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

TitleReproductive aging-associated common genetic variants and the risk of breast cancer.
Publication TypeJournal Article
Year of Publication2012
AuthorsHe C, Chasman DI, Dreyfus J, Hwang S-J, Ruiter R, Sanna S, Buring JE, Fernández-Rhodes L, Franceschini N, Hankinson SE, Hofman A, Lunetta KL, Palmieri G, Porcu E, Rivadeneira F, Rose LM, Splansky GL, Stolk L, Uitterlinden AG, Chanock SJ, Crisponi L, Demerath EW, Murabito JM, Ridker PM, Stricker BH
Secondary AuthorsHunter DJ
JournalBreast Cancer Res
Volume14
Issue2
PaginationR54
Date Published2012 Mar 20
ISSN1465-542X
KeywordsAdolescent, Adult, Breast Neoplasms, Case-Control Studies, Child, European Continental Ancestry Group, Female, Humans, Menarche, Menopause, Middle Aged, Polymorphism, Single Nucleotide, Risk Factors
Abstract

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 4th and 5th 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.

DOI10.1186/bcr3155
Alternate JournalBreast Cancer Res
PubMed ID22433456
PubMed Central IDPMC3446388
Grant ListUL1RR025005 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
HL 043851 / HL / NHLBI NIH HHS / United States
U01-CA98233 / CA / NCI NIH HHS / United States
N01-AG-1-2109 / AG / NIA NIH HHS / United States
RC2 HL102419 / HL / NHLBI NIH HHS / United States
HL69757 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
CA 047988 / CA / NCI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
R21AG032598 / AG / NIA NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
CA 40356 / CA / NCI NIH HHS / United States