Abstract
PNPLA3 GENOTYPES ARE SIGNIFICANTLY ASSOCIATED WITH LIVER-RELATED OUTCOMES IN INDIVIDUALS WITH BIOPSY-PROVEN NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)
Background:
The effect of PNPLA3 rs738409 I148M variant (G allele) on the clinical course of adults with biopsy-proven nonalcoholic fatty liver disease (NAFLD) has not been prospectively investigated. We examined (1) the association between PNPLA3 G allele and clinical outcomes and (2) how relationships among PNPLA3 G allele, age, and type 2 diabetes mellitus (T2DM) impact clinical outcomes in patients with biopsy-proven NAFLD.
Methods:
A total of 2,075 adults with biopsy-proven NAFLD were enrolled in the NASH CRN studies between October 2004 and May 2019, and prospectively followed until September 2020, death, or transplant. Cox proportional and competing risk models were used to examine associations between PNPLA3 G allele and all-cause mortality (death of any cause) or composite liver (liver-specific deaths or new-onset varices, hepatic decompensation, HCC, or liver transplant)-, cardiovascular (cardiovascular or cerebrovascular-specific events or deaths)-, non-HCC malignancies (cancers-specific events, and mortality, excluding HCC)-, and chronic kidney disease (CKD) (new onset glomerular filtration rate <60 mL/min/1.73 m2, or CKD-related death)-related outcomes. All analyses were adjusted by race/ethnicity, age, sex, T2DM, body mass index (kg/m2), hypertension, and smoking status.
Results:
The PNPLA3 genotypes were CC: 32%; CG: 44%; and GG: 24%. During a median follow-up of 3.4 years, there were 53 (3%) deaths of any cause. PNPLA3 G allele was not associated with all-cause mortality (Adj. HR: 0.85, 95% CI: 0.57-1.27), but it was significantly associated with an increased risk of the composite liver outcome (CLO) (Adj. sHR: 1.39, 95% CI: 1.06-1.81). PNPLA3 G allele was also not associated with cardiovascular events (Adj. sHR: 1.09, 95% CI: 0.86-1.39), non-HCC malignancies (Adj. sHR: 1.00, 95% CI: 0.72-1.40) or CKD (Adj. sHR: 1.25, 95% CI: 0.90-1.74).
The effect of PNPLA3 G allele on the risk of CLO increased positively and exponentially among those aged>60 years or with T2DM (P values for interactions <0.01). Adults 60 or older with CG (Adj. sHR: 3.3, 95% CI: 1.0-14.8) and GG (Adj. sHR; 5.8, 95% CI: 1.3-26.5) genotypes showed the highest risk of CLO as compared to those with CG/GG genotypes and aged <60 (Figure 1A). Similarly, T2DM patients with PNPLA3 CG (Adj. sHR: 3.2, 95% CI: 1.5-7.0) and GG (Adj. sHR: 7.8, 95% CI: 3.5-17.4) exhibited the highest risk of CLO compared to non-T2DM people with CG/GG genotypes (Figure 1B).
Conclusion:
The carriage of PNPLA3 G allele is associated with worse liver outcomes in patients with biopsy-proven NAFLD. Increasing age and type 2 diabetes amplify this relationship. Routine genotyping of PNPLA3 in patients with NAFLD is warranted.