Genetic variantes of TYKe gene as risk factor for endometriosis

• Grant number: 11/11887-0
• Support type: Regular Research Grants
• Duration: December 01, 2011 - November 30, 2012
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: Bianca Alves Vieira Bianco
• Grantee: Bianca Alves Vieira Bianco
• Home Institution: Faculdade de Medicina do ABC (FMABC). Organização Social de Saúde. Fundação do ABC. Santo André , SP, Brazil

Abstract

Endometriosis is a chronic inflammation that is one of the most common benign gynecological diseases. 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 currently it is estimated that about 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 autoantigens, 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, activation of T cells, 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 connected to the IFNAR in its inactive state. After IFN-binds to the IFNAR, TYK2 is the 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, STATs move to the nucleus where they bind to a specific sequence of DNA and stimulate the expression of several genes and leading to the production of IL-23 and IL-17, pro-inflammatory 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 investigated the association of these polymorphisms with autoimmune 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 the rs34536443 and rs2304256 polymorphisms were associated with autoimmune and inflammatory diseases, but not the rs280523 polymorphism, rs280519, rs12720270 and rs12720356. Since 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 may have different patterns of association with markers in different populations due to genetic heterogeneity. We hypothesized a possible relationship between TYK2 polymorphisms and endometriosis. To date, there is no studies in the literature linking this polymorphisms with endometriosis. (AU)

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)

BIANCO, BIANCA; ANDRE, GUSTAVO M.; VILARINO, FABIA L.; PELUSO, CARLA; MAFRA, FERNANDA ABANI; CHRISTOFOLINI, DENISE M.; BARBOSA, CAIO P.. The possible role of genetic variants in autoimmune-related genes in the development of endometriosis. HUMAN IMMUNOLOGY, v. 73, n. 3, p. 306-315, MAR 2012. (11/11887-0)