Splice variant rs72613567 prevents worst histologic outcomes in patients with nonalcoholic fatty liver disease.

Hydroxysteroid 17βdehydrogenase 13 (HSD17B13) is a lipid droplet-associated protein; its gene-encoding variants affect the chronic liver diseases, including nonalcoholic fatty liver disease (NAFLD). To estimate the effect of rs72613567, a splice variant with an adenine insertion (A-INS), on NAFLD susceptibility and severity, we performed a case-control study with 609 individuals. We investigated the effect of carrying the A-INS allele in 356 patients with biopsy-proven disease and explored the relationship between rs72613567genotypes and the hepatic transcriptome. The A-INS allele protected against NAFLD (odds ratio [OR] per A allele = 0.667; 95% CI, 0.486-0.916;P=0.012); this effect was non significant when logistic regression analysis included body mass index. The A-INS allele protected against nonalcoholic steatohepatitis (NASH; OR = 0.612; 95% CI, 0.388-0.964;P=0.033), ballooning degeneration (OR = 0.474; 95% CI, 0.267-0.842; P = 0.01), lobular inflammation (OR = 0.475; 95% CI, 0.275-0.821; P = 0.007), and fibrosis (OR = 0.590; 95% CI, 0.361-0.965; P = 0.035). In patients carrying A-INS, HSD17B13 levels decreased proportional to allele dosage. Whole-transcriptome genotype profiling showed overrepresented immune response-related pathways. Thus, the rs72613567 A-INS allele reduces the risk of NASH and progressive liver damage and may become a therapeutic target.