PNPLA3 Genotype and Diabetes Identify Patients With Nonalcoholic Fatty Liver Disease at High Risk of Incident Cirrhosis

Abstract

Background & 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: We included participants from 2 independent cohorts, they 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. We conducted time-to-event analyses using Fine-Gray competing risk models.

Results: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× 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 (FIB4) 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 FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 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 NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.

Keywords: Genetics; Polygenic Risk Score; Predictive Modeling; Risk Stratification; TRIB1.

Figure 1:

Genetic and environmental factors associated with progression to cirrhosis in Michigan Genomics Initiative. Models were run as Fine-Gray competing risk analyses. (A) Diabetes status. (B) Obesity status. (C) Alanine aminotransferase (ALT), with upper limit of normal (ULN) defined as 19 U/L in women and 30 U/L in men. (D) PNPLA3-rs738409 genotype. (E) TRIB1-rs28601761 genotype. (F) Cirrhosis polygenic risk score, divided into quartiles (Q), with Q1 indicating the lowest quartile.

Figure 2:

PNPLA3 genotype identifies a subgroup of patients with indeterminate FIB4 with cirrhosis incidence comparable to that of patients with high FIB4. (A-B) Patients were divided into three groups: high FIB4 (>2.67), indeterminate FIB4 (1.3–2.67) with diabetes [(+) DM] and PNPLA3-rs738409-GG genotype [(+) PNPLA3], and indeterminate FIB4 with diabetes and PNPLA3-rs738409-CC or -CG genotype [(−) PNPLA3]. (A) Michigan Genomics Initiative. (B) UK Biobank.

Figure 3:

Schematic for incorporating PNPLA3 genotype into risk stratification in non-alcoholic fatty liver disease. “PNPLA3 risk allele homozygosity” refers to PNPLA3-rs738409-GG genotype. FIB4, fibrosis-4 score.