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Identifier 000399380
Title Η επίδραση της κληρονομικότητας στην πρωτοπαθή χολική κίρρωση
Alternative Title Inheritance and primary biliary cirrhosis
Author Μάντακα, Αικατερίνη Ν.
Thesis advisor Κουρούμαλης, Ηλίας
Χλουβεράκης, Γρηγόρης
Κουτρουμπάκης, Ιωάννης
Reviewer Παπαδάκη, Ελένη
Σιαφάκας, Νικόλαος
Μουζάς, Ιωάννης
Τζαρδή, Μαρία
Abstract Introduction: Primary biliary cirrhosis (PBC) is an organ specific autoimmune disease of still unidentified etiology, with genetic and environmental pathogenetic background. Chemicals, infectious agents, hormone therapy, reproductive history and surgical interventions have been implicated in the induction of PBC. Familial PBC has been documented in first degree relatives (FDR). The prevalence of Primary biliary cirrhosis varies in different geographic areas. This might reflect genetic or environmental risk factors. On the other hand, we have shown that endothelins (ETs), produced by the liver endothelial cells are increased in PBC and may play a major pathogenetic role. Aims: Most cohort studies are genetically heterogeneous. Our study aimed a) to determine lifestyle or disease associations and familial occurrence rates in the genetically homogeneous and geographically defined Cretan population of PBC patients, b) to study gene polymorphisms related to the endothelial cells (eNOS, EDN-1 genes) and, to investigate whether the previously reported association with CTLA4 gene polymorphisms is also applicable in our genetically homogeneous population and c) to define PBC prevalence and incidence, describe patient’s spatial distribution, generate prediction maps and detect any possible routing pattern of time-spatial appearance of the disease in Crete, Greece. Methods: From 1990-2010, 245 Primary biliary cirrhosis patients diagnosed and followed up at the Gastroenterology Dept of the University Hospital and the District Hospitals of the island, were contacted and 222 were included in the time-spatial analysis. 111 consenting PBC patients, were compared with 115 FDR and 149 controls matched for age, sex, Cretan origin and residence. All participants completed a questionnaire regarding demographics, lifestyle, medical, surgical and reproductive history. Significant variables on the univariate analysis were analyzed by multivariate analysis using a forward step-wise logistic regression model. Genomic DNA was extracted from 100 PBC patients (83 females, 93% AMA+, 74/100 Ludwig stage I–II) and 158 healthy controls. eNOS, CTLA4 and ET1 polymorphisms were determined by PCR–RFLPs analysis. 13 To map the spatial distribution of the 222PBC patients per 5-year periods, geospatial models were applied in Gis–ArcMap 9.3 software. Kriging Interpolation methods were used to generate prediction maps for the disease in Crete. Areas of high and low probability of disease occurrence were estimated through multi-criteria modeling. The disease route was defined by Arc map’s toolbox. Results: Dyslipidaemia was found in 69.4% of PBC patients, 60% of FDR and 40.9% of controls (p < 0.0001 and p = 0.003 respectively), autoimmune diseases in 36.9% of patients, 30.4% of FDR and 13.4% of controls (p < 0.0001 and p = 0.011 respectively). Hashimoto’s disease (p = 0.003), Raynaud syndrome (p = 0.023) and Sjögren syndrome (p = 0.044) were significantly associated with PBC. On multivariate analysis statistically significant associations were found with primary educational level (AOR 2.304, 95% CI 1.024-5.181), cholecystectomy (AOR 2.927, 95% CI 1.347-6.362) and the presence of at least another autoimmune disease (AOR 3.318, 95% CI 1.177-6.22). Cancer history was more frequent in patients than in controls (p = 0.033). Familial PBC was found to be 9.9%. Both eNOS intron4 VNTR and eNOS exon7 G894T SNP were significantly associated with increased risk in PBC. EDN-1 rs2071942 ‘‘A’’ and rs5370 ‘‘T’’ alleles appeared a tendency for association with disease progression. No association was found between PBC and the CTLA4 SNPs analyzed. PBC prevalence was found to be 365 cases per million, with a mean incidence of 20.88(range 3.79-35.99). Prediction map estimates from 1.22 to 11 patients per 50 km2 all over Crete. Areas of high risk of disease occurrence are located in the Eastern part, while low risk in the Western part of the island Conclusions: Dyslipidaemia and autoimmune diseases were significantly increased not only in PBC patients as expected but also in their FDR. An increased prevalence of malignancies was found in PBC patients. Primary educational level, cholecystectomy and the presence of at least another autoimmune disease were found as putative risk factors for PBC. No association was found with smoking, urinary tract infection or reproductive history. The reported high familial occurrence of PBC could imply screening with AMA of FDR with at least another autoimmune disease. We also demonstrated that eNOS, a gene related to the liver endothelium function is associated with PBC. In contrast the important in adaptive immunity gene CTLA4 was not associated with the disease in the homogeneous population analyzed. These 14 results are partially compatible with our previous hypothesis that defects of the liver endothelial system, leading to endothelin overproduction, may be a fundamental early pathogenetic mechanism in PBC. Prevalence and incidence of Primary biliary cirrhosis in Crete are among the highest published in Europe. Given the homogeneous and stable study population and the geopolitics of the island, the heterogeneity in the time-spatial distribution and the route of disease appearance strongly suggest a role for environmental causative agents.
Language Greek
Issue date 2016-03-24
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/4/b/f/metadata-dlib-1455263740-568869-6554.tkl Bookmark and Share
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