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

Background: A splice variant in gene is demonstrated to protect against nonalcoholic fatty liver disease (NAFLD), and mitigate the effect of Patatin-like phospholipase domain-containing 3 (-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 1,020 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 and controls (Illumina; HiSeqX); -A-INS/I148M- variants were genotyped (sequencing/qR T-PCR); HSD17B13 protein expression was estimated (immunohistochemistry); the Student's t-test/Mann-Whitney U/Chi-square test and odds ratio (95% confidence interval) were used.

Results: There was no significant difference (Odds ratio = 0.76; 95% CI -0.57 to 1.03;  = 0.76) in the frequency of the rs72613567-A-INS between controls and patients (17.8% vs. 14.4%). No difference in the ALT (Alanine transaminase; 72.24 ± 65.13 vs. 73.70 ± 60.06;  = 0.51) and AST levels (Aspartate aminotransferase; 60.72 ± 55.59 vs. 61.63 ± 60.33;  = 0.91) between wild and variant carriers were noted. Significantly elevated liver enzymes were seen in -148-variant/wild compared with -148-variant/variant (90.44 ± 59.0 vs. 112.32 ± 61.78;  = 0.02). No difference in steatosis ( = 0.51) between -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 variant. Ethnicity-based validation must be carried out before including it in assessing protection against NAFLD.