Liver and Bile
Gastroenterology. 2023;164(6):966–77.e17
PNPLA3 genotype and diabetes identify patients with non-alcoholic fatty liver disease at high risk of incident cirrhosis
Background and aims: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain.
Methods: The authors included participants from 2 independent cohorts, the Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. They conducted time-to-event analyses using Fine-Gray competing risk models.
Results: 7893 and 46,880 participants from MGI and UKBB, respectively, were included. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥ 2 x upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate Fibrosis-4 (FIB-4) scores (1.3–2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB-4 scores (> 2.67) and 2.9–4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB-4 < 1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB-4 of > 2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype.
Conclusions: PNPLA3-rs738409 genotype and diabetes identified patients with non-alcoholic fatty liver disease currently considered indeterminate risk (FIB-4 1.3–2.67) who had a similar risk of cirrhosis as those considered high risk (FIB-4 > 2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.