Whole exome sequencing identifies new loci associated with NAFLD in the Indian ethnicity and improves prediction of developing the disease

Background and Aim: Non-alcoholic fatty liver disease (NAFLD) is one of the major causes of chronic liver disease. With no approved FDA drugs, the emphasis is on life style modification to manage the disease. Advances in genomics have enabled researchers uncover loci that confer susceptibility to the disease at genome-wide level. However, most of the published studies are from the West and few studies are carried-out in our ethnicity. Developing a reliable polygenic risk score based on data generated in Indians would enable predict the future onset of the disease, so that interventions can be planned very early in life. Methods: Whole blood was collected from individuals with/without liver fat (detected on the ARFI/biopsy proven NAFLD). DNA was isolated and Whole Exome Sequencing (WES) was carried out in patients with NAFLD (N=21) and controls (N=7). NAFLD-associated variants reported in published literature (GWAS and functional studies) were retrieved (PubMed). WES data were analyzed to identify causal variants by in-house assembled pipelines (Gene Ontology (GO)/lipid metabolism/Disease_in_liver) using bioinformatic tools (Ion Reporter-Lifetechnologies, GALAXY, SQL). Sensitivity and specificity of the reported variants and variants identified in our ethnicity were compared (MedCalc). Results: WES identified ∼90,000 variants in each individual. We retrieved 104 NAFLD-associated variants from published studies, of which, only 29 (27.9%) variants were bi-allelic in our ethnicity. The sensitivity and specificity was 55.3% and 63.1% (95%:CI-47.3-63.1;65.0-87.0) respectively for predicting NAFLD risk. However, an increase of 2.8% in sensitivity and 17.8% in specificity was noted with the addition of 18 variants (4 novel variants) in 12 genes (TIMM23B, SCGB1C2, NBPF9, NBPF10, NBPF26, GBP1, TTN, DSPP, IRGM, FAM120B, IRS4, KIR3DL2). Conclusions: We report a limited role of the association of variants from the published literature to NAFLD in our ethnicity. Addition of 18 variants from 12 genes identified by WES in our study improved the prediction power. Metabolites like 3-hyoxysebacic acid and like glycolithocholic acid might serve as inducers of liver regeneration through varied mechanisms.