No association of NAFLD-related polymorphisms in PNPLA3 and TM6SF2 with all-cause and cardiovascular mortality in an Austrian population study.

BACKGROUND AND AIMS: Single-nucleotide-polymorphisms in PNPLA3-rs738409 and the TM6SF2-rs58542926, associated with metabolic-dysfunction-associated fatty liver disease (MAFLD), have been discussed as potentially protective for cardiovascular diseases. Therefore, we aimed to study the associations of PNPLA3/TM6SF2 variants with MAFLD and cardiovascular risk in a population-based sample of asymptomatic patients. METHODS: The study cohort comprised 1742 patients of European decent aged 45-80 years from a registry study undergoing screening colonoscopy for colorectal cancer between 2010 and 2014. SCORE2 and Framingham risk score calculated to assess cardiovascular risk. Data on survival were obtained from the national death registry RESULTS: Half of included patients were male (52%, 59 ± 10 years), 819 (47%) carried PNPLA3­G and 278 (16%) TM6SF2-T-alleles. MAFLD (PNPLA3­G-allele: 46% vs. 41%, p = 0.041; TM6SF2­T-allele: 54% vs. 42%, p < 0.001) was more frequent in patients harbouring risk alleles with both showing independent associations with MAFLD on multivariable binary logistic regression analysis. While median Framingham risk score was lower in PNPLA3­G-allele carriers (10 vs. 8, p = 0.011), SCORE2 and established cardiovascular diseases were similar across carriers vs. non-carriers of the respective risk-alleles. During a median follow-up of 9.1 years, neither PNPLA3­G-allele nor TM6SF2­T-allele was associated with overall nor with cardiovascular mortality. CONCLUSION: Carriage of PNPLA3/TM6SF2 risk alleles could not be identified as significant factor for all-cause or cardiovascular mortality in asymptomatic middle-aged individuals undergoing screening colonoscopy.

Genetic Variants Determine Treatment Response in Autoimmune Hepatitis.

BACKGROUND: Autoimmune hepatitis (AIH) is a rare entity; in addition, single-nucleotide polymorphisms (SNPs) may impact its course and outcome. We investigated liver-related SNPs regarding its activity, as well as in relation to its stage and treatment response in a Central European AIH cohort. METHODS: A total of 113 AIH patients (i.e., 30 male/83 female, median 57.9 years) were identified. In 81, genotyping of PNPLA3-rs738409, MBOAT7-rs626238, TM6SF2-rs58542926, and HSD17B13-rs72613567:TA, as well as both biochemical and clinical data at baseline and follow-up, were available. RESULTS: The median time of follow-up was 2.8 years; five patients died and one underwent liver transplantation. The PNPLA3-G/G homozygosity was linked to a worse treatment response when compared to wildtype [wt] (ALT 1.7 vs. 0.6 × ULN, p < 0.001). The MBOAT7-C/C homozygosity was linked to non-response vs. wt and heterozygosity (p = 0.022). Male gender was associated with non-response (OR 14.5, p = 0.012) and a higher prevalence of PNPLA3 (G/G vs. C/G vs. wt 41.9/40.0/15.0% males, p = 0.03). The MBOAT7 wt was linked to less histological fibrosis (p = 0.008), while no effects for other SNPs were noted. A polygenic risk score was utilized comprising all the SNPs and correlated with the treatment response (p = 0.04). CONCLUSIONS: Our data suggest that genetic risk variants impact the treatment response of AIH in a gene-dosage-dependent manner. Furthermore, MBOAT7 and PNPLA3 mediated most of the observed effects, the latter explaining, in part, the predisposition of male subjects to worse treatment responses.