Functional Analyses of Endometriosis-Related Polymorphisms in the Estrogen Synthesis and Metabolism-Related Genes

Abstract

Endometriosis is determined by genetic factors, and the prevalence of genetic polymorphisms varies greatly depending on the ethnic group studied. The objective of this study was to investigate the relationship between single nucleotide polymorphisms (SNPs) of 9 genes involved in estrogen biosynthesis and metabolism and the risks of endometriosis. Three hundred patients with endometriosis and 337 non-endometriotic controls were recruited. Thirty four non-synonymous SNPs, which change amino acid residues, were analyzed using matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF MS). The functions of SNP-resulted amino acid changes were analyzed using multiple web-accessible databases and phosphorylation predicting algorithms. Among the 34 NCBI-listed SNPs, 22 did not exhibit polymorphism in this study of more than 600 Taiwanese Chinese women. However, homozygous and heterozygous mutants of 4 SNPs - rs6165 (genotype GG+GA, 307Ala/Ala+307Ala/Thr) of FSHR, rs 6166 (genotype GG+GA, 680Ser/Asn+680Ser/Ser) of FSHR, rs2066479 (genotype AA+AG, 289Ser/Ser+289Ser/Gly) of HSD17B3 and rs700519 (genotype TT+TC, 264Cys/Cys+264Cys/Arg) of CYP19, alone or in combination, were significantly associated with decreased risks of endometriosis. Bioinformatics results identified 307Thr of FSHR to be a site for O-linked glycosylation, 680Ser of FSHR a phosphorylated site by protein kinase B, and 289Ser of HSD17B3 a phosphorylated site by protein kinase B or ribosomal protein S6 kinase 1. Results of this study suggest that non-synonymous polymorphisms of FSHR, HSD17B3 and CYP19 genes may modulate the risk of endometriosis in Taiwanese Chinese women. Identification of the endometrosis-preferential non-synonymous SNPs and the conformational changes in those proteins may pave the way for the development of more disease-specific drugs.

Association between CYP19A1, GSTM1, GSTT1, and GSTP1 genetic polymorphisms and the development of endometriosis in a Chinese population

“…CYP19A1 gene polymorphism is associated with reduced aromatase activity, which can lead to the development of endometriosis (Wang et al, 2010;Zaree et al, 2015;Hosseini et al, 2016;Abu Hashim, 2016). While previous studies have investigated the association between CYP19A1 and risk of endometriosis, the results were inconsistent (Hur et al, 2007;Vietri et al, 2009;Yang et al, 2010;Szczepańska et al, 2013;Wang et al, 2012Wang et al, , 2014. We have shown that there is a significant correlation between CYP19A1 rs2899470 and risk of endometriosis in a Chinese population.…”

Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (Review)

“…Non-synonymous polymorphisms of CYP19A1 gene may modulate (CYP19A1) the risk of endometriosis in Taiwanese Chinese women (155,156). AA and CC genotypes were significantly represented in Val80 and 1558G/T polymorphisms of CYP19 in patients affected with endometriosis (157).…”

“…Non-synonymous polymorphisms of the FSHR gene may modulate the hormone receptor risk of endometriosis in Taiwanese Chinese women (155,156). Both the GG (680Ser/Ser) and GA (680Ser/Asn) genotypes of FSHR were associated with a significantly lower risk of endometriosis (177).…”

“…Hydroxysteroid (17-β) Non-synonymous polymorphisms of HSD17B3 gene may modulate dehydrogenase 3 the risk of endometriosis in Taiwanese Chinese women (155,156).…”

A review of the risk factors, genetics and treatment of endometriosis in Chinese women: a comparative update

“…These genes belong to diverse groups, both functionally as well as spatially. However, a strong association has been detected between single nucleotide polymorphisms (SNPs) in hormone receptor and metabolism related genes and endometriosis in Taiwanese Chinese Women [ 41 ]. A study in Taiwanese women also showed that MUC17 polymorphisms are involved in endometriosis development and associated infertility [ 11 ].…”