Gene polymorphisms in RANKL/RANK/OPG pathway are associated with ages at menarche and natural menopause in Chinese women

BACKGROUND: Age at menarche (AAM) and age at natural menopause (AANM) have been shown intimately associated with woman’s health later in life. Previous studies have indicated that AAM and AANM are highly heritable. RANKL/RANK/OPG signaling pathway is essential for mammary gland development, which is also found associated with post-menopausal and hormone-related diseases. The aim of this study was to evaluate associations between the polymorphisms in the TNFSF11, TNFRSF11A and TNFRSF11B genes in the RANKL/RANK/OPG pathway with AAM and AANM in Chinese women. METHODS: Post-menopausal Chinese women (n = 845) aged from 42 to 89 years were recruited in the study. Information about AAM and AANM were obtained through questionnaires and the genomic DNA was isolated from peripheral blood from the participants. Total 21 tagging single nucleotide polymorphisms (SNPs) of TNFSF11, TNFRSF11A and TNFRSF11B were genotyped. RESULTS: Three SNPs of TNFRSF11A (rs4500848, rs6567270 and rs1805034) showed significant association with AAM (P < 0.01, P = 0.02 and P = 0.01, respectively), and one SNP (rs9962159) was significantly associated with AANM (P = 0.03). Haplotypes TC and AT (rs6567270-rs1805034) of TNFRSF11A were found to be significantly associated with AAM (P = 0.01 and P = 0.02, respectively), and haplotypes GC and AC (rs9962159-rs4603673) of TNFRSF11A showed significant association with AANM (P = 0.03 and P < 0.01, respectively). No significant association between TNFSF11 or TNFRSF11B gene with AAM or AANM was found. CONCLUSIONS: The present study suggests that TNFRSF11A but not TNFSF11 and TNFRSF11B genetic polymorphisms are associated with AAM and AANM in Chinese women. The findings provide evidence that genetic variations in RANKL/RANK/OPG pathway may be associated with the onset and cessation of the menstruation cycle.