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Polymorphisms in VEGF and KDR genes in the development of endometriosis: a systematic review

Abstract

Objectives:

to review studies that used case-control design to verify the association of polymorphisms in VEGF and KDR genes in the development of endometriosis.

Methods:

the systematic review selected articles published until September 1, 2015 from PubMed, MEDLINE, BVS, SciELO databases, considering the following key words: endometriosis and ("polymorphism" or "SNP" or "genetic polymorphism") and ("VEGF" OR "Vascular endothelial growth factor" or "VEGFR-2" or "Vascular endothelial growth factor-2" or "KDR" or "Kinase Insert Domain Receptor").

Results:

106 articles were identified, only 11 were eligible. Discrepant results were observed regarding polymorphisms in VEGF gene in the development of endometriosis, which can be explained by methodological differences, sample size, eligible control type, using the unadjusted risk estimates and the heterogeneity of the studied population. Only one study investigated polymorphisms in KDR gene in the development of endometriosis, however it was ineligible for this review.

Conclusions:

to avoid discrepancy in the results, we suggest that the ideal control group should be formed by fertile women and free of gynecological diseases. Multicentric studies with adequate design, involving different population besides the combined analysis on polymorphisms in VEGF and KDR genes are still necessary to contribute in the understanding of this disease, which are social, clinical and economical problems.

Key words
Endometriosis; VEGF; KDR; Polymorphism; Infertilit

Resumo

Objetivos:

revisar os trabalhos que utilizaram o delineamento caso-controle para verificar a associação de polimorfismos nos genes VEGF e KDR no desenvolvimento da endometriose.

Métodos:

revisão sistemática que pesquisou nas bases de dados PubMed, MEDLINE, BVS, SciELO os artigos publicados até o dia 1 de setembro de 2015, considerando os descritores: endometriosis and ("polymorphism" or "SNP" or "geneticpolymorphism") and ("VEGF" or "Vascular endothelial growth factor" or "VEGFR-2" or "Vascular endothelial growth factor-2" or "KDR" or "Kinase Insert Domain Receptor").

Resultados:

identificou-se 106 artigos, sendo 11 considerados elegíveis. Observou-se resultados discrepantes quanto aos polimorfismos no gene VEGF no desenvolvimento da endometriose, podendo ser explicados pelas diferenças metodológicas, pelo tamanho amostral, pelo tipo de controle elegível, pela utilização da estimativa de risco não ajustada e pela heterogeneidade das populações estudadas. Apenas um estudo investigou polimorfismos no gene KDR no desenvolvimento da endometriose, contudo não foi elegível nesta revisão.

Conclusões:

para evitar as discrepâncias dos resultados observados sugerimos que o grupo controle ideal deva ser formado por mulheres férteis e livres de doenças ginecológicas. Estudos multicêntricos com delineamento adequado, envolvendo diferentes populações, além da análise combinada de polimorfismos nos genes VEGF e KDR ainda são necessários para contribuir no entendimento desta doença que é um problema social, clínico e econômico.

Palavras-chave
Endometriose; VEGF; KDR; Polimorfismos; Infertilidade

Introduction

Endometriosis is a gynecological disease characterized by the presence of functional endometrial tissue outside the uterine cavity, representing one of the most common gynecological disorders.11 Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010; 362: 2389-98. The real profile of patients with endometriosis is uncertain, although there is a consensus that it is present in at least 10% of the women at reproductive age,22 Giudice LC, kao LC. Endometriosis. Lancet. 2004; 364 (9447): 1789-99.,33 Buck Louis GM, Hediger ML, Peterson CM, Croughan M, Sundaram R, Stanford J, Chen Z, Fujimoto VY, Varner MW, Trumble A, Giudice LC; ENDO Study Working Group. Incidence of endometriosis by study population and diagnostic method: the ENDO study. Fertil Steril. 2011; 96 (2): 360-5. 30 to 50% of infertile women44 Viganò P, Parazzini F, Somigliana E, Vercellini P. Endometriosis: epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol. 2004; 18: 177-200. and 3 to 5% of postmenopausal women.55 Inceboz U. Endometriosis after menopause. Womens Health (Lond Engl). 2015; 11 (5): 711-5.

Women with endometriosis may be asymptomatic (10.7%), however, most of them present symptoms in different intensities, the main ones are: dysmenorrhoea (52-97%), chronic pelvic pain (22-69%), infertility (25-59%), dyspareunia (44-71%) and intestinal symptoms (71%) and cyclic urinary (60%).66 Fauconnier A, Staraci S, Roman Chh, Panel P, Descamps P. Comparison of patient- and physician-based descriptions of symptoms of endometriosis: a qualitative study. Human Reprod. 2013; 28: 2686-94.

7 Moradi M, Parker M, Sneddon A, Lopez V, Ellwood D. Impact of endometriosis on women's lives: a qualitative study. BMC Womens Health. 2014; 14: 123.
-88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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. Endometriosis causes physical, mental and social consequences to women, bearing in mind that their psyche, interpersonal and martial relationships are affected by the problems of the symptoms, in particularly, by the difficulty of bearing children.99 De Graaff AA, D'hooghe TM, Dunselman GA, Dirksen CD, Hummelshoj L, WERF EndoCost Consortium, et al. The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod. 2013; 28:2677-85.

There are several theories explaining about the appearance of endometriosis; however its etiology is still not clear. The most widely accepted theory until today is Sampson's proposal,1010 Sampson JA. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. Am J Obstet Gynecol. 1927; 14: 422-69. who described that the endometrial tissue, by backward menstrual flow, returns to the uterine tubes and adheres to the peritoneal cavity. For this to occur, the angiogenesis process is essential and it is characterized by the growth of new blood vessels from pre-existing ones.1111 Rocha ALL, Reis FM, Taylor RN. Angiogenisis and Endometriosis. Obstet Gynecol Int. 2013; 2013:859619. Among the pro-angiogenic factors, the vascular endothelial growth factor (VEGF) is highlighted and plays an important role in the development of endometriosis.1111 Rocha ALL, Reis FM, Taylor RN. Angiogenisis and Endometriosis. Obstet Gynecol Int. 2013; 2013:859619. In 2008, our group observed an increased distribution of VEGF and its receptor VEGFR-2 in samples of endometriosis of the ovary, bladder and the recto-sigmoid, when it was compared to control and the largest distribution of VEGF and VEGFR-2 was observed in the endometriosis of the recto-sigmoid,which is the most severe.1212 Machado DE, Abrão MS, Berardo PT, Takiya CM, Nasciutti LE. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril 2008; 90: 148-55.

VEGF is encoded by a gene with the same name, located on chromosome 6p21.3, composed by eight exons,1313 Vincenti V, Cassano C, Rocchi M, Persico G. Assignment of the vascular endothelial growth factor gene to human chromosome 6p21.3. Circulation. 1996; 93: 1493-5. while its receptor VEGFR-2 is encoded by KDR gene (kinase insert domain receptor), located on chromosome 4q11-q12, composed by 30 exons.1414 Lu D, Kussie P, Pytowski B, Persaud K, Bohlen P, Witte L, Zhu Z. Identification of the residues in the extracellular region of KDR important for interaction with vascular endothelial growth factor and neutralizing anti-KDR antibodies. J Biol Chem. 2000; 275: 14321-30. Both genes are polymorphic, highlighting in the study on endometriosis, five single nucleotide polymorphisms (SNPs) in VEGF gene (rs699947, rs833061, rs1570360, rs2010963 and rs3025039) and three in KDR gene (rs1870377, rs2305948 and rs2071559), due to the high frequency which occurs in different populations, although interfering significantly in the activity or in the enzyme expression.1515 Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E. A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res. 2000; 37: 443-8.

16 Jain L, Vargo CA, Danesi R, Sissung TM, Price DK, Venzon D, Venitz J, Figg WD. The role of vascular endothelial growth factor SNPs as predictive and prognostic markers for major solid tumors. Mol Cancer Ther. 2009; 8: 2496-508.

17 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7.
-1818 Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007; 50: 760-7.

Recently, our group observed a positive association for VEGF rs1570360 SNP in the development of endometriosis (OR: 1.90; CI95%: 1.23-2.97) in Brazilian women.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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. Several case-control studies also investigated the influence of SNPs in VEGF or KDR genes in the development of endometriosis.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,1717 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7.,1919 Hsieh YY, Chang CC, Tsai FI, Yeh LS, Lin CC, Peng CT. T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med. 2004; 49: 468-72.

20 Bhanoori M, Arvind Babu K, Pavankumar Reddy NG, Lakshmi Rao K, Zondervan K, Deenadayal M, Kennedy S, Shivaji S. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005; 20: 1844-9

21 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.

22 Ikuhashi Y, Yoshida S, Kennedy S, Zondervan K, Takemura N, Deguchi M, Ohara N, Maruo T. Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population. Acta Obstet Gynecol Scand. 2007; 86: 1352-8.

23 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.

24 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.

25 Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008; 14: 531-8.

26 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.

27 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.

28 Attar R, Agachan B, Kuran SB, Toptas B, Eraltan IY, Attar E, Isbir T. Genetic variants of vascular endothelial growth factor and risk for the development of endometriosis. In Vivo. 2010; 24: 297-301.

29 Lamp M, Saare M, Laisk T, Karro H, Kadastik U, Metspalu A, Peters M, Salumets A. Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women. Eur J Obstet Gynecol Reprod Biol. 2010; 153: 85-9.

30 Toktam M, Kioomars SN, Kourosh K, Adel S, Behrokh MM, Mohhamad Mehdi A, Hamid Reza KK. Association of vascular endothelial growth factor (VEGF) +405G>C polymorphism with endometriosis in an Iranian population. J Reprod Infertil. 2010; 11: 33-7.

31 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.

32 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.

33 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.

34 Saliminejad K, Memariani T, Ardekani AM, Kamali K, Edalatkhah H, Pahlevanzadeh Z, Khorram Khorshid HR. Association study of the TNF-α -1031T/C and VEGF +450G/C polymorphisms with susceptibility to endometriosis. Gynecol Endocrinol. 2013; 29: 974-7.

35 Ahmed MM, Khaled ARRN, Hisham SH, Wael TE, Waleed SAE. Vascular endothelial growth factor gene polymorphism as a risk factor of endometriosis. Evidence Based Women's Health J. 2014; 4 (2): 92-5.

36 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.
-3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. However, the results of the analysis are still controversial. In this context, the aim of this study was to review all the studies that used case-control design to investigate the magnitude of SNPs association of VEGF and/or KDR genes susceptibility to develop endometriosis, in order to discuss the possible causes of the conflicting results already described.

Methods

To identify all the studies published until September 1, 2015 on the associations among SNPs of VEGF and/or KDR and the development of endometriosis, an evaluation on titles and abstracts of the studies was performed by two researchers in an independent form and "blinded" in PubMed, Medline, BVS and SciELO databases using the following keywords: ("endometriosis") AND ("polymorphism" OR "SNP" OR "genetic polymorphism" OR "genetic polymorphisms") AND ("VEGF" OR "Vascular endothelial growth factor" OR "VEGFR-2" OR "Vascular endothelial growth factor-2" OR "Vascular endothelial growth factor-2" OR "KDR" OR "Kinase Insert Domain Receptor"). The studies were selected according to the inclusion and exclusion criteria, pre-selected and described as followed.

The inclusion criteria for this review were case-control design studies and that evaluated associations among polymorphisms of VEGF and/or KDR genes and the development of endometriosis. As for the period of the publication, articles that were published until September 2015 were included without any restriction of languages.

The exclusion criteria of the study were: (I) the absence of a control population; (II) incomplete data associations; (III) duplicated data; (IV) meta-analysis, review, letters, commentaries or editorial articles; (V) those that did not analyze SNPs in VEGF and/or KDR; (VI) and did not include patients with endometriosis; (VII) those that did not have access to the complete text.

After performing a search strategy in PubMed, Medline, BVS and SciELO databases in articles which studied SNPs in VEGF and/or KDR genes with the development of endometriosis, the following information was extracted: the first author, publication year, journal; country where the study was conducted; number of cases and controls; mean age of cases and controls with their respective deviation standard and/or interval; selection on criteria/eligibility and exclusion of cases of endometriosis and controls; endometriosis staging; control source; type of SNP; genotyping technique used to identify the studied SNPs; data of allelic and genotypic frequency of the SNPs and statistic data of odds ratio (OR) with its respective 95% confidence intervals (CI95%).

Evaluation on quality in the included studies

Two reviewers independently evaluated the methodological quality of 19 studies included in this review, using STROBE (Strengthening the Reporting of Observational Studies in Epidemiology), a criteria instrument.3838 Von EE. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Brit Med J. 2007; 355 (7624): 806-8. Twenty and two evaluated items received a score from 0 to 1. These items were related to the title and the abstract of the article (item 1), the introduction (items 2 and 3), the methods (items 4 to 12), the results (items 13 to 17), the discussion (items 18 to 21) and the financial information (item 22). After evaluating all the criteria, each article received a score from 0 to 22 of each researcher. The final score was performed an average of the two grades transformed into percentage to better evaluate the quality of the articles. Previously, the reviewers described if the articles reached a percentage higher than 50%, they would be consi-dered satisfactory.

Results

Figure 1 shows a flowchart on the selection of articles for this review. The search strategy identified 100 publications on VEGF gene and 6 publications on KDR, no articles were found evaluating simultaneously the influence of SNPs in both genes with the development of endometriosis. After removing the duplicated articles, 34 were selected for reading the titles and abstracts. However, 14 studies were excluded: 5 because they were meta-analyzes, 2 because they were reviews, one because it was a criticism on the meta-analysis published before, one because it explored SNPs in IL-10 gene instead of polymorphisms in VEGF and/or KDR genes, 4 because they studied patients with adenomyosis and one because it evaluated women with pterygium instead of patients with endometriosis. After the selection of the abstracts, a study was excluded because the text was not completely available.1919 Hsieh YY, Chang CC, Tsai FI, Yeh LS, Lin CC, Peng CT. T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med. 2004; 49: 468-72. After a thorough reading of 19 articles eligible for this review, the inclusion and exclusion criteria on cases and controls were evaluated and 8 studies were still excluded: 5 used endometriosis cases without histopathological confirmation of the disease;2020 Bhanoori M, Arvind Babu K, Pavankumar Reddy NG, Lakshmi Rao K, Zondervan K, Deenadayal M, Kennedy S, Shivaji S. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005; 20: 1844-9,2525 Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008; 14: 531-8.,2828 Attar R, Agachan B, Kuran SB, Toptas B, Eraltan IY, Attar E, Isbir T. Genetic variants of vascular endothelial growth factor and risk for the development of endometriosis. In Vivo. 2010; 24: 297-301.,3030 Toktam M, Kioomars SN, Kourosh K, Adel S, Behrokh MM, Mohhamad Mehdi A, Hamid Reza KK. Association of vascular endothelial growth factor (VEGF) +405G>C polymorphism with endometriosis in an Iranian population. J Reprod Infertil. 2010; 11: 33-7.,3434 Saliminejad K, Memariani T, Ardekani AM, Kamali K, Edalatkhah H, Pahlevanzadeh Z, Khorram Khorshid HR. Association study of the TNF-α -1031T/C and VEGF +450G/C polymorphisms with susceptibility to endometriosis. Gynecol Endocrinol. 2013; 29: 974-7. 2 which included controls did not have surgery procedures (laparoscopy and/or laparotomy) in confirming the diagnosis of endometriosis;2222 Ikuhashi Y, Yoshida S, Kennedy S, Zondervan K, Takemura N, Deguchi M, Ohara N, Maruo T. Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population. Acta Obstet Gynecol Scand. 2007; 86: 1352-8.,2929 Lamp M, Saare M, Laisk T, Karro H, Kadastik U, Metspalu A, Peters M, Salumets A. Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women. Eur J Obstet Gynecol Reprod Biol. 2010; 153: 85-9. and 1 which included controls only performed an ultrasound and was diagnosed negative for the disease.1717 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7. Thus, 11 case-control studies were included in this review that evaluated SNPs only in VEGF gene susceptibility to develop endometriosis from 2005 to 2015.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.

32 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.
-3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. In relation to evaluate the quality of 11 studies selected for this review, all the articles reached a percentage greater than 50%3838 Von EE. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Brit Med J. 2007; 355 (7624): 806-8. and the average score ranged between 12 to 21 points (55-96%). The studies that had the lowest and the highest score, according to the STROBE criteria were Kim et al.2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5. and Perini et al.,88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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. respectively (Table 1).

Figure 1
Flowchart of the selected articles included in the review.

Table 1
Description of the inclusion and exclusion criteria of the case group, established by eligible studies for this review.

In this review 4205 women´s data were included (2096 with endometriosis and 2109 controls) from Asian countries,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50. North America,3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5. North Africa,88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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. Europe,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. Euro-Asian countries3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72. and Africa.3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.

Table 1 describes the inclusion and exclusion criteria of the group with endometriosis, emphasizing that all the studies considered the women eligible who had surgical diagnosis of the disease with histopathological confirmation. Whereas the staging of the disease was found in 4 (36.3%) studies that included patients in stage I, II, III or IV;2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.,3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44. 3 (27.3%) grouped into stages I-II or III-IV;88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2. 2 (18.2%) included only women in stages I and II;3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. one (9.1%) included patients in stage III and IV2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8. and another (9.1%) showed no information on surgical staging of the disease.2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6. In relation to the exclusion criteria of the group with cases of endometriosis, 2 (18.2%) studies did not inform any criteria,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5. while others, a total of 9 (81.8%) considered patients who had a history of angiogenesis-dependent diseases or that it could be associated to polymorphisms of VEGF, and women who presented adenomyosis, a pelvic inflammatory disease, bilateral tubal occlusion and myoma.

For the control group (Table 2), all the studies included women with surgical diagnosis of endometriosis, although 3 (27.3%) studies included women who underwent surgery for tubal ligation,88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50. 3 (27.3%) included women who underwent surgery to remove cyst in the ovary;88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5. 2 (18.2%) included women who underwent surgery to remove myoma;88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5. 2 (18.2%) included women who underwent hysterectomy2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6. and 6 (54.5%) included women who were submitted to surgery because of various problems such as appendicitis, carcinoma in situ of the cervix, dermoid cysts, parovarium cysts, serous cysts and mucinous tumors, dysmenorrhoea, pelvic pain, fibroma ovarian, dysfunctional bleeding uterine, hydrosalpinges, infertility and malformation of the uterine and normal pelvis.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. The exclusion criteria for the control group was one (9.1%) study that did not inform any of the exclusion criteria.3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5. The remaining 10 (90.9%) considered almost the same exclusion criteria of the group with cases of endometriosis.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4.

Table 2
Description of the inclusion and exclusion criteria of the control group, established by eligible studies for this review.

In Table 3 shows investigated SNPs characteristics in the studies eligible for this review. 5 SNPs in VEGF gene were studied being genotyped by PCR-RFLP techniques (81.8%) and PCR at real time (18.2%). SNP rs699947 was evaluated in 2 (18.2%) studies and the frequency of VEGF -2578A allele ranged between 19- 40% and 26-34% in cases and controls, respectively. Liu et al.2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6. observed a negative association with endometriosis, while Perini et al.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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. found no association to the disease (Table 4). SNP rs833061 was evaluated in 8 (72.7%) studies and the frequency of VEGF -460C allele ranged between 3-53% in cases and 1-51% in controls, however no study found an association of SNP with the development of the disease.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. Three (27.3%) studies evaluated SNP rs1570360 and the frequency of VEGF -1154A allele ranged between 16-28% and 16-27% in cases and controls, respectively (Table 3). However, Liu et al.2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6. and Perini et al.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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. observed opposite effects, while Rotman et al.3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5. found no association with the development of endometriosis (Table 4). SNP rs2010963 investigated 8 (72.7%) studies and the frequency of VEGF +405C allele ranged between 33-56% in cases and 31-95% in controls (Table 3), although 4 studies (Table 4) found no association with endometriosis,88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. 1 study observed a positive association in the presence of VEGF +405G allele 31 and, contrary 3 studies verified a positive association in the presence of allele or +405C genotype.2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50. Six studies (54.5%) evaluated SNP rs3025039 and the frequency of VEGF +936T allele ranged between 13-25% and 10-17% in cases and controls, respectively (Table 3), however 4 studies found no association88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. and 2 verified a positive association with endometriosis in the presence of +936T allele.2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.

Table 3
Polymorphisms characteristics of VEGF gene analyzed in eligible studies for this review.
Table 4
Description of the results concerning the magnitude of association of the polymorphism in VEGF gene with endometriosis, according to studies eligible for this review.

Discussion

This review provides a detailed description of the studies that used a case-control design study to investigate the magnitude of association of the SNPs in VEGF and/or KDR genes susceptibility in the development of endometriosis. The angiogenesis, through VEGF-KDR signals, is an important event in the development of the disease,1111 Rocha ALL, Reis FM, Taylor RN. Angiogenisis and Endometriosis. Obstet Gynecol Int. 2013; 2013:859619.,1212 Machado DE, Abrão MS, Berardo PT, Takiya CM, Nasciutti LE. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril 2008; 90: 148-55. since endometriosis lesions are characterized by a dense vascularization and requires blood supply suitable for survival.1111 Rocha ALL, Reis FM, Taylor RN. Angiogenisis and Endometriosis. Obstet Gynecol Int. 2013; 2013:859619. Furthermore, an increased expression of VEGF and VEGFR-2 in samples of women with endometriosis was observed when compared to its control.1212 Machado DE, Abrão MS, Berardo PT, Takiya CM, Nasciutti LE. Vascular density and distribution of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) are significantly higher in patients with deeply infiltrating endometriosis affecting the rectum. Fertil Steril 2008; 90: 148-55.

The expression of VEGF and KDR genes as well as the activity of these proteins may be modified by the presence of polymorphisms in coding regions and non-coding genes. SNPs that occur in promoter regions, 5'-UTR and 3'-UTR, affect potential regulatory elements, are sensitive to hypoxia and contribute to high variability of production in VEGF tissues.1818 Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007; 50: 760-7.,3939 Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S. A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002; 51: 1635-9.,4040 Steffensen KD,Waldstrøm M, Brandslund I, Jakobsen A. The relationship of VEGF polymorphisms with serum VEGF levels and progression-free survival in patients with epithelial ovarian cancer. Gynecol Oncol. 2010; 117: 109. rs699947, rs833061 and rs1570360 SNPs present in the promoter region of VEGF gene, present higher activity of transcription and are associated to high levels of protein.4141 Brogan IJ, Khan N, Isaac K, Hutchinson JA, Pravica V, Hutchinson IV. Novel polymorphisms in the promoter and 5' UTR regions of the human vascular endothelial growth factor gene. Hum Immunol. 1999; 60: 1245-9. rs2010963 SNP located in region 5'-UTR of VEGF gene affects the efficiency of understanding and is related to the production of VEGF from the mononucleated cells of the peripheral blood.4242 Watson CJ, Webb NJ, Bottomley MJ, Brenchley PE. Identification of polymorphisms within the vascular endothelial growth factor (VEGF) gene: correlation with variation in VEGF protein production. Cytokine. 2000; 12: 1232-5. So, rs3025039 SNP in region 3'-UTR of VEGF gene influences the concentration of VEGF plasmatic stock.1515 Renner W, Kotschan S, Hoffmann C, Obermayer-Pietsch B, Pilger E. A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J Vasc Res. 2000; 37: 443-8. rs2305948 and rs1870377 SNPs located in the exons of KDR gene decrease the efficiency of VEGF binding to KDR.1818 Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007; 50: 760-7. The possible effect of rs7667298 SNP located in region 5'-UTR of KDR gene is unclear. However, this SNP is associated to rs2071559 SNP (KDR-604T>C) located in the promoter region. The presence of -604C allele reduces the transcriptional activity of KDR.1818 Wang Y, Zheng Y, Zhang W, Yu H, Lou K, Zhang Y, Qin Q, Zhao B, Yang Y, Hui R. Polymorphisms of KDR gene are associated with coronary heart disease. J Am Coll Cardiol. 2007; 50: 760-7. rs1531289 and rs7692791 SNPs located in introns of KDR gene were not yet studied in relation to the functional effects.

VEGF-KDR role in endometriosis physiopathology as well as the influence of SNPs to modulate the levels and activity of these proteins justify the high number of studies that attempted to describe the magnitude of SNPs association of VEGF and KDR genes susceptibility in endometriosis developing.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,1717 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7.,1919 Hsieh YY, Chang CC, Tsai FI, Yeh LS, Lin CC, Peng CT. T allele for VEGF gene-460 polymorphism at the 5'-untranslated region: association with a higher susceptibility to endometriosis. J Reprod Med. 2004; 49: 468-72.

20 Bhanoori M, Arvind Babu K, Pavankumar Reddy NG, Lakshmi Rao K, Zondervan K, Deenadayal M, Kennedy S, Shivaji S. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005; 20: 1844-9

21 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.

22 Ikuhashi Y, Yoshida S, Kennedy S, Zondervan K, Takemura N, Deguchi M, Ohara N, Maruo T. Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population. Acta Obstet Gynecol Scand. 2007; 86: 1352-8.

23 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.

24 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.

25 Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008; 14: 531-8.

26 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.

27 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.

28 Attar R, Agachan B, Kuran SB, Toptas B, Eraltan IY, Attar E, Isbir T. Genetic variants of vascular endothelial growth factor and risk for the development of endometriosis. In Vivo. 2010; 24: 297-301.

29 Lamp M, Saare M, Laisk T, Karro H, Kadastik U, Metspalu A, Peters M, Salumets A. Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women. Eur J Obstet Gynecol Reprod Biol. 2010; 153: 85-9.

30 Toktam M, Kioomars SN, Kourosh K, Adel S, Behrokh MM, Mohhamad Mehdi A, Hamid Reza KK. Association of vascular endothelial growth factor (VEGF) +405G>C polymorphism with endometriosis in an Iranian population. J Reprod Infertil. 2010; 11: 33-7.

31 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.

32 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.

33 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.

34 Saliminejad K, Memariani T, Ardekani AM, Kamali K, Edalatkhah H, Pahlevanzadeh Z, Khorram Khorshid HR. Association study of the TNF-α -1031T/C and VEGF +450G/C polymorphisms with susceptibility to endometriosis. Gynecol Endocrinol. 2013; 29: 974-7.

35 Ahmed MM, Khaled ARRN, Hisham SH, Wael TE, Waleed SAE. Vascular endothelial growth factor gene polymorphism as a risk factor of endometriosis. Evidence Based Women's Health J. 2014; 4 (2): 92-5.

36 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.
-3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. In 2013, Li et al.,4343 Li YZ, Wang LJ, Li X, Li SL, Wang JL, Wu ZH, Gong L, Zhang XD. Vascular endothelial growth factor gene polymorphisms contribute to the risk of endometriosis: an updated systematic review and meta-analysis of 14 case-control studies. Genet Mol Res. 2013; 12: 1035-44. conducted a meta-analysis study involving 14 studies which investigated the magnitude of association of 5 SNPs in the VEGF gene (rs699947, rs833061, rs1570360, rs2010963 and rs3025039) in the susceptibility on endometriosis. The increased risk of endometriosis developing was observed in the presence of VEGF + 936C>T SNP, while VEGF - 2578C>A and -1154G>A SNPs were protective factors for the development of the disease. Thus, VEGF -460T>C and +405G>C SNPs were not associated to the development of endometriosis.4343 Li YZ, Wang LJ, Li X, Li SL, Wang JL, Wu ZH, Gong L, Zhang XD. Vascular endothelial growth factor gene polymorphisms contribute to the risk of endometriosis: an updated systematic review and meta-analysis of 14 case-control studies. Genet Mol Res. 2013; 12: 1035-44. For KDR, only one case-control design study evaluated the magnitude of association among five SNPs (rs1531289, rs2305948, rs1870377, rs7692791 and rs7667298) and the development of endometriosis in Chinese women, noticing a negative association in the presence of 1192T allele (rs2305948).1717 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7. However, this study was excluded from this review because included controls performed only an ultrasound to diagnose negative for endometriosis and this method of imaging does not exclude the presence of pelvic endometriosis.4444 Menakaya U, Reid S, Infante F, Condous G. Systematic evaluation of women with suspected endometriosis using a 5-domain sonographically based approach. J Ultrasound Med. 2015; 34 (6): 937-47.,4545 Nisenblat V1, Bossuyt PM, Farquhar C, Johnson N, Hull ML. Imaging modalities for the non-invasive diagnosis of endometriosis. Cochrane Database Syst Rev. 2016 Feb 26; 2: CD009591. Moreover, until the present moment there are no data in literatures that assess the combined form of SNPs in VEGF and KDR genes and the development of endometriosis.

The controversial results observed in the case-control studies can be explained by the sample size, by methodological differences in each study design, mainly, by the eligible control type, by the difference in SNPs frequency in different populations and by the use of the measured of association, the unadjusted odds ratio (OR) used to evaluate the magnitude of association of SNPs in the VEGF and KDR genes in the development of endometriosis. The stratification techniques and multiple regression are two statistical methods which can be used to exclude potential confounding variables and consequently produce the adjusted OR.4646 Fuchs SC, Paim BS. Revisão Sistemática de Estudos Observacionais com Metanálise. Rev HCPA 2010; 30: 294-301.,4747 Camey SA, Torman VB, Hirakata VN, Cortes RX, Vigo A. Bias of using odds ratio estimates in multinomial logistic regressions to estimate relative risk or prevalence ratio and alternatives. Cad Saúde Pública. 2014; 30: 21-9. Among the 11 studies included in this review, only 3 (27.3%) used the adjusted OR (Table 4) to evaluate the magnitude of association of SNPs in VEGF gene and the development of endometriosis.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6. The manner in which the variables are measured may insert a bias and distort the estimated measurement of the effect.4848 Rego MAV. Aspectos históricos dos estudos caso-controle. Cad Saúde Pública. 2001; 17: 1017-24. The confounding variables occur when part of the association found is the result of the presence of a third variable that is related to the disease and the exposure of interest result in a change of the estimated risk.4949 Luiz Rr, Struchiner CJ. Inferência causal em epidemiologia: o modelo de respostas potenciais [online]. Rio de Janeiro: Editora FIOCRUZ; 2002. 112 p.

The analytical observational epidemiological studies of the case-control type are applied to evaluate exposures among similar groups, which present (cases) or not (controls) to the disease.5050 Schulz KF, Grimes DA. Case-control studies: research in reverse. Lancet. 2002; 359: 431-4. They are widely used in studies on rare diseases or in long period of induction and regular expositions,5151 Rêgo MAV. Estudos caso-controle: uma breve revisão. Gazeta Médica da Bahia. 2010; 79: 101-10. such as in the case of endometriosis. In addition, case-control studies tend to contribute in locating important findings and efficient in terms of relatively short time with little financial resource.4848 Rego MAV. Aspectos históricos dos estudos caso-controle. Cad Saúde Pública. 2001; 17: 1017-24. However, case-control studies tend to be more susceptible to biases than any other analytical epidemiological designs and how individuals are recruited for the study can distort the estimated measurement of the effect.5151 Rêgo MAV. Estudos caso-controle: uma breve revisão. Gazeta Médica da Bahia. 2010; 79: 101-10. The definition of the case group is a critical point in a case-control study, criteria for diagnosis and eligibility and two fundamental aspects for the selection of the subject. The aim is to ensure that all the true cases have equal probability of joining the group, and that no false case is selected, thus, it may distort the estimated measurement of the association in direction to a null hypothesis.5252 Lasky T, Stolley PD. Selection of cases and controls. Epidemiol Rev. 1994;16:6-17. In 19 published studies which analyzed VEGF and KDR polymorphisms in susceptibility to the development of endometriosis, it was observed that the cases of endometriosis had surgical diagnosis.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,1717 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7.,2020 Bhanoori M, Arvind Babu K, Pavankumar Reddy NG, Lakshmi Rao K, Zondervan K, Deenadayal M, Kennedy S, Shivaji S. The vascular endothelial growth factor (VEGF) +405G>C 5'-untranslated region polymorphism and increased risk of endometriosis in South Indian women: a case control study. Hum Reprod. 2005; 20: 1844-9

21 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.

22 Ikuhashi Y, Yoshida S, Kennedy S, Zondervan K, Takemura N, Deguchi M, Ohara N, Maruo T. Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population. Acta Obstet Gynecol Scand. 2007; 86: 1352-8.

23 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.

24 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.

25 Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008; 14: 531-8.

26 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.

27 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.

28 Attar R, Agachan B, Kuran SB, Toptas B, Eraltan IY, Attar E, Isbir T. Genetic variants of vascular endothelial growth factor and risk for the development of endometriosis. In Vivo. 2010; 24: 297-301.

29 Lamp M, Saare M, Laisk T, Karro H, Kadastik U, Metspalu A, Peters M, Salumets A. Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women. Eur J Obstet Gynecol Reprod Biol. 2010; 153: 85-9.

30 Toktam M, Kioomars SN, Kourosh K, Adel S, Behrokh MM, Mohhamad Mehdi A, Hamid Reza KK. Association of vascular endothelial growth factor (VEGF) +405G>C polymorphism with endometriosis in an Iranian population. J Reprod Infertil. 2010; 11: 33-7.

31 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.

32 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.

33 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.
-3434 Saliminejad K, Memariani T, Ardekani AM, Kamali K, Edalatkhah H, Pahlevanzadeh Z, Khorram Khorshid HR. Association study of the TNF-α -1031T/C and VEGF +450G/C polymorphisms with susceptibility to endometriosis. Gynecol Endocrinol. 2013; 29: 974-7.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. In spite of the available images of the method presented a good accuracy in the endometriosis diagnosis, according to a consensus of the European Society of Human Reproduction and Embryology (ESHRE) and the American Society for Reproductive Medicine (ASRM), the gold standard to diagnose endometriosis is the videolaparoscopy with direct inspection of the pelvic cavity and visualization of the implants, as well as the histopathological confirmation of the disease.5353 ASRM - American Society for Reproductive Medicine. Revised American Fertility Society Classification Of Endometriosis: 1996. Fertil Steril. 1997.,5454 ESHRE Guideline for the Diagnosis and Treatment of Endometriosis. http://guidelines endometriosis org/ 2008.
http://guidelines endometriosis org/...
Thus, 11 articles were included in this review using the "gold standard" to select the cases (surgical and histopathological confirmation), considered to be a good diagnostic criteria and eligibility, ensuring that all 2096 women included were true cases of endometriosis.88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,2727 Liu Q, Li Y, Zhao J, Sun DL, Duan YN, Wang N, Zhou RM, Kang S.. Association of polymorphisms -1154G/A and - 2578C/A in the vascular endothelial growth factor gene with decreased risk of endometriosis in Chinese women. Hum Reprod. 2009; 24: 2660-6.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.,3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4.

The selection of the control group requires special care and perhaps is the main challenge to guarantee the validity of the study, considering the complexity of the investigated disease (endometriosis). The control group of studies included in this review was formed by women who could have other diseases, including gynecological disorders associated to the development of endometriosis, along with the process of angiogenesis and/or polymorphisms in VEGF gene.1717 Kang S, Shi YY, Li Y, Wang N, Lu YC, Zhou RM, Zhao XW. Association between genetic variants of the VEGFR-2 gene and the risk of developing endometriosis in Northern Chinese Women. Gynecol Obstet Invest 2013; 76:32-7.,3939 Awata T, Inoue K, Kurihara S, Ohkubo T, Watanabe M, Inukai K, Inoue I, Katayama S. A common polymorphism in the 5'-untranslated region of the VEGF gene is associated with diabetic retinopathy in type 2 diabetes. Diabetes. 2002; 51: 1635-9.,5555 Boiardi L, Casali B, Nicoli D, Farnetti E, Chen Q, Macchioni P, Catanoso MG, Pulsatelli L, Meliconi R, Salvarani C. Vascular endotelial growth factor gene polymorphisms in giant cell arteritis. J Rheumatol. 2003; 30: 2160-4.,5656 Salvarani C, Boiardi L, Casali B, Olivieri I, Cantini F, Salvi F, Malatesta R, La Corte R, Triolo G, Ferrante A, Filippini D, Paolazzi G, Sarzi-Puttini P, Nicoli D, Farnetti E, Chen Q, Pulsatelli L. Vascular endotelial growth factor gene polymorphisms in Behçet's disease. J Rheumatol. 2004; 31: 1785-9. Approximately 82% (n=9) of the studies included in this review used the control group that presented other gynecological diseases or had no information about the reason for a surgical procedure performed by a gynecologist (laparoscopy and/or laparotomy), being able to provide low risk estimates, considering these diseases and/or the reason why a woman underwent surgery may be associated to the exposure under investigated (SNPs of VEGF gene). It is fundamental that the control group is directly determined by the definition and selection of the case group sampled by the same source.5757 Zondervan KT, Cardon LR, Kennedy SH. What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod. 2002; 17: 1415-23. Among the 11 studies included in this review, about 91% (n=10) used controls of hospital basis (Table 2).88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2424 Kim JG, Kim JY, Jee BC, Suh CS, Kim SH, Choi YM. Association between endometriosis and polymorphisms in endostatin and vascular endothelial growth factor and their serum levels in Korean women. Fertil Steril. 2008; 89: 243-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3131 Altinkaya SO, Ugur M, Ceylaner G, Ozat M, Gungor T, Ceylaner S. Vascular endothelial growth factor +405 C/G polymorphism is highly associated with an increased risk of endometriosis in Turkish women. Arch Gynecol Obstet 2011; 283: 267-72.

32 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50.
-3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5.,3636 Henidi B, Kaabachi W, Naouali A, Kaabachi S, Zhioua A, Haj Sassi F, Hamzaoui K. Vascular endothelial growth factor (-460 C/T, +405 G/C, and +936 C/T) polymorphisms and endometriosis risk in Tunisian population. Syst Biol Reprod Med. 2015; 61: 238-44.,3737 Szczepańska M, Mostowska A, Wirstlein P, Skrzypczak J, Jagodziłski PP. Involvement of vascular endothelial growth factor -460 C/T, +405 G/C and +936 C/T polymorphisms in the development of endometriosis. Biomed Rep. 2015; 3: 220-4. It has been described in the literature that about 11% of the women with endometriosis have no symptoms of the disease.66 Fauconnier A, Staraci S, Roman Chh, Panel P, Descamps P. Comparison of patient- and physician-based descriptions of symptoms of endometriosis: a qualitative study. Human Reprod. 2013; 28: 2686-94.,77 Moradi M, Parker M, Sneddon A, Lopez V, Ellwood D. Impact of endometriosis on women's lives: a qualitative study. BMC Womens Health. 2014; 14: 123. In addition, the average time between the onset of the symptoms and the diagnosis of endometriosis is extensively long, ranging between 7 to 12 years.5858 Arruda MS, Petta CA, Abrão MS, Benetti-Pinto CL. Time elapsed from onset of symptoms to diagnosis of endometriosis in a cohort study of Brazilian women. Hum Reprod. 2003; 18: 756-9. We emphasize that 4 articles were excluded from this review,2222 Ikuhashi Y, Yoshida S, Kennedy S, Zondervan K, Takemura N, Deguchi M, Ohara N, Maruo T. Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population. Acta Obstet Gynecol Scand. 2007; 86: 1352-8.,2525 Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008; 14: 531-8.,2929 Lamp M, Saare M, Laisk T, Karro H, Kadastik U, Metspalu A, Peters M, Salumets A. Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women. Eur J Obstet Gynecol Reprod Biol. 2010; 153: 85-9.,3030 Toktam M, Kioomars SN, Kourosh K, Adel S, Behrokh MM, Mohhamad Mehdi A, Hamid Reza KK. Association of vascular endothelial growth factor (VEGF) +405G>C polymorphism with endometriosis in an Iranian population. J Reprod Infertil. 2010; 11: 33-7. because they did not use adequate control to evaluate the magnitude of SNPs association to VEGF gene and the development of endometriosis. In a study conducted by Zhao et al.2525 Zhao ZZ, Nyholt DR, Thomas S, Treloar SA, Montgomery GW. Polymorphisms in the vascular endothelial growth factor gene and the risk of familial endometriosis. Mol Hum Reprod. 2008; 14: 531-8. the controls were women who reported not having endometriosis and only 27% had a negative diagnosis of endometriosis by laparoscopy or hysterectomy. Toktam et al.,3030 Toktam M, Kioomars SN, Kourosh K, Adel S, Behrokh MM, Mohhamad Mehdi A, Hamid Reza KK. Association of vascular endothelial growth factor (VEGF) +405G>C polymorphism with endometriosis in an Iranian population. J Reprod Infertil. 2010; 11: 33-7. used control of hospital basis, however it was not informed whether the women had undergone surgical procedure, they only reported that they had gynecological problems. Lamp et al.2929 Lamp M, Saare M, Laisk T, Karro H, Kadastik U, Metspalu A, Peters M, Salumets A. Genetic variations in vascular endothelial growth factor but not in angiotensin I-converting enzyme genes are associated with endometriosis in Estonian women. Eur J Obstet Gynecol Reprod Biol. 2010; 153: 85-9. used healthy fertile women (with at least 2 children), without clinical suspicion of endometriosis and without performing a surgical procedure to exclude the presence of the disease. Ikuhashi et al.2222 Ikuhashi Y, Yoshida S, Kennedy S, Zondervan K, Takemura N, Deguchi M, Ohara N, Maruo T. Vascular endothelial growth factor +936 C/T polymorphism is associated with an increased risk of endometriosis in a Japanese population. Acta Obstet Gynecol Scand. 2007; 86: 1352-8. used umbilical cord as control material obtained from newborn females.

The main limitations of the case-control studies are: the lack of validity due to the selected bias; the recruitment of controls are not representative to the population at risk; errors on the measurements associated to the function of different biases between cases and controls and the confounding variables that affect a causal association.5050 Schulz KF, Grimes DA. Case-control studies: research in reverse. Lancet. 2002; 359: 431-4. The differences in the allelic frequency pattern can be observed in the studies with ethnic groups, as well as environmental factors contributing to different phenotypic responses.5959 Kennedy S: Genetics of endometriosis: a review of the positional cloning approaches. Semin Reprod Med. 2003, 21: 111-8. Furthermore, it should be taken into account the sample size to avoid making type I errors, stating that the risk factor is associated to the disease, but, in fact, it is not; or type II errors, stating that the risk factor is not associated with the disease, but, in fact, it is.5050 Schulz KF, Grimes DA. Case-control studies: research in reverse. Lancet. 2002; 359: 431-4. Among the 11 articles included in this review, only 3 (27%) of them informed the calculated sample used in the study.2121 Kim SH, Choi YM, Choung SH, Jun JK, Kim JG, Moon SY. Vascular endothelial growth factor gene +405 C/G polymorphism is associated with susceptibility to advanced stage endometriosis. Hum Reprod. 2005; 20: 2904-8.,2323 Gentilini D, Somigliana E, Vigano P, Vignali M, Busacca M, Di Blasio AM. The vascular endothelial growth factor +405G>C polymorphism in endometriosis. Hum Reprod. 2008; 23: 211-5.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2. Moreover, we emphasize the limited number of cases and controls included in Rotman et al.3333 Rotman C, Fischel L, Cortez G, Greiss H, Rana N, Rinehart J, Coulam CB. A search to identify genetic risk factors for endometriosis. Am J Reprod Immunol. 2013; 69: 92-5. study (24 cases and 18 controls) and Attar et al.2828 Attar R, Agachan B, Kuran SB, Toptas B, Eraltan IY, Attar E, Isbir T. Genetic variants of vascular endothelial growth factor and risk for the development of endometriosis. In Vivo. 2010; 24: 297-301. (52 cases and 60 controls) and the latter was excluded from this review because they used cases without histological confirmation of endometriosis.

According to Zondervan et al.,5757 Zondervan KT, Cardon LR, Kennedy SH. What makes a good case-control study? Design issues for complex traits such as endometriosis. Hum Reprod. 2002; 17: 1415-23. the choice of the ideal control group for the study on genetic basis of endometriosis is free of diseases, whereas is submitted to surgery for tubal ligation. Among the 11 studies included in this review, approximately 27% (n=3) used women who underwent tubal ligation in the control group,88 Perini JA, Cardoso JV, Berardo PT, Vianna-Jorge R, Nasciutti LE, Bellodi-Privato M, Machado DE, Abrão MS. 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.,2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50. and only 2 (18%) studies were formed exclusively by a control group of women who underwent the procedure of tubal ligation.2626 Cosín R, Gilabert-Estellés J, Ramón LA, España F, Gilabert J, Romeu A, Estellés A. Vascular endothelial growth factor polymorphisms (-460C/T, +405G/C, and 936C/T) and endometriosis: their influence on vascular endothelial growth factor expression. Fertil Steril. 2009; 92: 1214-2.,3232 Emamifar B, Salehi Z, Mehrafza M, Mashayekhi F. The vascular endothelial growth factor (VEGF) polymorphisms and the risk of endometriosis in northern Iran. Gynecol Endocrinol 2012; 28: 447-50. Corroborating with these findings, we also suggest that the ideal control group perform case-control studies, which evaluates the genetic profile of women with endometriosis and should be informed by women submitted to tubal ligation, because it is possible to make a direct inspection of the pelvic cavity and exclude the presence of endometriosis lesions.

This review had the intention to describe and discuss the inclusion/exclusion criteria used to define the cases group with endometriosis and especially the controls group, in order to verify methodological differences that could contribute to the discrepancies in the results found in the literature. The analytical observational studies on case-control, when they are carefully designed can provide relevant information to identify risk factors, especially in cases of endometriosis, which is a complex disease and multifactorial. The epidemiological analyzes which explore the molecular profile of women with endometriosis may contribute to the etiologic investigation and build instruments for the actions and interventions in the field of the public health.

In conclusion, we suggest broader studies with correct methodological design involving different populations as well as a combined analysis of SNPs in VEGF and/or KDR genes are still necessary in virtue of the fundamental role of these factors in the endometriosis development. We suggest a selection of a control group from a hospital basis, without history of infertility and gynecological disorders, such as the case of women undergoing tubal ligation procedures corresponds to the appropriate control type to evaluate the magnitude of SNPs association of VEGF and/or KDR genes in the endometriosis development.

Acknowledgements

To the Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ);

To the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq);

To the Fundação do Câncer (Projeto Oncobiologia).

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Publication Dates

  • Publication in this collection
    Jul-Sep 2016

History

  • Received
    04 Apr 2016
  • Accepted
    09 Aug 2016
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