Combined Effect of the PGR +331C > T, CYP17A1 -34A > G and CYP19A1 1531G > A Polymorphisms on the Risk of Developing Endometriosis

Abstract

Purpose To evaluate the magnitude of the association of the polymorphisms of the genes PGR, CYP17A1 and CYP19A1 in the development of endometriosis.

Methods This is a retrospective case-control study involving 161 women with endometriosis (cases) and 179 controls. The polymorphisms were genotyped by real-time polymerase chain reaction using the TaqMan system. The association of the polymorphisms with endometriosis was evaluated using the multivariate logistic regression.

Results The endometriosis patients were significantly younger than the controls (36.0 ± 7.3 versus 38.0 ± 8.5 respectively, p = 0.023), and they had a lower body mass index (26.3 ± 4.8 versus 27.9 ± 5.7 respectively, p = 0.006), higher average duration of the menstrual flow (7.4 ± 4.9 versus 6.1 ± 4.4 days respectively, p = 0.03), and lower average time intervals between menstrual periods (25.2 ± 9.6 versus 27.5 ± 11.1 days respectively, p = 0.05). A higher prevalence of symptoms of dysmenorrhea, dyspareunia, chronic pelvic pain, infertility and intestinal or urinary changes was observed in the case group when compared with the control group. The interval between the onset of symptoms and the definitive diagnosis of endometriosis was 5.2 ± 6.9 years. When comparing both groups, significant differences were not observed in the allelic and genotypic frequencies of the polymorphisms PGR +331C > T, CYP17A1 -34A > G and CYP19A1 1531G > A, even when considering the symptoms, classification and stage of the endometriosis. The combined genotype PGR +331TT/CYP17A1 -34AA/CYP19A11531AA is positively associated with endometriosis (odds ratio [OR] = 1.72; 95% confidence interval [95%CI] = 1.09–2.72).

Conclusions The combined analysis of the polymorphisms PGR-CYP17A1-CYP19A1 suggests a gene-gene interaction in the susceptibility to endometriosis. These results may contribute to the identification of biomarkers for the diagnosis and/or prognosis of the disease and of possible molecular targets for individualized treatments.

Resumo

Objetivo Avaliar a magnitude de associação de polimorfismos nos genes PGR, CYP17A1 e CYP19A1 no desenvolvimento da endometriose.

Métodos Este é um estudo retrospectivo do tipo caso-controle, envolvendo 161 mulheres com endometriose (casos) e 179 controles. Os polimorfismos foram genotipados pela reação em cadeia da polimerase em tempo real utilizando o sistema TaqMan. A associação dos polimorfismos estudados com a endometriose foi avaliada pela regressão logística multivariada.

Resultados As pacientes com endometriose eram significativamente mais jovens do que os controles (36,0 ± 7,3 versus 38,0 ± 8,5, respectivamente, p = 0,023), apresentaram um índice de massa corporal menor (26,3 ± 4,8 versus 27,9 ± 5,7, respectivamente, p = 0,006), maior tempo médio de duração do fluxo menstrual (7,4 ± 4,9 versus 6,1 ± 4,4 dias, respectivamente, p = 0,03) e menor tempo médio do intervalo entre as menstruações (25,2 ± 9,6 versus 27,5 ± 11,1 dias, respectivamente, p = 0,05). Uma maior prevalência dos sintomas de dismenorreia, dispareunia, dor pélvica crônica, infertilidade, alterações intestinais e urinárias foi observada no grupo casos comparado ao grupo controle. O tempo médio entre o início dos sintomas e o diagnóstico definitivo de endometriose foi de 5,2 ± 6,9 anos. Comparando os dois grupos, não foram observadas diferenças significativas nas frequências alélicas e genotípicas dos polimorfismos PGR +331C > T, CYP17A1 -34A > G e CYP19A1 1531G > A, e nem considerando os sintomas, a classificação e o estadiamento da endometriose. O genótipo combinado PGR +331TT/CYP17A1 -34AA/CYP19A11531AA está associado positivamente com a endometriose (razão de possibilidades [RP] = 1,72; intervalo de confiança de 95% [IC95%] = 1,09–2,72).

Conclusões A análise combinada dos polimorfismos PGR-CYP17A1-CYP19A1 sugere uma interação gene-gene na susceptibilidade à endometriose. Estes resultados podem contribuir para a identificação de biomarcadores para o diagnóstico e/ou prognóstico da doença, assim como de possíveis alvos moleculares para um tratamento individualizado.

Keywords

polymorphisms - estrogens - endometriosis - biomarkers

Palavras-chave

polimorfismos - estrógenos - endometriose - biomarcadores

• References

• 1 Acién P, Velasco I. Endometriosis: a disease that remains enigmatic. ISRN Obstet Gynecol 2013; 2013: 242149
• 2 Perini JA, Cardoso JV, Berardo PT. , et al. Role of vascular endothelial growth factor polymorphisms (-2578C > A, -460 T > C, -1154G > A, +405G > C and +936C > T) in endometriosis: a case-control study with Brazilians. BMC Womens Health 2014; 14: 117
• 3 Zondervan KT, Rahmioglu N, Morris AP. , et al. Beyond endometriosis genome-wide association study: from genomics to phenomics to the patient. Semin Reprod Med 2016; 34 (04) 242-254
• 4 Bell DW, Brannigan BW, Matsuo K. , et al. Increased prevalence of EGFR-mutant lung cancer in women and in East Asian populations: analysis of estrogen-related polymorphisms. Clin Cancer Res 2008; 14 (13) 4079-4084
• 5 Barcelos ID, Donabella FC, Ribas CP. , et al. Down-regulation of the CYP19A1 gene in cumulus cells of infertile women with endometriosis. Reprod Biomed Online 2015; 30 (05) 532-541
• 6 Bedaiwy MA, Dahoud W, Skomorovska-Prokvolit Y. , et al. Abundance and Localization of Progesterone Receptor Isoforms in Endometrium in Women With and Without Endometriosis and in Peritoneal and Ovarian Endometriotic Implants. Reprod Sci 2015; 22 (09) 1153-1161
• 7 Lafay Pillet MC, Schneider A, Borghese B. , et al. Deep infiltrating endometriosis is associated with markedly lower body mass index: a 476 case-control study. Hum Reprod 2012; 27 (01) 265-272
• 8 Ghisari M, Eiberg H, Long M, Bonefeld-Jørgensen EC. Polymorphisms in phase I and phase II genes and breast cancer risk and relations to persistent organic pollutant exposure: a case-control study in Inuit women. Environ Health 2014; 13 (01) 19
• 9 De Vivo I, Huggins GS, Hankinson SE. , et al. A functional polymorphism in the promoter of the progesterone receptor gene associated with endometrial cancer risk. Proc Natl Acad Sci U S A 2002; 99 (19) 12263-12268
• 10 Kado N, Kitawaki J, Obayashi H. , et al. Association of the CYP17 gene and CYP19 gene polymorphisms with risk of endometriosis in Japanese women. Hum Reprod 2002; 17 (04) 897-902
• 11 Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. Cytochrome P450c17alpha 5′-untranslated region *T/C polymorphism in endometriosis. J Genet 2004; 83 (02) 189-192
• 12 Hsieh YY, Chang CC, Tsai FJ, Lin CC, Tsai CH. Estrogen receptor alpha dinucleotide repeat and cytochrome P450c17alpha gene polymorphisms are associated with susceptibility to endometriosis. Fertil Steril 2005; 83 (03) 567-572
• 13 Juo SH, Wang TN, Lee JN, Wu MT, Long CY, Tsai EM. CYP17, CYP1A1 and COMT polymorphisms and the risk of adenomyosis and endometriosis in Taiwanese women. Hum Reprod 2006; 21 (06) 1498-1502
• 14 Hur SE, Lee S, Lee JY, Moon HS, Kim HL, Chung HW. Polymorphisms and haplotypes of the gene encoding the estrogen-metabolizing CYP19 gene in Korean women: no association with advanced-stage endometriosis. J Hum Genet 2007; 52 (09) 703-711
• 15 van Kaam KJ, Romano A, Schouten JP, Dunselman GA, Groothuis PG. Progesterone receptor polymorphism +331G/A is associated with a decreased risk of deep infiltrating endometriosis. Hum Reprod 2007; 22 (01) 129-135
• 16 Vietri MT, Cioffi M, Sessa M. , et al. CYP17 and CYP19 gene polymorphisms in women affected with endometriosis. Fertil Steril 2009; 92 (05) 1532-1535
• 17 Bozdag G, Alp A, Saribas Z, Tuncer S, Aksu T, Gurgan T. CYP17 and CYP2C19 gene polymorphisms in patients with endometriosis. Reprod Biomed Online 2010; 20 (02) 286-290
• 18 Lamp M, Peters M, Reinmaa E. , et al. Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis. Gynecol Endocrinol 2011; 27 (06) 425-433
• 19 Trabert B, Schwartz SM, Peters U. , et al. Genetic variation in the sex hormone metabolic pathway and endometriosis risk: an evaluation of candidate genes. Fertil Steril 2011; 96 (06) 1401-1406.e3
• 20 Wang L, Lu X, Wang D. , et al. CYP19 gene variant confers susceptibility to endometriosis-associated infertility in Chinese women. Exp Mol Med 2014; 46: e103
• 21 Yang X, Chen SQ, Liu M. [Association of the CYP19 gene polymorphism with genetic susceptibility to endometriosis]. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2010; 27 (06) 692-696
• 22 Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril 1997; 67 (05) 817-821
• 23 Nisolle M, Donnez J. Peritoneal endometriosis, ovarian endometriosis, and adenomyotic nodules of the rectovaginal septum are three different entities. Fertil Steril 1997; 68 (04) 585-596
• 24 Chapron C, Santulli P, de Ziegler D. , et al. Ovarian endometrioma: severe pelvic pain is associated with deeply infiltrating endometriosis. Hum Reprod 2012; 27 (03) 702-711
• 25 Bianek-Bodzak A, Szurowska E, Sawicki S, Liro M. The importance and perspective of magnetic resonance imaging in the evaluation of endometriosis. BioMed Res Int 2013; 2013: 436589
• 26 Ma K, Majumder K, Clayton R, Rajashanker B, Ed-Osagie E. Correlation between magnetic resonance imaging results and findings at surgery for cases of severe endometriosis. J Minim Invasive Gynecol 2015; 22 (6S): S55
• 27 Barcellos MB, Lasmar B, Lasmar R. Agreement between the preoperative findings and the operative diagnosis in patients with deep endometriosis. Arch Gynecol Obstet 2016; 293 (04) 845-850
• 28 Ito TE, Abi Khalil ED, Taffel M, Moawad GN. Magnetic resonance imaging correlation to intraoperative findings of deeply infiltrative endometriosis. Fertil Steril 2017; 107 (02) e11-e12