Viewing Study NCT02388854



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Last Modification Date: 2024-10-26 @ 11:39 AM
Study NCT ID: NCT02388854
Status: UNKNOWN
Last Update Posted: 2021-02-15
First Post: 2015-03-09

Brief Title: Influence of WNT4 VEZT FSHB and SIRT1 SNPs in Endometriosis a Case Control Study of the Sardinian Population
Sponsor: University of Cagliari
Organization: University of Cagliari

Study Overview

Official Title: Influence of WNT4 VEZT FSHB and SIRT1 Genetic Polymorphisms in the Pathogenesis of Endometriosis a Case Control Study of the Sardinian Population
Status: UNKNOWN
Status Verified Date: 2021-02
Last Known Status: RECRUITING
Delayed Posting: No
If Stopped, Why?: Not Stopped
Has Expanded Access: False
If Expanded Access, NCT#: N/A
Has Expanded Access, NCT# Status: N/A
Acronym: None
Brief Summary: Endometriosis defined as the presence of endometrial tissue outside the uterine cavity affects 6-10 of the general population of women in childbearing age

The pathogenesis of the disease is unknown The purpose of this study is to evaluate the influence of certain polymorphisms of genes WNT4 VEZT FSHB known to be involved in molecular mechanisms associated with phenomena of proliferation and development of endometriotic lesions and SIRT1 that based on metabolomics studies could hypothetically have a role in the pathogenesis of the disease The study focus on the Sardinian population known to have unique genetic characteristics due to geographical isolation
Detailed Description: Endometriosis is a benign estrogen-dependent disease characterized by the presence of endometrial tissue in its glandular and stromal components in locations other than the uterine cavity Represents one of the most common gynecological chronic inflammatory diseases of women of reproductive age affecting approximately 10 of the female population although this estimate may be lower than the real data considering the heterogeneity of the clinical manifestations of the disease and the tendency to therefore be underdiagnosed Endometriosis is often associated with infertility and severe pain symptomatology including chronic pelvic pain dyspareunia and dysmenorrhea Despite numerous studies the pathogenesis of the disease is still unknown Studies on family aggregation and twins have given prominence to the genetic component demonstrating how the genetic structure inherited from an individual influences 51 of the predisposition to develop endometriosis in life A great deal of work has involved the identification of different gene polymorphisms able to help explain the susceptibility to the development of endometriosis often with conflicting results Genome-wide association studies GWAS and related meta-analyzes have led to the identification of disease risk loci by providing new insights into potential molecular pathways involved in endometriosis At present 19 independent single-nucleotide polymorphisms SNPs have been validly associated with endometriosis explaining 519 of the variance of the diseaseIn particular a recent study investigated three of these SNPs on the Greek population rs7521902 rs10859871 and rs11031006 mapped respectively on the WNT4 VEZT and FSHB genes highlighting a significant association with endometriosis The WNT4 gene located on chromosome 1 codes for a fundamental protein in the development of the female reproductive system The expression of WNT4 has also been demonstrated at the level of the normal peritoneum suggesting a possible metaplastic hypothesis in promoting the transformation of peritoneal cells into endometriotic cells using pathways involved in the development of female genital tracts Moreover WNT4 is equally expressed in the eutopic endometrium during the proliferative and secretory phases variants of this gene could hypothetically contribute to abnormal growth of endometrial cells in ectopic sites VEZT is a gene located on chromosome 12 and coding for vezatin an important component of the cadherin-catenin complex which is essential for the formation and maintenance of adherent joints The protein is expressed in most epithelial cells and is crucial for the formation of cell-cell contact junctions The expression of VEZT is altered in the endometrium of patients with endometriosis and is an excellent candidate for having a causal role in endometriosis In particular the rs10859871 polymorphism was associated with an increase in the expression of this geneThe FSHB gene located on chromosome 11 codes for the hormone-specific subunit b of the stimulating follicle hormone FSH a key promoter of ovarian follicle growth and estrogen production The extended GWAS of the Sapkota group identifies a significant association between the rs11031006 polymorphism and the risk of endometriosis

The metabolomic profile in patients affected by endometriosis have identified beta-hydroxybutyrate bOHB as a significantly increased metabolite in affected patients The bOHB is a ketonic body that acts as an energy carrier from adipocytes to peripheral tissues However it plays a heterogeneous role in cellular signaling and regulation of gene expression Several enzymes involved in the generation of ketone bodies from lipids are both acetylated and succinylated and target a group of enzymatic activity proteins that act as NAD-dependent deacylases sirtuins Sirtuins have recently been studied for their involvement in the field of female reproductive function Among these sirtuine 1 SIRT1 acts as histone-deacetylase and is implicated in innumerable phenomena such as the regulation of gene transcription aging stress resistance apoptosis energy efficiency Furthermore SIRT1 plays an important role in regulating the expression of inflammatory cytokines in endometriotic stromal cells The SIRT1 gene located on chromosome 10 is over-expressed in the eutopic endometrium of women with endometriosis and is probably involved in the pathogenesis of endometriosis SIRT1 controls among other things the acetylation of a fork transcription factor involved in the pathway metabolic synthesis of ketone bodies FOXA2 in turn involved in the phenomena of proliferation and migration of endometriotic cells Some SSPs of the SIRT1 gene are associated with insults from oxidative stress capable of inducing an abnormal proliferation of endometrial cells k endometrium

The study aims to verify the possible association between the presence of certain polymorphisms of genes known to have a hypothetical role in the pathogenesis of endometriosis and the development of this disease in the population of Sardinian origin

The study will be carried out by molecular typing of the following single substitution polymorphisms SNPs rs7521902 rs10859871 rs11031006 rs2273773 mapped respectively in the WNT4 VEZT FSHB and SIRT1 genes

In this work will be described the frequency of alleles genotypes and haplotypes of these SNPs among Sardinian women and will be evaluated their impact on susceptibility to the development of endometriosis

The molecular-biological analyzes of single-substitution polymorphisms will be carried out starting from whole blood taken subject to informed consent to exclusively Sardinian patients

The investigators have chosen to limit the study only to patients originating from Sardinia taking advantage of the peculiarity of this land which can be considered a genetic macro-isolate The genetic analysis of complex traits is in fact simplified in isolated populations like the Sardinian one in which inbreeding and founding effect reduce the genetic diversity of complex and polygenic diseases such as endometriosis which can in this way be studied more easilyThe goal is to identify a genetic characterization that can be used for the non-invasive diagnosis of the disease

Study Oversight

Has Oversight DMC: None
Is a FDA Regulated Drug?: None
Is a FDA Regulated Device?: None
Is an Unapproved Device?: None
Is a PPSD?: None
Is a US Export?: None
Is an FDA AA801 Violation?: None