17-Beta-Hydroxysteroid Dehydrogenase 13 Loss of Function Does Not Confer Protection to Non-alcoholic Fatty Liver Disease in Indian Population

Background A splice variant in HSD17B13 gene is demonstrated to protect against Non-alcoholic Fatty Liver Disease (NAFLD) and mitigate the effect of PNPLA3-I148M. It is being explored as a putative drug target and in polygenic risk scores. Based on whole exome sequencing (WES) in our cohort of biopsy proven NAFLD and limited data on the variant in our ethnicity, we sought to explore its role. Methods This is a cross-sectional study that recruited 1020 individuals with ultrasound/biopsy confirmed NAFLD and matched controls. Liver enzymes and lipid profiles were estimated (Beckman coulter LX750/DXH800). WES was performed in NAFLD patients (Illumina;HiSeqX). HSD17B13-A-INS/I148M-PNPLA3 variants were genotyped (Sequencing/qRT-PCR). HSD17B13 protein expression was estimated (Immunohistochemistry). Student's t test/Mann–Whitney U/Chi-square test and odds ratio (95% CI) were used. Results There was no significant difference (OR=0.76;95% CI-0.57-1.03;p=0.76) in the frequency of the rs72613567-A-INS between controls and patients (17.8% Vs 14.4%). No difference in the ALT (72.24±65.13Vs73.70±60.06;p=0.51) and AST levels (60.72±55.59Vs61.63±60.33;p=0.91) between HSD17B13-wild and variant carriers were noted. Significantly elevated liver enzymes were seen in PNPLA3-148-variant/HSD17B13-wild compared with PNPLA3-148-variant/HSD17B13-variant (90.44±59.0Vs112.32±61.78;p=0.02). No difference in steatosis (p=0.51) between HSD17B13-wild and variant carriers was noted. No other variants in the intron-exon boundaries were identified. Although, protein expression differences were noted between wild and variant carriers, no difference in the extent of steatosis was seen. Conclusion Our study reports lack of association of the splice variant with reduced risk of NAFLD and mitigating the effect of PNPLA3 variant. Ethnicity based validation must be carried out before including it in assessing protection against NAFLD.