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

Nicolás Mendoza ^*  ,
Rafael Sánchez-Borrego ,
Daniela Galiano ,
Alberto Salamanca  ,
Juan Mozas  ,
Francisco Quereda ^**,
Francisco Vázquez ,
Txantón Martínez-Astorquiza  and
Francisco Moron 

^* Clínica MAR&Gen, Granada, Spain
University of Granada, Spain
Clínica Diatros, Barcelona, Spain
Hospital Virgen de las Nieves, Granada, Spain
^** Hospital Universitario San Juan, Alicante, Spain
Clínica GEOGA, Lugo, Spain
Hospital Universitario Cruces, Bilbao, Spain
Departamento de Genómica Estructural, Neocodex, Sevilla, Spain

Correspondence: Nicolás Mendoza MD PhD, Maestro Montero, 21, 18004 Granada, Spain. Email: nmendozal{at}sego.es

Objective. Age at natural menopause (ANM) can be considered a complex parameterthat depends on the interaction of multiple factors. In thepresent study, the role of interaction between genetic variantswithin estrogen synthesis and signalling pathways in the ANMin Spanish women is studied.

Material and methods. Nine single nucleotide polymorphisms (SNPs) located at differentcandidate genes related to the estrogen signalling pathway wereanalysed in 1980 Spanish postmenopausal women.

Results. 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).

Conclusions. The results suggest that epistatic interactions of estrogen-relatedalleles may contribute to variance in ANM in Spanish women.Moreover, BMP15 and NRIP1 also appear as attractive candidategenes for premature menopause but require further investigationto confirm them.

Key Words: Age at menopause • polymorphism • estrogen

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