ABSTRACT
Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (ndiscovery = 52 654 and nreplication = 14 774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined = 1.8 × 10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined = 1.5 × 10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined = 1.2 × 10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.
Subject(s)
Genome-Wide Association Study , HLA-DRB1 Chains/genetics , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin-1/genetics , Interleukin-6/genetics , Receptors, Interleukin-6/genetics , Cohort Studies , Gene Expression Regulation , Genetic Loci , Genetic Predisposition to Disease , Humans , Interleukin-6/blood , Polymorphism, Single Nucleotide , White People/geneticsABSTRACT
BACKGROUND: The standard management of autoimmune hepatitis (AIH) is based on corticosteroids, alone or in combination with azathioprine. Second-line treatments are needed for patients who have refractory disease. However, high-quality data on the alternative management of AIH are scarce. AIM: To evaluate the efficacy and safety of tacrolimus and mycophenolate mofetil (MMF) and the quality of evidence by using the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE). METHODS: A systematic review and meta-analysis of the available data were performed. We calculated pooled event rates for three outcome measures: Biochemical remission, adverse events, and mortality, with their corresponding 95% confidence intervals (CI). RESULTS: The pooled biochemical remission rate was 68.9% (95%CI: 60.4-76.2) for tacrolimus, and 59.6% (95%CI: 54.8-64.2) for MMF, and rates of adverse events were 25.5% (95%CI: 12.4-45.3) for tacrolimus and 24.1% (95%CI: 15.4-35.7) for MMF. The pooled mortality rate was estimated at 11.5% (95%CI: 7.1-18.1) for tacrolimus and 9.01% (95%CI: 6.2-12.8) for MMF. Pooled biochemical remission rates for tacrolimus and MMF in patients with intolerance to standard therapy were 56.6% (CI: 43.4-56.6) vs 73.5% (CI: 58.1-84.7), and among non-responders were 59.1% (CI: 48.7-68.8) vs 40.8% (CI: 32.3-50.0), respectively. Moreover, the overall quality assessments using GRADE proved to be very low for all our outcomes in both treatment groups. CONCLUSION: Tacrolimus and MMF are in practice considered effective for patients with AIH who are non-responders or intolerant to first-line treatment, but we found no high-quality evidence to support this statement.
Subject(s)
Hepatitis, Autoimmune , Mycophenolic Acid , Hepatitis, Autoimmune/diagnosis , Hepatitis, Autoimmune/drug therapy , Humans , Immunosuppressive Agents/adverse effects , Mycophenolic Acid/adverse effects , Tacrolimus/adverse effects , Treatment OutcomeABSTRACT
INTRODUCTION: Chronic hepatitis is specified as inflammatory disease of the liver lasting for more than six months. Role of noninvasive fibrosis markers as prognostication factors of the presence or absence of significant fibrosis on liver biopsy of patients with chronic hepatitis is the aim of this study. METHODS: Two hundred twenty-one patients with chronic hepatitis involved in the study between 2011 and 2013. Routine biochemical indices and serum fibrosis markers such as aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR), AST to platelet ratio index (APRI) and Fibrosis 4 score (FIB-4) were evaluated, and the histological grade and stage of the liver biopsy specimens were scored according to the Ishak scoring system. Diagnostic accuracies of these markers for prediction of significant fibrosis were assessed by Receiver Operating Characteristic (ROC) curve analysis. RESULTS: Contemporaneous laboratory indices for imputing AAR, APRI, and FIB-4 were identified with liver biopsies. From all, 135 males (61.1%) and 86 females (38.9%), with mean age of 39.6±14.4 were studied. Significant correlation between stages of fibrosis and FIB-4, APRI and AAR were detected, with a correlation coefficient higher than that of other markers in the patients with Hepatitis B (r = 0.46), C (r = 0.58) and autoimmune hepatitis (r = 0.28). FIB-4 (AUROC = 0.84) and APRI (AUROC = 0.78) were superior to AAR at distinguishing severe fibrosis from mild-to-moderate fibrosis and gave the highest diagnostic accuracy. CONCLUSION: Application of these markers was good at distinguishing significant fibrosis and decreased the need for staging liver biopsy specimens among patients with chronic hepatitis.