Genetic variations, reproductive aging, and breast cancer risk in African American and European American women: The Women's Circle of Health Study.

Marie V Coignet,Song Yao,Michelle R Roberts,Thaer Khoury,Elisa V Bandera,Qianqian Zhu,Gary Robert Zirpoli

doi:10.1371/journal.pone.0187205

Abstract

Reproductive aging phenotypes, including age at menarche (AM) and age at natural menopause (ANM), are well-established risk factors for breast cancer. In recent years, many genetic variants have been identified in association with AM and ANM in genome-wide association studies among European populations. Using data from the Women’s Circle of Health Study (WCHS) of 1,307 European-American (EA) and 1,365 African-American (AA) breast cancer cases and controls, we aimed to replicate 53 earlier GWAS variants for AM and ANM in AA and EA groups and to perform analyses on total and net reproductive lifespan (TRLS; NRLS). Breast cancer risk was also examined in relation to a polygenic risk score (PRS) for each of the reproductive aging phenotypes. We replicated a number of variants in EA women, including rs7759938 in LIN28B for AM and rs16991615 in MCM8 for ANM; whereas in the AA group, only one SNP (rs2947411 in TMEM18) for AM was directionally consistent and nominally significant. In analysis of TRLS and NRLS, several SNPs were significant, including rs466639 in RXRG that was associated with both phenotypes in both AA and EA groups. None of the PRS was associated with breast cancer risk. Given the paucity of data available among AA populations, our study contributes to the literature of genetics of reproductive aging in AA women and highlights the importance of cross population replication of GWAS variants.

Highlights

Menarche and menopause are two fundamental physiological events in a woman’s life, respectively marking the beginning and the end of reproductive age
We considered total and net reproductive lifespan (TRLS) to be the difference between at natural menopause (ANM) and at menarche (AM), and net reproductive lifespan (NRLS) to be equal to TRLS with time spent on all pregnancies and breastfeeding subtracted
In a breast cancer case-control study with similar number of AA and EA women, we replicated several SNPs identified in previous genome-wide association studies (GWAS) of AM and ANM in the EA group, including the top GWAS signals rs7759938 in LIN28B and rs16991615 in MCM8

Summary

Objectives

Using data from the Women’s Circle of Health Study (WCHS) of 1,307 European-American (EA) and 1,365 African-American (AA) breast cancer cases and controls, we aimed to replicate 53 earlier GWAS variants for AM and ANM in AA and EA groups and to perform analyses on total and net reproductive lifespan (TRLS; NRLS). In the Women’s Circle of Health Study (WCHS), which enrolled a similar number of AA and EA women, with and without breast cancer, we aimed to replicate earlier GWAS findings in both AA and EA women, as well as to examine them with breast cancer risk in the two groups. Our goal was to replicate single nucleotide polymorphisms (SNPs) that were previously identified in GWAS of AM and ANM in EA populations

Methods

Results

Conclusion