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

Cardoso, Jéssica Vilarinho; Machado, Daniel Escorsim; Ferrari, Renato; Silva, Mayara Calixto da; Berardo, Plínio Tostes; Perini, Jamila Alessandra

doi:10.1055/s-0037-1604097

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Revista Brasileira de Ginecologia e Obstetrícia

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Original Article • Rev. Bras. Ginecol. Obstet. 39 (06) • June 2017 • https://doi.org/10.1055/s-0037-1604097 copy

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

Efeito combinado dos polimorfismos PGR + 331C > T, CYP17A1 -34A > G e CYP19A1 1531G > A no risco de desenvolvimento da endometriose

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

Keywords:
polymorphisms; estrogens; endometriosis; biomarkers

Variable	Controls(N= 179)	Cases(N= 161)	p*
Age (years)	n (%)
18–29	30 (16.8)	29 (18.0)	0.011
30–39	60 (33.5)	79 (49.1)
≥ 40	86 (48.0)	48 (29.8)
No information	3 (1.7)	5 (3.1)
Marital status
Married/partner	96 (53.6)	111 (68.9)	0.046
Single	53 (29.6)	38 (23.7)
Divorced/Widow	5 (2.8)	1 (0.6)
No information	25 (14.0)	11 (6.8)
Level of Schooling
Elementary education	38 (21.3)	24 (14.9)	< 0.001
High school	89 (49.7)	60 (37.3)
Higher education	26 (14.5)	67 (41.6)
No information	26 (14.5)	10 (6.2)
BMI
< 18.5	3 (1.7)	7 (4.4)	0.013
18.5–24.9	48 (26.8)	48 (29.8)
25–29.9	50 (27.9)	63 (39.1)
30–40	65 (36.3)	35 (21.7)
> 40	13 (7.3)	8 (5.0)
Infertility
Primary	19 (10.6)	53 (32.9)	< 0.001
Secondary	3 (1.7)	16 (9.9)
None**	133 (74.3)	58 (36.1)
No attempt	20 (11.2)	32 (19.9)
No information	4 (2.2)	2 (1.2)
Parity
0	19 (10.6)	53 (32.8)	< 0.001
1	23 (12.8)	37 (23.0)
2	58 (32.5)	27 (16.8)
3 or more	55 (30.7)	10 (6.2)
No attempt	20 (11.2)	32 (20.0)
No information	4 (2.2)	2 (1.2)
Symptoms***
Dysmenorrhea	29 (16.1)	77 (47.5)	< 0.001
Chronic pelvic pain	70 (38.9)	124 (76.5)
Dyspareunia	50 (27.8)	102 (63.0)
Cyclical urinary complaints****	9 (6.4)	41 (27.5)
Cyclical intestinal complaints****	8 (6.0)	74 (49.7)

Genotypes	ControlsN (%)	CasesN (%)	p *	OR(95%CI)**
PGR +331C > T, CYP17 -34A > G and CYP19 1531G > A
WT / WT / WT	23 (13.5)	11 (7.3)		1***
WT / WT / VAR	29 (17.1)	28 (18.6)	0.20	1.82 (0.73–4.57)
WT / VAR / VAR	70 (41.2)	60 (40.0)	0.17	1.35 (0.88–2.05)
VAR / WT / WT	2 (1.2)	4 (2.7)	0.18	1.57 (0.82–3.00)
VAR / VAR / WT	7 (4.1)	10 (6.7)	0.20	1.23 (0.90–1.67)
VAR / WT / VAR	1 (0.6)	7 (4.7)	0.02	1.72 (1.09–2.72)
WT / VAR / WT	25 (14.7)	22 (14.7)	0.15	1.13 (0.96–1.34)
VAR / VAR / VAR	13 (7.6)	8 (5.3)	0.87	1.02 (0.85–1.21)

Polymorphism	Population	N*	Frequency among the controls (%)	Frequency among the cases (%)	Association with endometriosis	Reference
PGR +331 C > T (rs10895068)			PGR +331 T
	Estonia	349	8.8	6.7	No association	Lamp et al¹⁸18 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
	United States	823	4.8	5.1	No association	Trabert et al¹⁹19 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
	Netherlands	165	9.7	2.3	Protective (T allele)	van Kaam et al¹⁵15 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
	Brazil	179	6.6	10.1	No association	Present study
CYP17A1 -34 A > G (rs743572)			CYP17A1 -34 G
	Turkey	93	30.8	57.6	No association	Bozdag et al¹⁷17 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
	China	247	60.2	50.8	Risk (A allele)	Hsieh et al¹¹11 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
	China	227	62.9	50.8	Risk (A allele)	Hsieh et al¹²12 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
	China	510	54.3	58.2	No association	Juo et al¹³13 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
	Japan	317	39.8	42.9	No association	Kado et al¹⁰10 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
	United States	823	39.3	34.8	No association	Trabert et al¹⁹19 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
	Italy	190	37.2	42.3	No association	Vietri et al¹⁶16 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
	Brazil	180	42.7	44.4	No association	Present study
CYP19A1 1531 G > A (rs10046)			CYP19A1 1531 A
	Korea	412	55.9	55.8	No association	Hur et al¹⁴14 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
	Estonia	349	59.8	55.0	No association	Lamp et al¹⁸18 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
	China	371	56.4	57.5	No association	Wang et al²⁰20 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
	China	202	41.0	35.3	No association	Yang et al²¹21 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
	Brazil	180	39.4	40.6	No association	Present study

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[1] Address for correspondence Jamila Alessandra Perini, PhD, Research Laboratory of Pharmaceutical Sciences, Pharmacy Unit, Centro Universitário Estadual da Zona Oeste, Av. Manoel Caldeira de Alvarenga, 1203 - Campo Grande, 23070-200 - Rio de Janeiro, RJ, Brazil (e-mail: jamilaperini@yahoo.com.br; jamila.perini@pq.cnpq.br).