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Genetic variants in codificants regions of the TYK2 gene as a risk factor for endometriosis

Grant number: 12/00566-1
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2012
Effective date (End): March 31, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Bianca Alves Vieira Bianco
Grantee:Cecília Schwartzman Goldman
Host Institution: Faculdade de Medicina do ABC (FMABC). Organização Social de Saúde. Fundação do ABC. Santo André , SP, Brazil


Endometriosis is a chronic inflammation that is one of the most common benign gynecological disease. It is a steroid-dependent condition in which tissue histologically similar to endometrium with glands and stroma grows outside the uterine cavity and can cause pelvic pain, dysmenorrhea and infertility. It is estimated that approximately 10-15% of women of reproductive period, 40% of women with pelvic pain and 50% of women with fertility problems have this disease. It is also known that endometriosis, especially advanced disease, may impair fertility and is currently estimated that approximately 20-50% of women with endometriosis are infertile. However, the mechanisms responsible for these effects are unknown. However, a number of different studies have described changes in immune parameters in women with endometriosis and infertility. Autoimmune and inflammatory diseases are a group of complex diseases, affecting up to 5% of the population, characterized by loss of tolerance to auto antigens, causing tissue destruction and whose pathogenesis involves a combination of multiple genetic and environmental factors. The type I interferons (IFNs) comprise a large family of cytokines that have many important immunoregulatory functions, such as the maturation of dendritic cells, T cell activation, stimulation of B cells and antibody production. The tyrosine kinase 2 (TYK2) is part of the Janus kinase (JAK) that binds to the IFN-receptor (IFNAR) on the surface of cells producing IFN. The TYK2 is bound to IFNAR in its inactive state. After that IFN-binds to the IFNAR, the TYK2 is phosphorylated and thus activated. Once activated, the TYK2 then phosphorylates IFNAR to allow its binding genes in signal transducers and activators of transcription 3 and 5 (STAT3 and STAT5). After phosphorylation by JAK, the STATs move to the nucleus where they bind to a specific sequence of DNA and stimulate the expression of several genes and leading to production of IL-23 and IL-17, proinflammatory cytokines from cells natural killer (NK) cells and CD4 + and CD8 +. This signaling pathway also plays an important role in the differentiation of CD4 + T cells inactive in Th17 cells, which are involved in controlling the immune response and in mediating inflammation. Therefore, the TYK2 gene may have crucial importance in the etiology of autoimmune and inflammatory diseases. Furthermore, TYK2 also interacts with receptors of several other cytokines such as IL-6, IL-10, IL-12, IL-13 and IL-23.Many TYK2 gene polymorphisms have been identified and, recently, several case-control studies investigating the association of these polymorphisms with autoimmune diseases and inflammatory diseases with conflicting results. In a meta-analysis, Tao et al (2010) summarized data from 11 studies that included data from 21,497 cases and 22,647 controls and found that polymorphisms rs2304256 and rs34536443 were associated with autoimmune and inflammatory diseases, but not polymorphisms rs280523, rs280519, rs12720270 and rs12720356. Like many autoimmune diseases may share common pathophysiological mechanisms, the genes that were found in combination in an autoimmune disease can also be considered as candidates for other diseases with immunological components, such as endometriosis. Although the pathogenesis of the disease has not yet been clarified, several studies have shown aberrant function of immune cells, suggesting an important role of genetic and immunological factors. Moreover, the same allele can have different patterns of association with markers in different populations due to genetic heterogeneity. We hypothesized a possible relationship between gene polymorphisms and endometriosis TYK2. To date, no studies in the literature relating this gene polymorphisms with endometriosis. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
PELUSO, CARLA; CHRISTOFOLINI, DENISE M.; GOLDMAN, CECILIA S.; MAFRA, FERNANDA A.; CAVALCANTI, VIVIANE; BARBOSA, CAIO P.; BIANCO, BIANCA. TYK2 rs34536443 polymorphism is associated with a decreased susceptibility to endometriosis-related infertility. HUMAN IMMUNOLOGY, v. 74, n. 1, p. 93-97, . (12/00566-1, 11/15045-4)
PELUSO, CARLA; GOLDMAN, CECILIA; CAVALCANTI, VIVIANE; GASTALDO, GUILHERME; TREVISAN, CAMILA MARTINS; CHRISTOFOLINI, DENISE MARIA; BARBOSA, CAIO PARENTE; BIANCO, BIANCA. Use of Bone Morphogenetic Protein 15 Polymorphisms to Predict Ovarian Stimulation Outcomes in Infertile Brazilian Women. GENETIC TESTING AND MOLECULAR BIOMARKERS, v. 21, n. 5, p. 328-333, . (12/00566-1, 14/06177-2)

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