Association of Estrogen-Related Polygenetic Risk Scores with Breast Cancer and Interactions with Alcohol Intake, Early Menarche, and Nulligravida

Abstract

Backgrounds: Early menstruation, late menopause, no pregnancy, and genetic factors are known risk factors of the disease, but their effects may differ in Asian and Caucasian women. The purpose of this study was to identify geneticvariants of genes related to estrogen signaling in a large city hospital-based cohort and to determine their interactionswith lifestyles. Methods: This is a case-control study. Three hundred ninety participants diagnosed with breast cancerwere compared with 36,290 controls(no cancer)to explore the genetic variants to influence breast cancer risk. Based onGWAS results, the selected genetic variants were subjected to their interactions by generalized multifactor dimensionalityreduction (GMDR) analysis. Results: Early menstruation(OR=1.55), early menopause (OR=1.70), and no experienceof pregnancy(OR=2.86) had a positive association with breast cancer risk(P<0.05). The selected polygenetic riskscore(PRS) models included four SNPs and seven SNPs: The four-SNP PRS model included CDH13_rs12600325,SMYD3_rs3753686, FGF12_rs2134635, and ESRRB_rs10873289, and in the seven-SNP PRS model, ESR1_ rs2046210,estrogen-related receptor gamma(ESRRG)_rs17043393, and EGFR_ rs6958497 were added into the four-SNP PRSmodel. Early menstruation, early menopause, and no pregnancy experience interacted with four-SNP PRS. For theparticipants who had early menstruation and early menopause, high-PRS had an association with a much higher breastcancer risk than the low-PRS in the four-SNP model. However, metabolic parameters, nutrient intakes, and differentdietary patterns did not interact with PRS for breast cancer risk. However, alcohol intake interacted with PRS for breastcancer risk (OR=2.33 and 8.07 for mild and moderate alcohol consumption, respectively; P=0.0004). Conclusion:Consideration of age at menarche and menopause, pregnancy experience, and alcohol intake may be required to reducebreast cancer risk in women with a high-PRS of genes related to the estrogen signaling pathway