ABSTRACT
BACKGROUND/PURPOSE: Genome-wide association studies have reported the association of common variants with nonalcoholic fatty liver disease in genes, namely, PNPLA3/TM6SF2/MBOAT7/HSD17B13, across ethnicities. However, the approach does not identify rarer variants with a higher effect size. We therefore sequenced the complete exonic regions of patients with nonalcoholic steatohepatitis and controls to compare rare and common variants with a role in the pathogenesis. METHODS: This is a prospective study that recruited 54 individuals with/without fatty infiltration. Patients with biopsy-proven nonalcoholic steatohepatitis and persistently elevated liver enzymes were included. Controls were with normal CT/MR fat fraction. DNA was isolated from whole blood, amplified (SureSelectXT Human All Exon V5 + UTR kit) and sequenced (Illumina). Data were filtered for quality, aligned (hg19), and annotated (OpenCRAVAT). Pathogenic (Polyphen-2/SIFT/ClinVar) variants and variants reported to be associated with NAFLD based on published literature were extracted from our data and compared between patients and controls. RESULTS: The mean age of controls (N = 17) and patients (N = 37) was 46.88 ± 6.94 and 37.46 ± 13.34 years, respectively. A total of 251 missense variants out of 89 286 were classified as pathogenic. Of these, 106 (42.23%) were unique to the patients and remaining (n = 145; 57.77%) were found in both patients and controls. Majority (25/37; 67.57%) patients had a minimum of one or more rare pathogenic variant(s) related to liver pathology that was not seen in the controls. CONCLUSION: Elucidating the contribution of rare pathogenic variants would enhance our understanding of the pathogenesis. Including the rarer genes in the polygenic risk scores would enhance prediction power.
Subject(s)
Non-alcoholic Fatty Liver Disease , Humans , Adult , Middle Aged , Non-alcoholic Fatty Liver Disease/pathology , Genome-Wide Association Study , Prospective Studies , Exome Sequencing , Liver/pathology , Genetic Predisposition to Disease , Polymorphism, Single NucleotideABSTRACT
BACKGROUND: Treatment of recurrent hepatitis C after liver transplantation is associated with poor sustained virological response (SVR) in genotype 1, and data on genotype 3 is limited to small numbers. We report one of the largest series of genotype 3 patients treated for recurrent hepatitis C following living donor liver transplantation (LDLT). METHODS: From January 2002 to November 2013, of 1349 transplants, 359 patients had hepatitis C. Patients with histological recurrence were treated with pegylated interferon in escalating dose regimen for 48 weeks and weight-based ribavirin. Virological response was defined as rapid virological response (RVR-4 weeks), early virological response (EVR-12 weeks), end of treatment response (ETR-48 weeks), and SVR (24 weeks after end of treatment). SVR and no-SVR groups were compared for age, sex, body mass index (BMI), diabetes, total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides, ferritin, genotype, and hepatitis C virus (HCV) RNA levels before initiation of treatment. RESULTS: The study included 67 patients who had at least 18 months of follow up after treatment initiation (45 males), aged 51 ± 6.3 years. Treatment was started after 16 months (median); baseline median RNA was 2.7 × 10(6) IU/mL. There was no significant difference between the SVR and no-SVR groups regarding age, sex ratio, follow up period, total cholesterol, triglycerides, HDL, BMI, prevalence of diabetes, HCV RNA, and ferritin levels. Genotype 3, RVR, EVR, ETR, and higher LDL levels were significantly associated with SVR. Genotype 3 had a significantly higher SVR rate of 71 % as compared to an SVR rate of only 14 % in genotype 1, p = 0.0003. Absence of RVR and EVR predicted treatment failure with a specificity of 88 % and 92 %, respectively. CONCLUSION: Genotype 3 and higher LDL levels predict SVR in patients treated for hepatitis C recurrence following LDLT, whereas absence of RVR and EVR strongly predict treatment failure.