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Involvement of 17?-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis.

ABSTRACT: Endometriosis is considered to be an estrogen-related chronic inflammatory disease. The 17?-hydroxysteroid dehydrogenase 1 (HSD17B1) converts estrone to 17? estradiol. The role of HSD17B1 937 A>G (rs605059) single nucleotide polymorphism (SNP) in development of endometriosis is still disputable. This study evaluated the association of the HSD17B1 937 A>G (rs605059) SNP with infertile women affected by endometriosis from Polish Caucasian population.The genotyping of cases (n = 290) and fertile women (n = 410) was conducted by high-resolution melting curve analysis.Statistical analysis demonstrated that the HSD17B1 937 A>G SNP is associated with endometriosis in stages I and II. The p trend and p allelic values calculated for the HSD17B1 937 A>G polymorphism were statistically significant and were equal to 0.001 and 0.0009, respectively. There was a significant association for the dominant model: (AG + GG vs AA) OR = 1.973 (95% CI = 1.178-3.304), p = 0.009, and for the recessive model: (GG vs AG + AA) OR = 1.806 (95% CI = 1.178-2.770), p = 0.006. However, we did not find statistical association of HSD17B1 937 A>G polymorphism with all infertile women with endometriosis or infertile women with endometriosis in stages III and IV.Our genetic study demonstrated HSD17B1 937 G variant as a risk factor for infertility in women with stage I and II endometriosis in Polish Caucasian patients.

SUBMITTER: Osinski M

PROVIDER: S-EPMC5445048 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Involvement of 17β-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis.

Osiński Maciej M Mostowska Adrianna A Wirstlein Przemyslaw P Skrzypczak Jana J Jagodziński Paweł Piotr PP Szczepańska Malgorzata M

Journal of assisted reproduction and genetics 20170412 6

<h4>Purpose</h4>Endometriosis is considered to be an estrogen-related chronic inflammatory disease. The 17β-hydroxysteroid dehydrogenase 1 (HSD17B1) converts estrone to 17β estradiol. The role of HSD17B1 937 A>G (rs605059) single nucleotide polymorphism (SNP) in development of endometriosis is still disputable. This study evaluated the association of the HSD17B1 937 A>G (rs605059) SNP with infertile women affected by endometriosis from Polish Caucasian population.<h4>Methods</h4>The genotyping o ...[more]

PMID: 28405865

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Project description:17?-Hydroxysteroid dehydrogenase type 1 (17?-HSD1) catalyzes the reduction of estrone to estradiol, which is the most potent estrogen in humans. Inhibition of 17?-HSD1 and thereby reducing the intracellular estradiol concentration is thus a promising approach for the treatment of estrogen dependent diseases. In the past, several steroidal and non-steroidal inhibitors of 17?-HSD1 have been described but so far there is no cocrystal structure of the latter in complex with 17?-HSD1. However, a distinct knowledge of active site topologies and protein-ligand interactions is a prerequisite for structure-based drug design and optimization. An elegant strategy to enhance this knowledge is to compare inhibition values obtained for one compound toward ortholog proteins from various species, which are highly conserved in sequence and differ only in few residues. In this study the inhibitory potencies of selected members of different non-steroidal inhibitor classes toward marmoset 17?-HSD1 were determined and the data were compared with the values obtained for the human enzyme. A species specific inhibition profile was observed in the class of the (hydroxyphenyl)naphthols. Using a combination of computational methods, including homology modelling, molecular docking, MD simulation, and binding energy calculation, a reasonable model of the three-dimensional structure of marmoset 17?-HSD1 was developed and inhibition data were rationalized on the structural basis. In marmoset 17?-HSD1, residues 190 to 196 form a small ?-helix, which induces conformational changes compared to the human enzyme. The docking poses suggest these conformational changes as determinants for species specificity and energy decomposition analysis highlighted the outstanding role of Asn152 as interaction partner for inhibitor binding. In summary, this strategy of comparing the biological activities of inhibitors toward highly conserved ortholog proteins might be an alternative to laborious x-ray or site-directed mutagenesis experiments in certain cases. Additionally, it facilitates inhibitor design and optimization by offering new information on protein-ligand interactions.

Dataset Information

Involvement of 17?-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis.

Publications

Involvement of 17β-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis.

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