Multigenic combination of estrogen-related genes is associated with age at natural menopause in a Spanish population

Age at natural menopause (ANM) can be considered a complex parameter that depends on the interaction of multiple factors. In the present study, the role of interaction between genetic variants within estrogen synthesis and signalling pathways in the ANM in Spanish women is studied.

Nine single nucleotide polymorphisms (SNPs) located at different candidate genes related to the estrogen signalling pathway were analysed in 1980 Spanish postmenopausal women.

Independently, none of the nine markers were significantly associated with early ANM. Only heterozygosis at the NRIP rs2229741 locus could be associated with early menopause; however, this marker does not maintain statistical significance. In contrast, linear regression analysis suggests several epistatic interactions including these markers in relation to ANM, especially between ESR2, NRIP1 and BMP15. The genetic variant that appears most in these interactions is that of the BMP15 rs3897937. It was observed that AA-TC combined genotype for NRIP-BMP15 (rs3897937), respectively, appears to be associated with a lower ANM than other possible combinations of these SNP (46.1+/-5.9 versus 50.4+/-3.3; P = 0.002). In the multilocus analysis, the multigenic interaction formed by ESR2 (AA), BMP15 rs3897937 (TC) and NRIP1 (AA) has the lower ANM (45.37+/-6.8 versus 48.69+/-5; P = 0.038).

The results suggest that epistatic interactions of estrogen-related alleles may contribute to variance in ANM in Spanish women. Moreover, BMP15 and NRIP1 also appear as attractive candidate genes for premature menopause but require further investigation to confirm them.