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

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.

Figure 1

Forest plots for the three candidate loci (rs1079866, rs7821178, and rs2517388) in association with breast cancer risk. Per-risk-allele odds ratios (ORs) and 95% confidence intervals (CIs) were obtained from unconditional logistic regression in each study, and age and potential population stratification were adjusted for. The size of the box is inversely proportional to the standard error of the log OR estimate. P values for heterogeneity across studies are 0.37, 0.43, and 0.08, respectively. ARIC, Atherosclerosis Risk in Communities Study; FHS, Framingham Heart Study; NHS, Nurses' Health Study; RSI+II, Rotterdam Study I, II; SardiNIA, SardiNIA Breast Cancer Study; WGHS, Women's Genome Health Study.

Figure 2

The associations between groups defined by quintiles of genetic risk scores (GRSs) and risk of breast cancer by estrogen receptor (ER) status in the Nurses' Health Study and the Women's Genome Health Study. (a) Count GRS for age at menarche. (b) Count GRS for age at natural menopause. (c) Count GRS for breast cancer-associated SNPs. CI, confidence interval.