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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, 307(Ala/Ala)+307(Ala/Thr)) of FSHR, rs 6166 (genotype GG+GA, 680(Ser/Asn)+680(Ser/Ser)) of FSHR, rs2066479 (genotype AA+AG, 289(Ser/Ser)+289(Ser/Gly)) of HSD17B3 and rs700519 (genotype TT+TC, 264(Cys/Cys)+264(Cys/Arg)) of CYP19, alone or in combination, were significantly associated with decreased risks of endometriosis. Bioinformatics results identified 307(Thr) of FSHR to be a site for O-linked glycosylation, 680(Ser) of FSHR a phosphorylated site by protein kinase B, and 289(Ser) 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.

SUBMITTER: Wang HS

PROVIDER: S-EPMC3490981 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Functional analyses of endometriosis-related polymorphisms in the estrogen synthesis and metabolism-related genes.

Wang Hsin-Shih HS Wu Hsien-Ming HM Cheng Bi-Hwa BH Yen Chih-Feng CF Chang Pi-Yueh PY Chao Angel A Lee Yun-Shien YS Huang Hsien-Da HD Wang Tzu-Hao TH

PloS one 20121106 11

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 r ...[more]

PMID: 23139742

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Project description:BACKGROUND: Many epidemiological studies have suggested an association between estrogen receptor-beta (ER-?) polymorphisms with endometriosis risk. However, the results of these studies have been inconsistent. In the present study, we performed a meta-analysis to clarify the associations between the ER-? rs4986938 and rs1256049 polymorphisms and endometriosis risk. METHODS: Eligible publications were retrieved from the PubMed, ISI Web of Science, and several Chinese language databases. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using a random or fixed effect model. RESULTS: A total of eight studies (1100 cases/1485 controls) for the rs4986938 polymorphism and four studies (353 cases/450 controls) for the rs1256049 polymorphism were included in this meta-analysis. Regarding the rs4986938 polymorphism, no obvious associations were found for all genetic models when all studies were pooled into the meta-analysis. In the subgroup analyses by ethnicity, study sample size, endometriosis-associated infertility, and stage of endometriosis, a significantly increased risk was observed among mixed populations (dominant model, OR=2.03, 95% CI=1.56-2.64) and among cases with endometriosis-associated infertility (dominant model, OR=1.83, 95% CI=1.26-2.67). Regarding the rs1256049 polymorphism, no obvious associations were found for all genetic models in the overall population. Subgroup analyses by ethnicity and study sample size revealed that only one study of a mixed population with small sample size showed an increased risk of endometriosis. No publication bias was found in the present study. CONCLUSIONS: The results of this meta-analysis suggest that the ER-? rs4986938 and rs1256049 polymorphisms may not be associated with endometriosis risk, while the observed increased risk of endometriosis-associated infertility may be due to bias by the inclusion of small-scale studies. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/13000_2014_184.

Dataset Information

Functional analyses of endometriosis-related polymorphisms in the estrogen synthesis and metabolism-related genes.

Publications

Functional analyses of endometriosis-related polymorphisms in the estrogen synthesis and metabolism-related genes.

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