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Abstract Neonatal cholestasis is a group of disorders of impaired bile flow characterized by conjugated hyperbilirubinemia in the newborn and young infant arising from a wide variety of disorders. Biliary atresia is one of the most commonly identifiable etiologies of neonatal cholestasis. Representing the most common cause of death from liver disease in children and the most common cause for liver transplant in pediatrics. It is a fibroinflammatory disease, if untreated results in progressive cholestasis with hepatic fibrosis and cirrhosis. BA prognosis relates to timely surgical correction and therefore early diagnosis is mandatory. Surgical intervention by KPE may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. The causes of BA remain actually unknown but genetic and immune dysregulation play a major role in the disease. Current research focuses on the identification of blood or liver factors linked to the pathogenesis of BA that could become therapeutic targets and avoid the need for liver transplantation. Genetic predisposition is one of the explored fields to explain biliary atresia pathogenicity. It has been associated with several inborn syndromes, chromosomal anomalies, and gene polymorphisms in specific populations. MicroRNAs (miRNAs) are an abundant class of small non - coding RNAs. Accumulating evidence indicates that disruption of miRNA expression levels plays crucial roles in all aspects of different human diseases. Summary 107 Recent research has ascribed the role of miRNAs in all aspects of liver disease from initiation, progression, diagnosis and treatment. Injury to liver tissue in biliary atresia is supposed to release certain microRNAs. High levels of these micro RNAs are found in the intrahepatic bile ducts confirming the source of release and their specificity. Single nucleotide polymorphisms (SNPs) in miRNA genes are a novel class of genetic variations in the human genome that confer the risk of many diseases. It has been shown that SNPs in miRNA genes could change the conformation of the secondary structure and thereby directly affect both the binding to target mRNAs and the miRNA maturation process, thus altering protein expression and potentially contributing to disease susceptibility. MiRNA-499 is a newly discovered member of miRNAs. It has been shown to be expressed in myocardium and skeletal muscle in mammals. It regulates the expression of the beta myosin heavy chain, leading to enhancement of myocardial oxygen metabolism and tolerance. In some studies, it has been found that miRNA 499 modulate T cell selection and receptor sensitivity and also T cell development , which suggests that miRNA may be associated with the development of autoimmune diseases. Recently, functional SNP has been identified in the miR499 gene (adenine to guanine [A/G]). This polymorphism leads to a change from A: U pair to G: U mismatch in the stem structure of miR 499 precursor. Therefore, in this study we investigated the effects of the miR- 499 rs3746444 polymorphism on the risk of BA and the effect of this polymorphism on the clinicopathologic data and whether this gene Summary 108 polymorphism affect the prognosis after Kasai operation in patient who underwent this procedure . The study included 300 patients selected from the inpatient and outpatient clinic at National Liver Institute, Menoufia University. The patients are divided into three groups: group І 100: healthy children as control group . group II 100: Patients with cholestatic liver disease other than biliary atresia. group IП 100: Patients with biliary atresia. All individuals were subjected to; Clinical assessment, routine laboratory investigations and miR-499 rs3746444gene polymorphism analysis. Six months after Kasai, 86 of biliary atresia cases who undergwent Kasai procedure were subjected to reevaluation by laboratory investigations The gained results showed that. 1. The genotypes distribution of miR-499 polymorphism SNP (rs3746444) in control, non-BA and BA groups revealed a significant difference (P= 0.019). 2. The AG genotype is the most common genotype among the studied groups. 3. It was observed that the distribution of miR-499 SNP (rs3746444) genotypes, alleles ,dominant, or recessive models were not significantly associated with the disease risk in nonBA groups as compared to control groups . 4. The comparison of genotypes distribution and allele frequencies of miR-499 SNP (rs3746444) between control and BA groups Summary 109 showed that GG genotypes were associated with a significantly increased risk of BA. 5. The subjects with the variant G allele had a significant risk of BA compared with wild allele A. 6. The comparison of genotypes distribution and allele frequencies of miR-499 SNP( rs3746444 )between BA and non- BA groups showed that GG genotypes were associated with a significantly increased risk of BA. 7. A significant difference between different genotypes regarding baseline ALT, AST, GGT, and total bilirubin. 8. There was no significant phenotypic difference between the different genotypes in the BA group. 9. There was a significant difference between different genotypes as regard the degree of fibrosis with worsening in the degree of fibrosis with the GG genotype which signifies increase its severity in this genotype. 10.Regarding the association between genotypes in the recessive of miR-499 SNP (rs3746444) polymorphism with the change in the laboratory parameters six months after Kasai in biliary atresia group, it was found that total, direct bilirubin, and INR levels were significantly more improved in patients carrying AA or AG genotypes but not GG, revealing bad prognosis after Kasai operation for patients with the GG genotype. In summary, this study, as far as we know, is the first to demonstrate the relationship between miR-499 polymorphism and BA in Egyptian population. Our study showed that this polymorphism might modify BA susceptibility and the condition after Kasai Summary 110 operation. In particular, some evidence of genotypes modifying liver inflammation was observed in the analysis of clinicopathological status. |