Genetic Susceptibility to Chronic Liver Disease in Individuals from Pakistan

Abstract

Chronic liver disease, with viral or non-viral etiology, is endemic in many countries and is a growing burden in Asia. Among the Asian countries, Pakistan has the highest prevalence of chronic liver disease. Despite this, the genetic susceptibility to chronic liver disease in this country has not been investigated. We performed a comprehensive analysis of the most robustly associated common genetic variants influencing chronic liver disease in a cohort of individuals from Pakistan. A total of 587 subjects with chronic liver disease and 68 healthy control individuals were genotyped for the HSD17B13 rs7261356, MBOAT7 rs641738, GCKR rs1260326, PNPLA3 rs738409, TM6SF2 rs58542926 and PPP1R3B rs4841132 variants. The variants distribution between case and control group and their association with chronic liver disease were tested by chi-square and binary logistic analysis, respectively. We report for the first time that HSD17B13 variant results in a 50% reduced risk for chronic liver disease; while MBOAT7; GCKR and PNPLA3 variants increase this risk by more than 35% in Pakistani individuals. Our genetic analysis extends the protective role of the HSD17B13 variant against chronic liver disease and disease risk conferred by the MBOAT7; GCKR and PNPLA3 variants in the Pakistani population.

Keywords: ADPN; Asia; LPIAT1; NAFLD; TMC4; adiponutrin.

Figure 1

Minor allele frequency of main genetic determinants of liver disease and the corresponding risk for chronic liver disease in Pakistani individuals. (a) Minor allele frequency of main genetic determinants of liver disease stratified by case and control group. Data are shown as percentage. P-values calculated by chi-square. (b) The risk for chronic liver disease conferred by the minor allele of the main genetic determinants of chronic liver disease expressed as Odds ratio (OR) and its 95% confidence interval (CI). The risk was estimated by binary logistic regression under an additive genetic model with the exception of TM6SF2 where a dominant genetic model has been assumed, considering the relative lower MAF. Case group: n = 587 individuals with chronic liver disease (n = 522 viral and 62 non-viral). Control group: n = 164 individuals without liver disease (n = 68 recruited in the present study plus 96 Punjabi individuals reported on 1000 Genomes Project ((Ensembl release 99—January 2020)). Abbreviations: HSD17B13, Hydroxysteroid 17-Beta Dehydrogenase 13; MBOAT7, Membrane Bound O-Acyltransferase Domain Containing 7; PNPLA3, Patatin-like phospholipase domain-containing protein 3; CGKR, Glucokinase regulator; TM6SF2, Transmembrane 6 Superfamily Member 2; PPP1R3B, Protein Phosphatase 1 Regulatory Subunit 3B. * p < 0.05; ** p < 0.005; *** p < 0.0001; **** p < 0.00005.