PNPLA3 L148M (rs738409) polymorphism as a risk for new onset diabetes mellitus and obesity in non-NASH/cryptogenic living related donor liver transplant recipients

Background: Liver transplantation is considered the main treatment for end stage liver disease and the early stages of hepatocellular carcinoma. Long-term metabolic outcomes after liver transplantation affect morbidity and mortality, and the genetic rule has not been well studied for such complications. The patatin-like phospholipase domain-containing 3 (PNPLA3) gene L148M (rs738409) polymorphism has been associated with a wide spectrum of metabolic affection, but mainly fatty liver, in the general population. Here, we demonstrate the impact of the PNPLA3 polymorphism on living related donor liver transplantation (LRDLT) recipients' new onset diabetes mellitus and obesity. Methods: Genotyping of PNPLA3 rs738409 variants was analyzed using an allele discrimination assay with real-time PCR in 158 LRDLT donors and their recipients, who had no history of diabetes mellitus or fatty liver disease before transplantation and survived > 1 year after transplantation. The LRDLT recipients were assessed for the development of new onset diabetes and the risk of obesity 1 year after transplantation. Results: Recipients' PNPLA3 genotypes were associated with the development of new onset diabetes mellitus after liver transplantation (CC genotype 18.8%, CG genotype 39.1%, GG genotype 42.2%, P = 0.000; GG genotype: odds ratio 24, (95% CI 8.1-70.5). Logistic regression for the predictors of new onset diabetes showed significant risk for recipients with the PNPLA3 CG genotype (P = 0.000, OR 5.5, 95% CI 2.4-12.7) and the GG genotype (P = 0.000, OR 32, 95% CI 9-116.7). In recipients, the GG genotype enhanced the incidence of obesity, with an odds ratio of 3.8 (95% CI 1.6-8.9). The PNPLA3 gene of variants of donors did not show any significant variations with different parameters. Conclusion: The PNPLA3 L148M (rs738409) polymorphism of recipients, not donors carries a risk for new onset diabetes and obesity in LRDLT recipients post-transplant. That means there is a peripheral effect, rather than a central effect, of genotype.