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DOI: 10.1055/s-0038-1677096
Role of PNPLA3 rs738409 and MBOAT7 rs626283 during alcohol detoxification: Indication of different mechanisms for fibrosis development
Publication History
Publication Date:
04 January 2019 (online)
Background & Aim:
The PNPLA3 rs738409 and MBOAT7 rs626283 polymorphisms have been identified as genetic risk factors for ALD progression; however, their molecular mechanisms are not understood. We here study the impact of these two variants and alcohol withdrawal on important liver parameters.
Methods:
We prospectively enrolled heavy drinkers primarily undergoing alcohol withdrawal (n = 516). Mean alcohol intake was 184 g/day and the mean duration of detoxification was 6.3 days. All patients were genotyped for PNPLA3 rs738409 and MBOAT7 rs626283. In addition, inflammation, fibrosis and steatosis were non-invasively characterized in all patients using laboratory markers including M30 levels, CAP, LS and ultrasound before and after detoxification.
Results:
The PNPLA3 genotype frequencies were 41%, 50% and 9% for CC, CG and GG and for MBOAT7 18%, 52% and 30% for CC, CG and GG. Both genotypes (MBOAT7 CC and PNPLA3 GG) showed a strong and combined effect on fibrosis development in the overall cohort (ANOVA, P < 0.05). However, we observed striking differences between both genetic polymorphisms with regard to inflammation, fibrosis and steatosis in response to alcohol withdrawal. While inflammation showed no difference with a significant decrease while detoxification in all MBOAT7 genotypes, PNPLA3 GG showed significantly increased signs of liver injury after detoxification and a delayed resolution of inflammation (M30 and AST, P < 0.001). In contrast, inflammation resolved equally in all MBOAT7 genotypes (AST, P < 0.001 after detox). Finally, steatosis resolved to the same extent in both polymorphisms and all genotypes and no differences prior and after detox were observed.
Conclusion:
While both variants showed a significant and combined effect on fibrosis progression, the response of steatosis and liver injury to alcohol withdrawal suggests important mechanistic differences. So, PNPLA3 is primarily associated with liver injury, while MBOAT7 seems to sensitize directly for fibrosis development without affecting liver injury. Interestingly, both genetic polymorphisms did not affect the resolution of steatosis during alcohol withdrawal.
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