Combined effect of vascular endothelial growth factor and its receptor polymorphisms in endometriosis: a case-control study.
OBJECTIVE
Endometriosis is a multifactorial gynecological disease, whose pathogenesis is crucially dependent on angiogenesis, which is signaled via vascular endothelial growth factor (VEGF) and its receptor (VEGFR2). We hypothesize that single nucleotide polymorphisms (SNPs) in VEGF and VEGFR2 genes may influence the onset and/or the progression of endometriosis. The main aim of this study was to investigate the contribution of VEGF and VEGFR2 SNPs as risk factors for endometriosis, as well as their association with endometriosis symptoms.


METHODS
A case-control study was conducted, involving 293 endometriosis patients and 223 controls, who were submitted to laparoscopic or laparotomy surgery at hospitals from the Brazilian public health system. Genotyping of VEGF (-2578C>A, -460T>C, -1154G>A, +405G>C and +936C>T) and VEGFR2 (-604T>C, 1192C>T) SNPs was performed by TaqMan real-time polymerase chain reaction. The association between SNPs and endometriosis, deep infiltrating endometriosis (DIE) or endometriosis symptoms was estimated by odds ratios (OR) with their 95% confidence intervals (CI), which were calculated using multivariate logistic regression models.


RESULTS
VEGF variant alleles -2578A and -1154A were associated with increased endometriosis risk (OR: 1.39, 95% CI: 1.04-1.87 and OR: 1.63, 95% CI: 1.12-2.37, respectively), whereas VEGF 405C and VEGFR2 1192T were associated with lower risk of endometriosis (OR: 0.66, 95% CI: 0.43-1.00 and OR: 0.58, 95% CI: 0.40-0.84, respectively). The combination of wild-type genotypes of both VEGF -2578C>A and -1154G>A with variant genotypes of both VEGF +405G>C and VEGFR2 1192C>T showed the best protective effect against the development of endometriosis, either considering all cases (OR: 0.33, 95% CI: 0.12-0.89) or only DIE (OR: 0.30, 95% CI: 0.10-0.87). The combination of variant genotypes of VEGF -2578C>A, -1154G>A, +405G>C and VEGFR2 1192C>T was also protective against DIE (OR: 0.67, 95% CI: 0.46-0.96). VEGFR2 1192C>T were associated with reduced cyclical urinary complaints (OR: 0.40, 95% CI: 0.18-0.88).


CONCLUSIONS
Our results indicate that VEGF SNPs -2578C>A and -1154G>A increase endometriosis risk, whereas VEGF +405G>C and VEGFR2 1192C>T are protective against disease development, with VEGFR2 1192C>T also reducing cyclical urinary symptoms. The combined analysis of VEGF-VEGFR2 genotypes suggests a gene-gene interaction in endometriosis susceptibility.
Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública, Fundação Osvaldo Cruz, Rio de Janeiro, RJ, Brazil; Laboratório de Pesquisa de Ciências Farmacêuticas, Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste, Rio de Janeiro, RJ, Brazil.
Jéssica Vilarinho
JV
Cardoso
Departamento de Obstetrícia e Ginecologia da Faculdade de Medicina da Universidade de São Paulo, Rio de Janeiro, SP, Brazil.
Maurício Simões
MS
Abrão
Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública, Fundação Osvaldo Cruz, Rio de Janeiro, RJ, Brazil; Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil.
Rosane
R
Vianna-Jorge
Instituto de Ginecologia da Universidade Federal do Rio de Janeiro, Hospital Moncorvo Filho, Rio de Janeiro, RJ, Brazil.
Renato
R
Ferrari
Serviço de Ginecologia, Hospital Federal dos Servidores do Estado, Rio de Janeiro, RJ, Brazil.
Plínio Tostes
PT
Berardo
Laboratório de Pesquisa de Ciências Farmacêuticas, Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste, Rio de Janeiro, RJ, Brazil.
Daniel Escorsim
DE
Machado
Programa de Pós-Graduação em Saúde Pública e Meio Ambiente, Escola Nacional de Saúde Pública, Fundação Osvaldo Cruz, Rio de Janeiro, RJ, Brazil; Laboratório de Pesquisa de Ciências Farmacêuticas, Unidade de Farmácia, Centro Universitário Estadual da Zona Oeste, Rio de Janeiro, RJ, Brazil. Electronic address: jamilaperini@yahoo.com.br.
Jamila Alessandra
JA
Perini
D000328:Adult; D016022:Case-Control Studies; D004715:Endometriosis / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010049:Ovarian Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*; D055815:Young Adult
D042461:Vascular Endothelial Growth Factor A; D040262:Receptors, Vascular Endothelial Growth Factor
Angiogenesis; Endometriosis; Polymorphisms; VEGF; VEGFR2