The role of PNPLA3, MBOAT7 and TM6SF2 during alcohol detoxification: different mechanisms of fibrosis and steatosis development

Background and Aims PNPLA3, MBOAT7 and TM6SF2 were identified as important risk genes for the development of alcoholic cirrhosis. We here present first data on the role of PNPLA3, MBAOT7 and TM6SF2 genotypes on liver stiffness (LS), steatosis (CAP) and inflammation during alcohol withdrawal.

Method 763 patients with ALD which were hospitalized for alcohol withdrawal at Salem Medical Center between 2007 and 2018 were genotyped for PNPLA3 s738409, MBOAT7 rs626283 and TM6SF2 rs58542926 polymorphisms. All patients had routine laboratory, ultrasound and a LS measurement.

Results 71% of the patients were male, median age was 52 years, BMI was 24.7 kg/m2 and alcohol consumption was 163 g/day. At admission, no difference between the genotypes was seen regarding age, BMI, gender, alcohol consumption or transaminase levels. Significant differences were observed for PNPLA3 and MBOAT7 during alcohol detoxification. While MBOAT7 was associated with higher LS, no differences were observed between genotypes upon alcohol detoxification. In contrast, PNPLA3 caused clearly a delayed resolution of LS during withdrawal of alcohol due to inflammation. This could be recapitulated when looking at serum markers of liver inflammation. TM6SF2 showed no effect on alcohol withdrawal. A multivariate model confirmed that PNPLA3 was associated with steatosis and inflammation but not fibrosis. MBOAT7 was only associated with fibrosis/cirrhosis but not inflammation or steatosis.

Conclusion These first genotype data on a “human alcohol knock-out” intervention underscore important differences between the three genes. PNPLA3 seems to primarily drive fibrosis through inflammation while MBOAT7 seems to have a direct effect on fibrosis.

Publication History

Article published online:
26 January 2022