Investigation of biomarkers in Endometriosis-associated infertility: Systematic Review

EGASHIRA, ERIKA M.; TROVÓ-MARQUI, ALESSANDRA B.; TANAKA, SARAH C.S.V.; CINTRA, MARIANGELA T.R.

doi:10.1590/0001-3765202220211572

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HEALTH SCIENCES • An. Acad. Bras. Ciênc. 94 (suppl 3) • 2022 • https://doi.org/10.1590/0001-3765202220211572 copy

Investigation of biomarkers in Endometriosis-associated infertility: Systematic Review

Authorship SCIMAGO INSTITUTIONS RANKINGS

Abstract

The relationship between endometriosis and infertility is still unknown, but it is possible that genetic polymorphisms influence these two variables. This study aims to identify, in the literature, which polymorphisms are related to infertility in women with endometriosis. A search was performed in databases using the descriptors: polymorphisms genetics and infertility and endometriosis. 386 articles were identified, and after applying the inclusion and exclusion criteria, 33 case-control studies were included. Genes and their respective polymorphisms, which exhibited statistically significant values, were classified into three categories: related to metabolic/cellular processes, steroidogenesis and sex hormone receptors, inflammation and immune response. In summary, the results of these studies suggest that the polymorphisms rs882605 of MUC4 gene, rs16826658 of WNT4 gene, rs10953316 of MUC17 gene, rs10928050 of KAZN gene, rs1799889 of PAI-1 gene, (TA)n repeats of ESR1 gene, (CA)n repeats of ESR2 gene, rs605059 of HSD17B1 gene, rs743572 of CYP17A1 gene, insLQ of LHR gene, p.Ile49Ser of AMH gene, rs12700667 of NPVF/NFE2L3 gene, G1502A of LHβ gene, G + 1730A of ERβ gene, rs7528684 of FCRL3 gene, rs3761549 of FOXP3 gene and rs28362491 of NFKβ1 gene are implicated in the etiology of infertility in women with endometriosis.

Key words
endometriosis; genetic polymorphism; infertility; Systematic Review

Reference	Country	Sample size C/ED	Genotyping method	Gene	Polymorphism (s)	Polymorphic allele frequency C/ED	HWE C/ED	p value (genotypic frequency)	Quality
Ribeiro Júnior et al. 2009RIBEIRO JÚNIOR CL, ARRUDA JT, SILVA CT & MOURA KK. 2009. Analysis of p53 codon 72 gene polymorphism in Brazilian patients with endometriosis. Genet Mol Res 8: 494-499.	Brazil	19/19	PCR	TP53	rs1042522	Pro 0.42/0.23	Unrealized	p= 1.0	05
Chang et al. 2011CHANG CY, CHANG HW, CHEN CM, LIN CY, CHEN CP, LAI CH, LIN WY, LIU HP, SHEU JJ & TSAI FJ. 2011. MUC4 gene polymorphisms associate with endometriosis development and endometriosis-related infertility. BMC Med 9: 19.	Taiwan	150/140	Allelic discrimination	MUC4	rs882605	T 0.22/0.28	0.07/0.62	p= 0.04	06
					rs1104760	T 0.80/0.76	0.09/0.94	p= 0.30
					s2246901	T 0.78/0.75	0.15/0.96	p= 0.56
					rs2258447	G 0.79/0.77	0.07/0.37	p= 0.70
					rs2291652	C 0.26/0.30	0.26/0.92	p= 0.52
					rs2688513	T 0.78/0.77	0.09/0.62	p= 0.66
Lamp et al. 2011LAMP M, PETERS M, REINMAA E, HALLER-KIKKATALO K, KAART T, KADASTIK U, KARRO H, METSPALU A & SALUMETS A. 2011. Polymorphisms in ESR1, ESR2 and HSD17B1 genes are associated with fertility status in endometriosis. Gynecol Endocrinol 27: 425-433.	Estonia	199/150	PCR PCR–RFLP	ESR1	rs2234693	C 0.45/0.51	>0.05/>0.05	p= 0.21	08
					(TA)n	L 0.39/0.48	>0.05/>0.05	p<0.05
				ESR2	(CA)n	L 0.49/0.36	>0.05/>0.05	p<0.05
				HSD17B1	rs605059	A 0.50/0.57	>0.05/>0.05	p<0.05
				PGR	rs10895068	A 0.09/0.07	>0.05/>0.05	p= 0.35
					Ins/Del Alu	Del 0.87/0.84	>0.05/>0.05	p= 0.10
				CYP19A1	rs10046	T 0.60/0.55	>0.05/>0.05	p= 0.1
					(TTTA)n	L 0.41/0.40	>0.05/>0.05	p= 0.75
					Ins/Del	Del 0.41/0.26	>0.05/>0.05	p= 0.34
Szczepańska et al. 2011SZCZEPAŃSKA M, MOSTOWSKA A, WIRSTLEIN P, LIANERI M, MARIANOWSKI P, SKRZYPCZAK J & JAGODZIŃSKI PP. 2011. Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol 157: 67-72.	Poland	150/163	PCR–RFLP	CBS	844ins68	ins 0.10/0.06	>0.05/>0.05	p= 0.05	09
				MTHFD1	rs2236225	T 0.42/0.40	>0.05/>0.05	p= 0.67
				MTHFR	rs1801133	T 0.27/0.32	>0.05/>0.05	p= 0.11
				MTR	rs1805087	G 0.17/0.23	>0.05/>0.05	p= 0.07
				MTRR	rs1801394	G 0.38/0.42	>0.05/>0.05	p= 0.20
				TCN2	rs1801198	C 0.45/0.46	>0.05/>0.05	p= 0.72
				BHMT	rs7356530	A 0.41/0.40	>0.05/>0.05	p= 0.63
					rs3733890	A 0.31/0.30	>0.05/>0.05	p= 0.65
				CYP19A1	rs10046	T 0.60/0.55	>0.05/>0.05	p= 0.1
					(TTTA)n	L 0.41/0.40	>0.05/>0.05	p= 0.75
					Ins/Del	Del 0.41/0.26	>0.05/>0.05	p= 0.34
Szczepańska et al. 2011SZCZEPAŃSKA M, MOSTOWSKA A, WIRSTLEIN P, LIANERI M, MARIANOWSKI P, SKRZYPCZAK J & JAGODZIŃSKI PP. 2011. Polymorphic variants of folate and choline metabolism genes and the risk of endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol 157: 67-72.	Poland	150/163	PCR–RFLP	CBS	844ins68	ins 0.10/0.06	>0.05/>0.05	p= 0.05	09
				MTHFD1	rs2236225	T 0.42/0.40	>0.05/>0.05	p= 0.67
				MTHFR	rs1801133	T 0.27/0.32	>0.05/>0.05	p= 0.11
				MTR	rs1805087	G 0.17/0.23	>0.05/>0.05	p= 0.07
				MTRR	rs1801394	G 0.38/0.42	>0.05/>0.05	p= 0.20
				TCN2	rs1801198	C 0.45/0.46	>0.05/>0.05	p= 0.72
				BHMT	rs7356530	A 0.41/0.40	>0.05/>0.05	p= 0.63
					rs3733890	A 0.31/0.30	>0.05/>0.05	p= 0.65
				CYP19A1	rs10046	T 0.60/0.55	>0.05/>0.05	p= 0.1
				BHMT2	rs625879	T 0,41/0,38	>0,05/>0,05	p= 0,54
				CHDH	rs893363	C 0,35/0,36	>0,05/>0,05	p= 0,95
					rs2289205	A 0,24/0,30	>0,05/>0,05	p= 0,26
				CHKA	rs7928739	A 0,58/0,58	>0,05/>0,05	p= 0,77
				PCYT1A	rs712012	T 0.36/0.38	>0.05/>0.05	p= 0.62
					rs7639752	A 0.49/0.46	>0.05/>0.05	p= 0.47
				PEMT	rs4244593	A 0.43/0.46	>0.05/>0.05	p= 0.46
					rs4646406	A 0.43/0.46	>0.05/>0.05	p= 0.47
Chang et al. 2012CHANG CY, CHEN Y, LIN WC, CHEN CM, CHEN CP, LEE SC, SHEU JJ & TSAI FJ. 2012. MUC2 polymorphisms are associated with endometriosis development and infertility: a case-control study. BMC Med Genet 13: 15.	Taiwan	196/195	Allelic discrimination	MUC2	rs2856111	T 0.53/0.56	Unrealized	p= 0.29	05
					rs11245936	A 0.09/0.06	Unrealized	p= 0.34
					rs10794288	T 0.52/0.60	Unrealized	p= 0.09
					rs10902088	C 0.53/0.62	Unrealized	p= 0.05
					rs7103978	G 0.10/0.06	Unrealized	p= 0.05
							Unrealized
				BHMT2	rs625879	T 0,41/0,38	>0,05/>0,05	p= 0,54
				CHDH	rs893363	C 0,35/0,36	>0,05/>0,05	p= 0,95
					rs2289205	A 0,24/0,30	>0,05/>0,05	p= 0,26
				CHKA	rs7928739	A 0,58/0,58	>0,05/>0,05	p= 0,77
				PCYT1A	rs712012	T 0.36/0.38	>0.05/>0.05	p= 0.62
					rs7639752	A 0.49/0.46	>0.05/>0.05	p= 0.47
				PEMT	rs4244593	A 0.43/0.46	>0.05/>0.05	p= 0.46
					rs4646406	A 0.43/0.46	>0.05/>0.05	p= 0.47
Chang et al. 2012CHANG CY, CHEN Y, LIN WC, CHEN CM, CHEN CP, LEE SC, SHEU JJ & TSAI FJ. 2012. MUC2 polymorphisms are associated with endometriosis development and infertility: a case-control study. BMC Med Genet 13: 15.	Taiwan	196/195	Allelic discrimination	MUC2	rs2856111	T 0.53/0.56	Unrealized	p= 0.29	05
					rs11245936	A 0.09/0.06	Unrealized	p= 0.34
					rs11245954	G 0.07/0.05	Unrealized	Not included
Zhang et al. 2012ZHANG QY, GUAN Q, WANG Y, FENG X, SUN W, KONG FY, WEN J, CUI W, YU Y & CHEN ZY. 2012. BDNF Val66Met polymorphism is associated with Stage III-IV endometriosis and poor in vitro fertilization outcome. Hum Reprod 27: 1668-1675.	China	244/425	Fluorescence Resonance Energy Transfer	BDNF	Val66Met	Met 0.46/0.51	>0.05/>0.05	p= 0.17	09
Szczepańska et al. 2013aSZCZEPAŃSKA M, WIRSTLEIN P, HOŁYSZ H, SKRZYPCZAK J & JAGODZIŃSKI PP. 2013a. The FCRL3 -169T>C polymorphism and the risk of endometriosis-related infertility in a Polish population. Arch Gynecol Obstet 288: 799-804.	Poland	519/141	PCR–RFLP	FCRL3	rs7528684	C 0.48/0.59	>0.05/>0.05	p<0.05	09
Szczepańska et al. 2013bSZCZEPAŃSKA M, WIRSTLEIN P, SKRZYPCZAK J & JAGODZIŃSKI PP. 2013b. Polymorphic variants of CYP17 and CYP19A and risk of infertility in endometriosis. Acta Obstet Gynecol Scand 92: 1188-1193.	Poland	197/115	High-Resolution Melting	CYP17A1	rs743572	A 0.41/ Not included	Unrealized	p<0.05	08
				CYP19A1	rs10046	T 0.39/ Not included	Unrealized	p= 0.79
Mafra et al. 2015MAFRA F, CATTO M, BIANCO B, BARBOSA CP & CHRISTOFOLINI D. 2015. Association of WNT4 polymorphisms with endometriosis in infertile patients. J Assist Reprod Genet 32: 1359-1364.	Brazil	400/400	Allelic discrimination	WNT4	rs2235529	A 0.12/0.15	0.65/0.18	p= 0.09	09
					rs3820282	A 0.12/0.15	0.48/0.12	p= 0.05
					rs16826658	G 0.35/0.35	0.70/0.74	p<0.05
					rs7521902	A 0.16/0.19	0.72/0.20	p= 0.18
Schmitz et al. 2015SCHMITZ CR, SOUZA CA, GENRO VK, MATTE U, CONTO ED & CUNHA-FILHO JS. 2015. LH (Trp8Arg/Ile15Thr), LHR (insLQ) and FSHR (Asn680Ser) polymorphisms genotypic prevalence in women with endometriosis and infertility. J Assist Reprod Gene 32: 991-997.	Brazil	65/67	Sequencing PCR–RFLP	LH	Trp8Arg	0.12/0.16	>0.05/>0.05	p= 0.51	07
					Ile15Thr	0.12/0.16	>0.05/>0.05	p= 0.51
				LHR	insLQ	0.10/0.25	>0.05/>0.05	p= 0.01
					rs11245954	G 0.07/0.05	Unrealized	Not included
Zhang et al. 2012ZHANG QY, GUAN Q, WANG Y, FENG X, SUN W, KONG FY, WEN J, CUI W, YU Y & CHEN ZY. 2012. BDNF Val66Met polymorphism is associated with Stage III-IV endometriosis and poor in vitro fertilization outcome. Hum Reprod 27: 1668-1675.	China	244/425	Fluorescence Resonance Energy Transfer	BDNF	Val66Met	Met 0.46/0.51	>0.05/>0.05	p= 0.17	09
Szczepańska et al. 2013aSZCZEPAŃSKA M, WIRSTLEIN P, HOŁYSZ H, SKRZYPCZAK J & JAGODZIŃSKI PP. 2013a. The FCRL3 -169T>C polymorphism and the risk of endometriosis-related infertility in a Polish population. Arch Gynecol Obstet 288: 799-804.	Poland	519/141	PCR–RFLP	FCRL3	rs7528684	C 0.48/0.59	>0.05/>0.05	p<0.05	09
Szczepańska et al. 2013bSZCZEPAŃSKA M, WIRSTLEIN P, SKRZYPCZAK J & JAGODZIŃSKI PP. 2013b. Polymorphic variants of CYP17 and CYP19A and risk of infertility in endometriosis. Acta Obstet Gynecol Scand 92: 1188-1193.	Poland	197/115	High-Resolution Melting	CYP17A1	rs743572	A 0.41/ Not included	Unrealized	p<0.05	08
				CYP19A1	rs10046	T 0.39/ Not included	Unrealized	p= 0.79
Mafra et al. 2015MAFRA F, CATTO M, BIANCO B, BARBOSA CP & CHRISTOFOLINI D. 2015. Association of WNT4 polymorphisms with endometriosis in infertile patients. J Assist Reprod Genet 32: 1359-1364.	Brazil	400/400	Allelic discrimination	WNT4	rs2235529	A 0.12/0.15	0.65/0.18	p= 0.09	09
					rs3820282	A 0.12/0.15	0.48/0.12	p= 0.05
					rs16826658	G 0.35/0.35	0.70/0.74	p<0.05
				FSHR	Asn680Ser	Not included	>0.05/>0.05	p= 0.78
Szczepańska et al. 2015SZCZEPAŃSKA M, MOSTOWSKA A, WIRSTLEIN P, SKRZYPCZAK J, MISZTAL M & JAGODZIŃSKI PP. 2015. Polymorphic variants in vitamin D signaling pathway genes and the risk of endometriosis-associated infertility. Mol Med Rep 12: 7109-7115.	Poland	347/154	High Resolution Melting PCR–RFLP	GC	rs7041	T 0.40/0.44	>0.05/>0.05	p= 0.16	09
					rs1155563	C 0.28/0.32	>0.05/>0.05	p= 0.31
					rs2298849	C 0.20/0.21	>0.05/>0.05	p= 0.48
				RXRA	rs10881578	G 0.30/0.28	>0.05/>0.05	p= 0.52
					rs10776909	C 0.20/0.18	>0.05/>0.05	p= 0.27
					rs749759	G 0.25/0.20	>0.05/>0.05	p= 0.13
				VDR	rs1544410	A 0.35/0.39	>0.05/>0.05	p= 0.44
					rs2228570	Não consta	>0.05/>0.05	p= 0.12
Yang et al. 2015YANG CW ET AL. 2015. Genetic variations of MUC17 are associated with endometriosis development and related infertility. BMC Med Genet 16: 60.	Taiwan	191/189	Allelic discrimination	MUC17	rs4729645	T 0.21/0.17	Unrealized	p= 0.12	06
					rs10953316	G 0.80/0.88	Unrealized	p<0.05
					rs74974199	C 0.13/0.11	Unrealized	p= 0.42
				FSHR	Asn680Ser	Not included	>0.05/>0.05	p= 0.78
Szczepańska et al. 2015SZCZEPAŃSKA M, MOSTOWSKA A, WIRSTLEIN P, SKRZYPCZAK J, MISZTAL M & JAGODZIŃSKI PP. 2015. Polymorphic variants in vitamin D signaling pathway genes and the risk of endometriosis-associated infertility. Mol Med Rep 12: 7109-7115.	Poland	347/154	High Resolution Melting PCR–RFLP	GC	rs7041	T 0.40/0.44	>0.05/>0.05	p= 0.16	09
					rs1155563	C 0.28/0.32	>0.05/>0.05	p= 0.31
					rs2298849	C 0.20/0.21	>0.05/>0.05	p= 0.48
				RXRA	rs10881578	G 0.30/0.28	>0.05/>0.05	p= 0.52
					rs10776909	C 0.20/0.18	>0.05/>0.05	p= 0.27
					rs749759	G 0.25/0.20	>0.05/>0.05	p= 0.13
				VDR	rs1544410	A 0.35/0.39	>0.05/>0.05	p= 0.44
					rs2228570	Não consta	>0.05/>0.05	p= 0.12
Yang et al. 2015YANG CW ET AL. 2015. Genetic variations of MUC17 are associated with endometriosis development and related infertility. BMC Med Genet 16: 60.	Taiwan	191/189	Allelic discrimination	MUC17	rs4729645	T 0.21/0.17	Unrealized	p= 0.12	06
					rs10953316	G 0.80/0.88	Unrealized	p<0.05
					rs74974199	C 0.13/0.11	Unrealized	p= 0.42
				FSHR	Asn680Ser	Not included	>0.05/>0.05	p= 0.78
Szczepańska et al. 2015SZCZEPAŃSKA M, MOSTOWSKA A, WIRSTLEIN P, SKRZYPCZAK J, MISZTAL M & JAGODZIŃSKI PP. 2015. Polymorphic variants in vitamin D signaling pathway genes and the risk of endometriosis-associated infertility. Mol Med Rep 12: 7109-7115.	Poland	347/154	High Resolution Melting PCR–RFLP	GC	rs7041	T 0.40/0.44	>0.05/>0.05	p= 0.16	09
					rs1155563	C 0.28/0.32	>0.05/>0.05	p= 0.31
					rs2298849	C 0.20/0.21	>0.05/>0.05	p= 0.48
				RXRA	rs10881578	G 0.30/0.28	>0.05/>0.05	p= 0.52
					rs4729655	C 0.61/0.59	Unrealized	p= 0.55
					rs4729656	A 0.68/0.66	Unrealized	p= 0.66
Zhang et al. 2015ZHANG H, ZHANG Z, LI G, WANG S, ZHANG S & XIE B. 2015. Association of FCRL3 Genetic Polymorphisms With Endometriosis-Related Infertility Risk: An Independent Study in Han Chinese. Medicine (Baltimore) 94: e1168.	China	220/217	PCR–RFLP	FCRL3	rs7528684	C 0.41/0.50	0.35/0.83	p= 0.01	09
					rs11264799	A 0.28/0.30	0.37/0.48	p= 0.57
					rs945635	G 0.42/0.45	0.64/0.73	p= 0.30
					rs3761959	A 0.47/0.49	0.74/0.83	p= 0.65
Barbosa et al.2016	Brazil	42/52	PCR–RFLP	CYP1A1	CYP1A1m1	m1 0.14/0.32	Unrealized	p= 0.08	04
De Conto et al. 2017DE CONTO E, MATTE Ú, BILIBIO JP, GENRO VK, SOUZA CA, LEÃO DP & CUNHA-FILHO JS. 2017. Endometriosis-associated infertility: GDF-9, AMH, and AMHR2 genes polymorphisms. J Assist Reprod Genet 34: 1667-1672.	Brazil	70/74	Allelic discrimination	GDF-9	c.398-39C > G	G 0.15/0.11	>0.05/>0.05	p= 0.51	09
					c.447C > T	T 0.49/0.53	>0.05/>0.05	p= 0.19
					c.546G > A	A 0.13/0.18	>0.05/>0.05	p= 0.44
				AMH	p.Ile49Ser	Ser 0.28/0.16	>0.05/>0.05	p= 0.03
				AMHR2	-482A > G	G 0.20/0.16	>0.05/>0.05	p= 0.68
					rs4729655	C 0.61/0.59	Unrealized	p= 0.55
					rs4729656	A 0.68/0.66	Unrealized	p= 0.66
Zhang et al. 2015ZHANG H, ZHANG Z, LI G, WANG S, ZHANG S & XIE B. 2015. Association of FCRL3 Genetic Polymorphisms With Endometriosis-Related Infertility Risk: An Independent Study in Han Chinese. Medicine (Baltimore) 94: e1168.	China	220/217	PCR–RFLP	FCRL3	rs7528684	C 0.41/0.50	0.35/0.83	p= 0.01	09
					rs11264799	A 0.28/0.30	0.37/0.48	p= 0.57
					rs945635	G 0.42/0.45	0.64/0.73	p= 0.30
					rs3761959	A 0.47/0.49	0.74/0.83	p= 0.65
Barbosa et al. 2016BARBOSA AM, DE SOUZA SR, FRARE AB, COSTA E SILVA RC, DA COSTA IR, FREITAS E SILVA KS, RIBEIRO JÚNIOR CL, BORDIN BM & MOURA KK. 2016. Association of CYP1A1 (cytochrome P450) MspI polymorphism in women with endometriosis. Genet Mol Res 15(3).	Brazil	42/52	PCR–RFLP	CYP1A1	CYP1A1m1	m1 0.14/0.32	Unrealized	p= 0.08	04
De Conto et al. 2017DE CONTO E, MATTE Ú, BILIBIO JP, GENRO VK, SOUZA CA, LEÃO DP & CUNHA-FILHO JS. 2017. Endometriosis-associated infertility: GDF-9, AMH, and AMHR2 genes polymorphisms. J Assist Reprod Genet 34: 1667-1672.	Brazil	70/74	Allelic discrimination	GDF-9	c.398-39C > G	G 0.15/0.11	>0.05/>0.05	p= 0.51	09
					c.447C > T	T 0.49/0.53	>0.05/>0.05	p= 0.19
Osiński et al. 2017OSIŃSKI M, MOSTOWSKA A, WIRSTLEIN P, SKRZYPCZAK J, JAGODZIŃSKI PP & SZCZEPAŃSKA M. 2017. Involvement of 17β-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis. J Assist Reprod Genet 34: 789-794.	Poland	410/290	High Resolution MeltingPCR	HSD17B1	rs605059	A 0.48/0.52	>0.05/>0.05	p= 0.19	06
Osiński et al. 2018aOSIŃSKI M, MOSTOWSKA A, WIRSTLEIN P, WENDER-OŻEGOWSKA E, JAGODZIŃSKI PP & SZCZEPAŃSKA M. 2018a. The assessment of GWAS - identified polymorphisms associated with infertility risk in Polish women with endometriosis. Ginekol Pol 89: 304-310.	Poland	406/315	High Resolution Melting	NPVF/NFE2L3	rs12700667	A 0.76/0.81	0.56/0.82	p= 0.04	09
				WNT4	rs12037376	A 0.16/0.18	0.73/0.91	p= 0.30
				WNT4/ZBTB40	rs7521902	A 0.26/0.27	0.87/0.35	p= 0.46
				GREB1	rs13394619	A 0.45/0.44	0.37/0.98	p= 0.62
				VEZT/METAP2	rs10859871	C 0.31/0.31	0.72/0.11	p= 0.83
				CDKN2B/ DMRTA1	rs1537377	C 0.39/0.41	0.74/0.23	p= 0.49
				ETAA1/C1D	rs4141819	C 0.31/0.35	0.99/0.31	p= 0.08
				RNF144B/ID4	rs7739264	C 0.46/0.46	0.63/0.80	p= 0.77
				RND3/RBM43	rs1519761	G 0.42/0.40	0.35/0.31	p= 0.39
				CKAP2L/IL1A	rs6542095	C 0.28/0.27	0.21/0.92	p= 0.50
Osiński et al. 2017OSIŃSKI M, MOSTOWSKA A, WIRSTLEIN P, SKRZYPCZAK J, JAGODZIŃSKI PP & SZCZEPAŃSKA M. 2017. Involvement of 17β-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis. J Assist Reprod Genet 34: 789-794.	Poland	410/290	High Resolution MeltingPCR	HSD17B1	rs605059	A 0.48/0.52	>0.05/>0.05	p= 0.19	06
Osiński et al. 2018aOSIŃSKI M, MOSTOWSKA A, WIRSTLEIN P, WENDER-OŻEGOWSKA E, JAGODZIŃSKI PP & SZCZEPAŃSKA M. 2018a. The assessment of GWAS - identified polymorphisms associated with infertility risk in Polish women with endometriosis. Ginekol Pol 89: 304-310.	Poland	406/315	High Resolution Melting	NPVF/NFE2L3	rs12700667	A 0.76/0.81	0.56/0.82	p= 0.04	09
				WNT4	rs12037376	A 0.16/0.18	0.73/0.91	p= 0.30
				WNT4/ZBTB40	rs7521902	A 0.26/0.27	0.87/0.35	p= 0.46
				GREB1	rs13394619	A 0.45/0.44	0.37/0.98	p= 0.62
				VEZT/METAP2	rs10859871	C 0.31/0.31	0.72/0.11	p= 0.83
				CDKN2B/ DMRTA1	rs1537377	C 0.39/0.41	0.74/0.23	p= 0.49
				ETAA1/C1D	rs4141819	C 0.31/0.35	0.99/0.31	p= 0.08
				RNF144B/ID4	rs7739264	C 0.46/0.46	0.63/0.80	p= 0.77
				RND3/RBM43	rs1519761	G 0.42/0.40	0.35/0.31	p= 0.39
				CKAP2L/IL1A	rs6542095	C 0.28/0.27	0.21/0.92	p= 0.50
Osiński et al. 2017OSIŃSKI M, MOSTOWSKA A, WIRSTLEIN P, SKRZYPCZAK J, JAGODZIŃSKI PP & SZCZEPAŃSKA M. 2017. Involvement of 17β-hydroxysteroid dehydrogenase type gene 1 937 A>G polymorphism in infertility in Polish Caucasian women with endometriosis. J Assist Reprod Genet 34: 789-794.	Poland	410/290	High Resolution MeltingPCR	HSD17B1	rs605059	A 0.48/0.52	>0.05/>0.05	p= 0.19	06
Osiński et al. 2018aOSIŃSKI M, MOSTOWSKA A, WIRSTLEIN P, WENDER-OŻEGOWSKA E, JAGODZIŃSKI PP & SZCZEPAŃSKA M. 2018a. The assessment of GWAS - identified polymorphisms associated with infertility risk in Polish women with endometriosis. Ginekol Pol 89: 304-310.	Poland	406/315	High Resolution Melting	NPVF/NFE2L3	rs12700667	A 0.76/0.81	0.56/0.82	p= 0.04	09
				WNT4	rs12037376	A 0.16/0.18	0.73/0.91	p= 0.30
				WNT4/ZBTB40	rs7521902	A 0.26/0.27	0.87/0.35	p= 0.46
				GREB1	rs13394619	A 0.45/0.44	0.37/0.98	p= 0.62
				VEZT/METAP2	rs10859871	C 0.31/0.31	0.72/0.11	p= 0.83
				CDKN2B/ DMRTA1	rs1537377	C 0.39/0.41	0.74/0.23	p= 0.49
				ETAA1/C1D	rs4141819	C 0.31/0.35	0.99/0.31	p= 0.08
				RNF144B/ID4	rs7739264	C 0.46/0.46	0.63/0.80	p= 0.77
Santos et al. 2018SANTOS TR, SILVA KSF, SILVA RCPC, MOURA KKVO, GUILLO LA, JÚNIOR CL & COSTA LR. 2018. Infertility caused by an association between Arg72Pro polymorphism of the p53 gene and Glu298Asp of the eNOS gene in patients with endometriosis. Genet Mol Res 17: GMR1804.	Brazil	18/17	Amplification Refractory Mutation System- Polymerase Chain ReactionPCR	TP53	rs1042522	Pro Not included	Unrealized	Not included	06
				eNOS	rs1799983	Asp Not included	Unrealized	Not included
Cardoso et al. 2019CARDOSO JV, MACHADO DE, DA SILVA MC, BERARDO PT, FERRARI R, ABRÃO MS & PERINI JA. 2019. Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study. Eur J Obstet Gynecol Reprod Biol X 3: 100041.	Brazil	217/283		MMP3	rs679620	A 0.34/0.40	>0.05/>0.05	p= 0.09	09
Christofolini et al. 2019CHRISTOFOLINI DM, CAVALHEIRO CM, TELES JS, LERNER TG, BRANDES A, BIANCO B & BARBOSA CP. 2011a. Promoter -817C>T variant of B lymphocyte stimulator gene (BLyS) and susceptibility to endometriosis-related infertility and idiopathic infertility in Brazilian population. Scand J Immunol 74: 628-631.	Brazil	650/394	Allelic discrimination	TAC3	rs733629	C 0.09/0.08	0.73/1	p= 0.57	09
				KAZN	rs10928050	G 0.16/0.20	0.14/1	p<0.05
			Allelic discrimination	LAMA5	rs2427284	A 0.07/0.05	<0.05/<0.05	p= 0.1
Tanase et al. 2020TANASE A, NEMESCU D, POPESCU R, TOMA BF, MATASARIU RD & ONOFRIESCU M. 2020. FSH receptor and FSH beta chain polymorphism involvement in infertility and endometriosis disease. Acta Endocrinol (Buchar) 16: 142-147.	Romania	34/44		FSHR	rs1394205	A 0.23/0.22	Unrealized	p= 0.87	05
				FSHβ	rs10835638	T 0.09/0.07	Unrealized	p= 0.63
Santos et al. 2018SANTOS TR, SILVA KSF, SILVA RCPC, MOURA KKVO, GUILLO LA, JÚNIOR CL & COSTA LR. 2018. Infertility caused by an association between Arg72Pro polymorphism of the p53 gene and Glu298Asp of the eNOS gene in patients with endometriosis. Genet Mol Res 17: GMR1804.	Brazil	18/17	Amplification Refractory Mutation System- Polymerase Chain ReactionPCR	TP53	rs1042522	Pro Not included	Unrealized	Not included	06
				eNOS	rs1799983	Asp Not included	Unrealized	Not included
Cardoso et al. 2019CARDOSO JV, MACHADO DE, DA SILVA MC, BERARDO PT, FERRARI R, ABRÃO MS & PERINI JA. 2019. Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study. Eur J Obstet Gynecol Reprod Biol X 3: 100041.	Brazil	217/283		MMP3	rs679620	A 0.34/0.40	>0.05/>0.05	p= 0.09	09
Christofolini et al. 2019CHRISTOFOLINI DM, VILARINO FL, MAFRA FA, ANDRÉ GM, BIANCO B & BARBOSA CP. 2011b. Combination of polymorphisms in luteinizing hormone β, estrogen receptor β and progesterone receptor and susceptibility to infertility and endometriosis. Eur J Obstet Gynecol Reprod Biol 158: 260-264.	Brazil	650/394	Allelic discrimination	TAC3	rs733629	C 0.09/0.08	0.73/1	p= 0.57	09
				KAZN	rs10928050	G 0.16/0.20	0.14/1	p<0.05
			Allelic discrimination	LAMA5	rs2427284	A 0.07/0.05	<0.05/<0.05	p= 0.1
Tanase et al. 2020TANASE A, NEMESCU D, POPESCU R, TOMA BF, MATASARIU RD & ONOFRIESCU M. 2020. FSH receptor and FSH beta chain polymorphism involvement in infertility and endometriosis disease. Acta Endocrinol (Buchar) 16: 142-147.	Romania	34/44		FSHR	rs1394205	A 0.23/0.22	Unrealized	p= 0.87	05
				FSHβ	rs10835638	T 0.09/0.07	Unrealized	p= 0.63
Santos et al. 2018SANTOS TR, SILVA KSF, SILVA RCPC, MOURA KKVO, GUILLO LA, JÚNIOR CL & COSTA LR. 2018. Infertility caused by an association between Arg72Pro polymorphism of the p53 gene and Glu298Asp of the eNOS gene in patients with endometriosis. Genet Mol Res 17: GMR1804.	Brazil	18/17	Amplification Refractory Mutation System- Polymerase Chain ReactionPCR	TP53	rs1042522	Pro Not included	Unrealized	Not included	06
				eNOS	rs1799983	Asp Not included	Unrealized	Not included
Cardoso et al. 2019CARDOSO JV, MACHADO DE, DA SILVA MC, BERARDO PT, FERRARI R, ABRÃO MS & PERINI JA. 2019. Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study. Eur J Obstet Gynecol Reprod Biol X 3: 100041.	Brazil	217/283		MMP3	rs679620	A 0.34/0.40	>0.05/>0.05	p= 0.09	09
Christofolini et al. 2019	Brazil	650/394	Allelic discrimination	TAC3	rs733629	C 0.09/0.08	0.73/1	p= 0.57	09
				KAZN	rs10928050	G 0.16/0.20	0.14/1	p<0.05
			Allelic discrimination	LAMA5	rs2427284	A 0.07/0.05	<0.05/<0.05	p= 0.1
Tanase et al. 2020TANASE A, NEMESCU D, POPESCU R, TOMA BF, MATASARIU RD & ONOFRIESCU M. 2020. FSH receptor and FSH beta chain polymorphism involvement in infertility and endometriosis disease. Acta Endocrinol (Buchar) 16: 142-147.	Romania	34/44		FSHR	rs1394205	A 0.23/0.22	Unrealized	p= 0.87	05
				FSHβ	rs10835638	T 0.09/0.07	Unrealized	p= 0.63
Santos et al. 2018SANTOS TR, SILVA KSF, SILVA RCPC, MOURA KKVO, GUILLO LA, JÚNIOR CL & COSTA LR. 2018. Infertility caused by an association between Arg72Pro polymorphism of the p53 gene and Glu298Asp of the eNOS gene in patients with endometriosis. Genet Mol Res 17: GMR1804.	Brazil	18/17	Amplification Refractory Mutation System- Polymerase Chain ReactionPCR	TP53	rs1042522	Pro Not included	Unrealized	Not included	06
				eNOS	rs1799983	Asp Not included	Unrealized	Not included
Cardoso et al. 2019CARDOSO JV, MACHADO DE, DA SILVA MC, BERARDO PT, FERRARI R, ABRÃO MS & PERINI JA. 2019. Matrix metalloproteinases 3 polymorphism increases the risk of developing advanced endometriosis and infertility: A case-control study. Eur J Obstet Gynecol Reprod Biol X 3: 100041.	Brazil	217/283		MMP3	rs679620	A 0.34/0.40	>0.05/>0.05	p= 0.09	09
Christofolini et al. 2019	Brazil	650/394	Allelic discrimination	TAC3	rs733629	C 0.09/0.08	0.73/1	p= 0.57	09
				KAZN	rs10928050	G 0.16/0.20	0.14/1	p<0.05

Reference	Country	Sample size C/ED/II	Genotyping method	Gene	Polymorphism (s)	Polymorphic allele frequency C/ED/II	HWE C/ED/II	p value (genotypic frequency) (CxED/ EDxII)	Quality
Mafra et al. 2010MAFRA FA, BIANCO B, CHRISTOFOLINI DM, SOUZA AM, ZULLI K & BARBOSA CP. 2010. Luteinizing hormone beta-subunit gene (LHbeta) polymorphism in infertility and endometriosis-associated infertility. Eur J Obstet Gynecol Reprod Biol 151: 66-69.	Brazil	209/110/84	PCR–RFLP	LHβ	G1502A	A 0.20/0.30/0.29	Unrealized	<0.05/Not included	08
Zulli et al. 2010ZULLI K, BIANCO B, MAFRA FA, TELES JS, CHRISTOFOLINI DM & BARBOSA CP. 2010. Polymorphism of the estrogen receptor β gene is related to infertility and infertility-associated endometriosis. Arq Bras Endocrinol Metabol 54: 567-571.	Brazil	209/136/69	PCR-RFLPAllelic discrimination	ERβ	G + 1730A	A 0.12/0.21/0.21	>0.05/<0.05/>0.0 5	<0.05/0.15	08
André et al. 2011ANDRÉ GM, BARBOSA CP, TELES JS, VILARINO FL, CHRISTOFOLINI DM & BIANCO B. 2011. Analysis of FOXP3 polymorphisms in infertile women with and without endometriosis. Fertil Steril 95: 2223-2227.	Brazil	171/177/71	Allelic discrimination	FOXP3	rs3761548	C 0.70/0.66/0.62	-/0.97/<0.05	0.28/0.42	09
					rs3761549	T 0.07/0.14/0.03	-/0.52/0.87	<0.05/<0.05
					rs2232366	T 0.97/0.97/0.99	-/1.0/1.0	0.86/0.37
					rs2232368	A 0.28/0.31/0.38	-/0.53/<0.05	0.38/0.17
					rs2280883	G 0.27/0.31/0.38	-/0.60/<0.05	0.30/0.17
Bianco et al. 2011BIANCO B, TELES JS, LERNER TG, VILARINO FL, CHRISTOFOLINI DM & BARBOSA CP. 2011. Association of FCRL3 -169T/C polymorphism with endometriosis and identification of a protective haplotype against the development of the disease in Brazilian population. Hum Immunol 72: 774-778.	Brazil	166/170/91	Allelic discrimination	FCRL3	rs7528684	C 0.38/0.49/0.46	>0.05/>0.05/>0.05	<0.05/Not included	09
					rs11264799	A 0.34/0.30/0.29	>0.05/>0.05/>0.05	0.63/Not included
					rs945635	G 0.60/0.54/0.54	>0.05/>0.05/>0.05	0.24/Not included
					rs3761959	G 0.52/0.49/0.50	>0.05/>0.05/>0.05	0.80/Not included
Christofolini et al. 2011a	Brazil	145/165/83	Allelic discrimination	BLyS	rs9514828	T 0.30/0.34/0.39	0.99/0.66/0.99	0.33/Not included	09
Christofolini et al. 2011b	Brazil	206/201/80	PCR-RFLP	PROGINS	PR	C 0.07/0.05/0.08	Unrealized	0.56/Not included	08
				ERβ	G + 1730A	A 0.15/0.20/0.22	Unrealized	<0.05/0.85
				LHβ	G1502A	A 0.20/0.35/0.16	Unrealized	<0.05/<0.05
Gonçalves- Filho et al. 2011	Brazil	148/140/64	PCR–RFLP	PAI-1	rs1799889	5G0.58/0.48/0.53	Unrealized	<0.05/0.20	08
Teles et al. 2011TELES JS, BIANCO B, VILARINO FL, ANDRÉ GM, CHRISTOFOLINI DM & BARBOSA CP. 2011. Association of FCRL3 C-169T promoter single-nucleotide polymorphism with idiopathic infertility and infertility-related endometriosis. J Reprod Immunol 89: 212-215.	Brazil	167/167/60	Allelic discrimination	FCRL3	rs7528684	T 0.63/0.50/0.50	>0.05/>0.05/>0.05	<0.05/Not included	09
Bianco et al. 2012BIANCO B, LERNER TG, TREVISAN CM, CAVALCANTI V, CHRISTOFOLINI DM & BARBOSA CP. 2012. The nuclear factor-kB functional promoter polymorphism is associated with endometriosis and infertility. Hum Immunol 73: 1190-1193.	Brazil	189/172/77	PCR–RFLP	NFKβ1	rs28362491	Del 0.47/0.38/0.31	0.65/0.50/ 0.97	<0.05/Not included	09
Peluso et al. 2013PELUSO C, CHRISTOFOLINI DM, GOLDMAN CS, MAFRA FA, CAVALCANTI V, BARBOSA CP & BIANCO B. 2013. TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility. Hum Immunol 74: 93-97.	Brazil	307/275/92	Allelic discrimination	TYK2	rs34536443	C 0.06/0.02/0.03	0.51/0.05/ <0.05	<0.05/Not included	06
					rs2304256	A 0.23/0.24/0.17	0.83/0.92/ 0.76	0.71/Not included
					rs280523	A 0.89/0.91/0.89	0.92/0.35/ 0.07	0.25/Not included
					rs12720270	T 0.17/0.19/0.13	0.30/0.78/ 0.96	0.42/Not included
					rs12720356	G 0.93/0.93/0.95	0.28/0.99/ 0.90	1.0/Not included
Wang et al.2014WANG L, LU X, WANG D, QU W, LI W, XU X, HUANG Q, HAN X & LV J. 2014. CYP19 gene variant confers susceptibility to endometriosis-associated infertility in Chinese women. Exp Mol Med 46: e103.	China	225/146/65	Allele-specific PCR PCR–RFLP PCR	CYP19A1	rs2236722	C 0.05/0.03/0.01	>0.05/>0.05/>0.05	0.36/Not included	08
					rs700518	G 0.46/0.43/0.33	>0.05/>0.05/>0.05	0.11/Not included
					rs10046	T 0.56/0.57/0.53	>0.05/>0.05/>0.05	0.64/Not included
					[TTTA]n	L 0.57/0.58/0.56	>0.05/>0.05/>0.05	0.8/Not included
Cavalcanti et al. 2016CAVALCANTI V, PONCE TG, MAFRA FA, ANDRÉ GM, CHRISTOFOLINI DM, BARBOSA CP & BIANCO B. 2016. Evaluation of the frequency of G-765C polymorphism in the promoter region of the COX-2 gene and its correlation with the expression of this gene in the endometrium of women with endometriosis. Arch Gynecol Obstet 293: 109-115.	Brazil	522/114/251	High-Resolution Melting	COX-2	rs20417	G 0.75/0.79/0.79	<0.05/0.30/ 0.08	Not included	09

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[1] Correspondence to: Mariangela Torreglosa Ruiz Cintra E-mail: mariangela.cintra@uftm.edu.br