Candidate genes for age at menarche are associated with endometrial hyperplasia.

Abstract

To study associations candidate genes for age at menarche with a risk of endometrial hyperplasia (EH). 52 candidate loci for age at menarche were analyzed for possible association with EH in a sample of 520 patients and 981 controls. Association of the polymorphisms was analyzed using the method of logistic regression. The gene-gene and gene-environment interactions were analyzed using MB-MDR. 21 polymorphisms, which were associated with EH, and 397 polymorphisms linked to them (r2≥0.8) were analyzed in silico for their functional significance. 21 out of the 52 studied polymorphisms had association with EH. Locus rs11031010 FSHB was individually associated with the disease according to the dominant (OR=0.62, pperm=0.001) and additive (OR=0.67, pperm=0.002) models. Haplotype GAA of loci rs555621-rs11031010-rs1782507 FSHB were associated with the EH (OR=0.66, pperm=0.007). Seventeen loci were associated with EH within 12 most significant models of intergenic interactions (pperm≤0.001). Locus rs4374421 of the LHCGR gene appeared in the largest number of models (four models). Nine loci involved in 14 most significant models of interactions between SNP, induced abortions, and chronic endometritis were associated with EH. The polymorphisms of genes FTO (rs12324955) and FSHB (rs11031010) appeared in the largest number of the models (9 and 6, respectively). Among the 21 loci associated with EH, 16 manifested association also with either age at menarche (7 SNPs) or height and/or BMI (13 SNPs). The above 21 SNPs and 397 SNPs linked to them have non-synonymous, regulatory and eQTL significance for 25 genes, which play roles in the pathways related to development of the female reproductive organs and hormone-mediated signaling (FDR≤0.05). Candidate genes for age at menarche are associated with endometrial hyperplasia.