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

Hydroxysteroid 17-β dehydrogenase 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 rs72613567 genotypes and the hepatic transcriptome. The A-INS allele protected against NAFLD [odds ratio (OR) per adenine allele = 0.667; 95% CI, 0.486-0.916; <i>P</i> = 0.012]; this effect was nonsignificant when logistic regression analysis included BMI. The A-INS allele protected against nonalcoholic steatohepatitis (NASH) (OR = 0.612; 95% CI, 0.388-0.964; <i>P</i> = 0.033), ballooning degeneration (OR = 0.474; 95% CI, 0.267-0.842; <i>P</i> = 0.01), lobular inflammation (OR = 0.475; 95% CI, 0.275-0.821; <i>P</i> = 0.007), and fibrosis (OR = 0.590; 95% CI, 0.361-0.965; <i>P</i> = 0.035). In patients carrying A-INS, HSD17B13 levels decreased proportionally 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.