Investigation of PNPLA3 and IL28B Genotypes on Diabetes and Obesity After Liver Transplantation: Insight Into Mechanisms of Disease

To identify genetic risks for obesity and diabetes postliver transplantation (LT), LT recipients underwent genotyping for IL28B rs12979860 (n=295) and PNPLA3 rs738409 (n=205) polymorphism in both donors and recipients. The development of obesity and diabetes/impaired fasting glucose (IFG) was determined 1-5 years post-LT. Recipient PNPLA-3 genotype was independently associated with obesity (BMI>30) at 3 years posttransplant (genotype CC 33.7%, CG 48.3% and GG 82.4%, p=0.002), with an odds ratio (OR 2.54, CI 1.38-4.66, p=0.003), associated with the G allele. Diabetes/IFG diagnosed within 5 years posttransplant associated with PNPLA-3 non-CC genotype (HR 1.59, 1.12-2.26, p=0.010), but not IL28B TT genotype (HR 1.46, 0.94-2.27, p=0.092). No genotype variable was independently predictive of diabetes/IFG. The combination of PNPLA-3 non-CC and IL28B TT genotype was associated with increased risk of diabetes/IFG compared to PNPLA-3 CC, IL28B non-TT (HR 2.64, CI 1.30-5.39, p=0.008). Donor genotypes were not associated with any of the outcomes analyzed. In conclusion, PNPLA-3 non-CC genotype is associated with posttransplant obesity but not independently with diabetes/IFG. The lack of donor related risk suggests a peripheral rather than central mechanism of insulin resistance in liver transplant recipients. Analysis of donor and recipient genetic risk factors for obesity and diabetes after transplant finds that recipient, but not donor, PNPLA-3 G allele is independently associated with obesity after liver transplantation, pointing to a peripheral rather than central mechanism of action and explaining some of the risk for posttransplant obesity.