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Genetic variant of eNOS gene as a risk factor for endometriosis-related infertility

Grant number: 13/01016-8
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2013
Effective date (End): April 30, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Caio Parente Barbosa
Grantee:Maria Thereza Sichi Machado
Host Institution: Faculdade de Medicina do ABC (FMABC). Organização Social de Saúde. Fundação do ABC. Santo André , SP, Brazil


Infertility is characterized by the absence of spontaneous pregnancy after a minimum period of twelve months, with the practice of regular sexual activity and lack of contraceptive methods. Statistics show that 20% of couples of childbearing age experience difficulties in bearing children. Approximately 30% of the causes of infertility are related to female factors, 30% to male factors, 30% of cases both factors are present and 10% have no apparent cause. Despite scientific advances in the field of assisted reproduction, pregnancy occurs, on average, 31% of couples of treatments available today and the failure of embryo implantation is considered a major cause of failure in the procedures of in vitro fertilization (IVF).Possible causes of implantation failure in ¬ embryonal have been widely investigated, but there is no consensus in the literature. It is believed that the embryo quality, endometrial receptivity, communication, maternal-fetal and endocrine factors, immunologic and genetic factors constitute relevant in pregnancy failure. Various uterine pathologies may impair embryo implantation, including endometriosis. Endometriosis is a chronic inflammation which is one of the most common benign gynecological diseases. It is a condition in which steroid-dependent tissue histologically similar to endometrium with glands and stroma outside the uterine cavity grows and can cause pelvic pain, dysmenorrhea and infertility. It is estimated that approximately 10-15% of women of reproductive period, about 40% of women with pelvic pain and 50% of women with fertility problems have this disease. Clinically, one of the main concerns regarding endometriosis is its propensity to cause infertility. It is estimated that 25% to 50% of women with endometriosis who are infertile and 25% to 30% of infertile women have endometriotic lesions as the only identifiable cause infertility. The association between endometriosis and infertility is well established, but the mechanisms responsible for these effects are unknown. Oxidative stress is a major issue associated with male and female infertility and failure results in assisted reproduction. Nitric oxide (NO) can induce cell damage, vascular resistance changes and signal transduction, and affect many angiogenic factors. Thus, eNOS may play a role in the development of endometriosis by increased angiogenesis, since the formation of new vessels is essential for the survival of endometrial tissue out of the uterus as well as the progression of endometriosis. The G894T polymorphism in exon 7 (rs1799983, Glu298Asp) of the eNOS gene represents an exchange of glutamic acid for aspartic acid at codon 298. There is a trend to reduced activity of the enzyme in the presence of eNOS 894T allele in comparison with the homozygous GG. Bhanoori et al (2008) investigated the association of the Glu298Asp polymorphism in the eNOS gene in 232 infertile women with endometriosis and 210 women with no evidence of disease by PCR and subsequent sequencing. Statistical analysis showed no significant difference in genotype distribution between cases and controls. Later, Kim et al (2009) assessed the frequency of the Glu298Asp polymorphism in a group of 299 Korean women with advanced endometriosis and 459 women without the disease by PCR-RFLP. The results revealed that the T allele that results in the encoding aspartic acid polymorphism Glu298Asp was more common in women with endometriosis, suggesting an association of this polymorphism and severe form of the disease. In order to try to clarify a possible mechanism leading to infertility in women with endometriosis, we propose to study the eNOS gene Glu298Asp polymorphism in a group of women with endometriosis fertile and infertile and a control group of fertile women without the disease. (AU)

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