HSD17B13 hepatoprotective variant limits liver disease severity in homozygous carriers of the PNPLA3 p. 148MM risk genotype

 

Background:

Carriers of the adiponutrin (PNPLA3) p. 148MM genotype have an increased risk of hepatic steatosis and fibrosis. Exome analysis (Abul-Husn et al. N Engl J Med 2018) demonstrated that the HSD17B13 rs72613567 splice variant reduces the general risk of chronic liver disease (CLD) and fatty liver progression. Here we aim to investigate how the HSD17B13 variant affects liver steatosis and fibrosis in patients who are homozygous carriers of the PNPLA3risk variant p.I148 M.

Patients and methods:

In total, we screened 2,278 patients and genotyped them for the PNPLA3variant in our academic medical center. Clinical, laboratory and imaging data were collected, including non-invasive liver stiffness measurements (LSM, marker of hepatic fibrosis) and controlled attenuation parameter (CAP, marker of hepatic steatosis) by transient elastography in all patients. Additionally, HSD17B13 rs72613567 and MBOAT7 rs641738 were genotyped using allelic discrimination assays.

Results:

In total, 144 patients (6.3%) were carriers of the homozygous PNPLA3 p. 148MM genotype (86 men, age 19 – 83 years, 19.7% diabetes). Diagnosis of NAFLD and/or alcoholic liver disease had been established in 73.0% of the patients. Their median ALT was 42 U/l (range 10 – 194), median CAP was 279 dB/m (range 100 – 400) and median LSM was 12.0 kPa (range 2 – 75), consistent with advanced fibrosis and steatosis. The following dsitributions of HSD17B13 and MBOAT7 genotypes were detected: [T|T] 0.65, [T|TA] 0.29, [TA|TA] 0.06; [CC] 0.31, [CT] 0.49, [TT] 0.20, both consistent with Hardy-Weinberg equilibrium. Although HSD17B13 rs72613567 and MBOAT7 rs641738 did not affect mean LSM and CAP values, the maximum LSM and CAP in patients with the [TA|TA] genotype were 34 kPa and 342 dB/b, respectively, i.e. were 41 kPa and 58 dB/m lower than in carriers of the common HSD17B13 allele.

Conclusions:

Advanced liver fibrosis and steatosis are frequent in the PNPLA3 p. 148MM individuals with CLDS. The HSD17B13 rs72613567 variant might mitigate, to a certain extent, harmful effects of PNPLA3homozygosity. Epistatic effects of combined PNPLA3-MBOAT7-HSD17B13 variants are to be studied further.