive aging-associated common genetic variants and the risk of breast cancer

Chunyan He, Daniel I. Chasman, Jill Dreyfus, Shih Jen Hwang, Rikje Ruiter, Serena Sanna, Julie E. Buring, Lindsay Fernández-Rhodes, Nora Franceschini, Susan E. Hankinson, Albert Hofman, Kathryn L. Lunetta, Giuseppe Palmieri, Eleonora Porcu, Fernando Rivadeneira, Lynda M. Rose, Greta L. Splansky, Lisette Stolk, André G. Uitterlinden, Stephen J. ChanockLaura Crisponi, Ellen W. Demerath, Joanne M. Murabito, Paul M. Ridker, Bruno H. Stricker, David J. Hunter

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16 Scopus citations


Introduction: A younger age at menarche and an older age at menopause are well established risk factors for breast cancer. Recent genome-wide association studies have identified several novel genetic loci associated with these two traits. However, the association between these loci and breast cancer risk is unknown.Methods: In this study, we investigated 19 and 17 newly identified single nucleotide polymorphisms (SNPs) from the ReproGen Consortium that have been associated with age at menarche and age at natural menopause, respectively, and assessed their associations with breast cancer risk in 6 population-based studies among up to 3,683 breast cancer cases and 34,174 controls in white women of European ancestry. In addition, we used these SNPs to calculate genetic risk scores (GRSs) based on their associations with each trait.Results: After adjusting for age and potential population stratification, two age at menarche associated SNPs (rs1079866 and rs7821178) and one age at natural menopause associated SNP (rs2517388) were associated with breast cancer risk (p values, 0.003, 0.009 and 0.023, respectively). The odds ratios for breast cancer corresponding to per-risk-allele were 1.14 (95% CI, 1.05 to 1.24), 1.08 (95% CI, 1.02 to 1.15) and 1.10 (95% CI, 1.01 to 1.20), respectively, and were in the direction predicted by their associations with age at menarche or age at natural menopause. These associations did not appear to be attenuated by further controlling for self-reported age at menarche, age at natural menopause, or known breast cancer susceptibility loci. Although we did not observe a statistically significant association between any GRS for reproductive aging and breast cancer risk, the 4 th and 5 th highest quintiles of the younger age at menarche GRS had odds ratios of 1.14 (95% CI, 1.01 to 1.28) and 1.13 (95% CI, 1.00 to 1.27), respectively, compared to the lowest quintile.Conclusions: Our study suggests that three genetic variants, independent of their associations with age at menarche or age at natural menopause, were associated with breast cancer risk and may contribute modestly to breast cancer risk prediction; however, the combination of the 19 age at menarche or the 17 age at natural menopause associated SNPs did not appear to be useful for identifying a high risk subgroup for breast cancer.

Original languageEnglish (US)
Article numberR54
JournalBreast Cancer Research
Issue number2
StatePublished - Mar 20 2012

Bibliographical note

Funding Information:
The NHS breast cancer GWAS scan was performed as part of the Cancer Genetic Markers of Susceptibility initiative of the National Cancer Institute (NCI). We particularly acknowledge the contributions of Robert Hoover, Amy Hutchinson, Kevin Jacobs, and Gilles Thomas. The present research is supported by CA 40356 and U01-CA98233 from the NCI. We acknowledge the study participants in the NHS for their contribution in making this study possible. The WGHS is supported by HL 043851 and HL69757 from the National Heart, Lung, and Blood Institute (NHLBI) and CA 047988 from the NCI, the Donald W Reynolds Foundation, and the Fondation Leducq, and collaborative scientific support and funding for genotyping were provided by Amgen (Thousand Oaks, CA, USA). We thank Joseph Miletich and Alex Parker and the technical staff at Amgen for their collaboration and scientific support in performing the genotyping for the WGHS. The SardiNIA Breast Cancer Study was funded by National Institutes of Health (NIH) contract NO1-AG-1-2109 from the National Institute of Aging (NIA) to the SardiNIA team (principal investigator: Manuela Uda). We thank Grazia Palomba, Antonio Cossu, Francesco Tanda, Mario Budroni, and the other members of the Sardinian Translational Oncology Group for their contribution in collecting Sardinian patients with breast cancer. The generation and management of GWAS genotype data for the Rotterdam Study are supported by The Netherlands Organisation for Scientific Research (NWO) Investments (175.010.2005.011 and 911-03-012). This study is funded by the Research Institute for Diseases in the Elderly (RIDE2) (014-93-015) and The Netherlands Genomics Initiative/NWO project 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera, and Marjolein Peters for their help in creating the GWAS database and Karol Estrada and Maksim V Struchalin for their support in creation and analysis of imputed data. The Rotterdam Study is funded by the Erasmus Medical Center and Erasmus University, Rotterdam; the Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The authors acknowledge the essential role of the Cohorts for Heart and Aging Research in Genome Epidemiology (CHARGE) Consortium in the development and support of this manuscript. CHARGE members consist of The Netherlands’ Rotterdam Study, the FHS, the Cardiovascular Health Study, the NHLBI’s ARIC study, and the NIA’s Iceland Age, Gene/Environment Susceptibility (AGES) study. The FHS phenotype-genotype analyses were supported in part by the NIA (Genetics of Reproductive Life Period and Health Outcomes, R21AG032598; JMM, KLL). The FHS of the NHLBI of the NIH and Boston University School of Medicine was supported by NHLBI’s FHS contract N01-HC-25195 and its contract with Affymetrix, Inc. (Santa Clara, CA, USA) for genotyping services (contract N02-HL-6-4278). Analyses reflect intellectual input and resource development from the FHS investigators participating in the SNP Health Association Resource (SHARe) project. A portion of this research was conducted by using the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The ARIC study is carried out as a collaborative study supported by NHLBI contracts N01-HC- 55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, and RC2 HL102419; National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. The authors thank the staff and participants of the ARIC study for their important contributions. Infrastructure was partly supported by grant UL1RR025005, a component of the NIH, and NIH Roadmap for Medical Research.


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