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

FLICHMAN, DIEGO; GAZZI, CARLA; GARAYCOECHEA, MARTIN; SAN MARTINO, JULIO; SOOKOIAN, SILVIA; PIROLA, CARLOS J; ARRESE, MARCO; CASTA&NTILDEO, GUSTAVO O

JLR PAPERS IN PRESS

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2018 vol. 60 p. 176 - 185

0022-2275

Hydroxysteroid 17- dehydrogenase 13 (HSD17B13) is a lipid droplet?associated protein; itsgene-encoding variants affect the chronic liver diseases, including nonalcoholic fatty liverdisease (NAFLD). To estimate the effect of rs72613567, a splice variant with an adenineinsertion (A-INS), on NAFLD susceptibility and severity, we performed a case-control studywith 609 individuals. We investigated the effect of carrying the A-INS allele in 356 patientswith biopsy-proven disease and explored the relationship between rs72613567genotypes andthe hepatic transcriptome. The A-INS allele protected against NAFLD (odds ratio [OR] per Aallele = 0.667; 95% CI, 0.486−0.916;P=0.012); this effect was non significant when logisticregression analysis included body mass index. The A-INS allele protected againstnonalcoholic 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 decreasedproportional to allele dosage. Whole-transcriptome genotype profiling showedoverrepresented immune response?related pathways. Thus, the rs72613567 A-INS allelereduces the risk of NASH and progressive liver damage and may become a therapeutic target.