HSD17B13 and MBOAT7 as modulators of PNPLA3-associated cirrhosis

Background Carriers of the adiponutrin (PNPLA3) p.I148M variant, and in particular homozygous patients, have an increased risk for progression of chronic liver diseases and cirrhosis. In addition, a hepatoprotective splice variant of HSD17B13 reduces the cirrhosis risk (Abul-Husn et al. N Engl J Med 2018), whereas mutations in the MBOAT7 gene aggravate liver injury. Our aim was to investigate how the HSD17B13 and MBOAT7 variants modulate the risk for an advanced stage of cirrhosis in homozygous carriers of the PNPLA3 variant.

Methods In total, 998 patients with cirrhosis were screened for the PNPLA3 variant. Clinical, laboratory and imaging data were collected. Decompensation was defined as the presence of ascites, prior variceal bleeding, hepatic encephalopathy, or jaundice (serum bilirubin ≥ 3.0 mg/dl). Within this cohort, MBOAT7 (rs641738) and HSD17B13 (rs72613567) variants were genotyped by PCR-based allelic discrimination assays, and genotype-to-phenotype correlations were analyzed.

Results Overall, 148 patients (15 %) were homozygous carriers of the PNPLA3 p.148M/M genotype (64 % men, age 30–81 years). Causes of cirrhosis resembled a typical European population (59 % alcoholic, viral 14 %, NASH 9 %, 14 % other etiologies). Two thirds of the patients were in the decompensated stage of the disease. When comparing patients according to the presence or absence of the protective HSD17B13 variant, 36 % were carriers in the decompensated stage versus 56 % in the compensated stage (p=0.025). Similarly, MELD scores (13.1 versus 10.9; p=0.04), Child-Pugh score (7.6 versus 7.1; p=0.23) and bilirubin concentrations (3.3 versus 1.7 mg/dl, p=0.035) where significantly higher when the HSD17B13 variant was absent, contributing to the advanced stage of cirrhosis. These parameters were not influenced by MBOAT7 alleles.

Conclusions The risk of progressive cirrhosis is increased in homozygous carriers of the PNPLA3 genotype p.148M/M. Notably, the presence of a HSD17B13 allele mitigates, at least in part, the harmful effects conferred by PNPLA3 homozygosity. As both PNPLA3 and HSD17B13 localize to hepatic lipid droplets, the functional interaction might occur at this intracellular localization.

Publication History

Article published online:
04 January 2021