Donor PNPLA3 rs738409 Genotype Affects Fibrosis Progression in Liver Transplantation for Hepatitis C

• DOI: 10.1002/hep.26758
• Publication Date: 2013-10-12T01:42:25Z
• Authors: Winston Dunn; Maura O'Neil; Jie Zhao; Chuang Hong Wu; Benjamin Roberts; Shweta Chakraborty; Craig Sherman; Brandy Weaver; Ryan Taylor; Jody Olson; Mojtaba Olyaee; Richard Gilroy; Timothy Schmitt; Yu-Jui Yvonne Wan; Steven A. Weinman
• Keywords: Liver Cirrhosis; Male; 0301 basic medicine; Biopsy; Clinical sciences; Medical Biochemistry and Metabolomics; Oral and gastrointestinal; Hepatitis; Cohort Studies; Cardiovascular Medicine and Haematology; screening and diagnosis; Liver Disease; Single Nucleotide; Middle Aged; Hepatitis C; Tissue Donors; 3. Good health; Detection; Infectious Diseases; Treatment Outcome; Liver; Disease Progression; Female; Genotype; Chronic Liver Disease and Cirrhosis; Clinical Sciences; Immunology; 610; Polymorphism, Single Nucleotide; 03 medical and health sciences; Hepatitis - C; Clinical Research; 616; Genetics; Humans; Polymorphism; Retrospective Studies; Transplantation; Biomedical and Clinical Sciences; Gastroenterology & Hepatology; Prevention; Membrane Proteins; Organ Transplantation; Lipase; 4.1 Discovery and preclinical testing of markers and technologies; Liver Transplantation; Emerging Infectious Diseases; Good Health and Well Being; Multivariate Analysis; Digestive Diseases; Follow-Up Studies

The rs738409 G>C single nucleotide polymorphism occurring in the patatin-like phospholipase 3 gene has been identified as a novel genetic marker for hepatic steatosis. Recent studies also associated rs738409 with fibrosis in hepatitis C (HCV). Therefore, we sought to determine the impact of donor and recipient rs738409 genotype on the progression of fibrosis after liver transplantation for HCV. This cohort study included 101 patients infected with HCV who underwent liver transplantation between January 2008, and June 2011. Donor and recipient rs738409 genotypes were determined from donor wedge biopsies and recipient explants. The time to Ishak stage 3 fibrosis, or HCV-related mortality/graft loss was analyzed by the Cox model adjusting for HCV-Donor Risk Index, warm ischemic time, pretransplant Model for Endstage Liver Disease (MELD) and viral load. The rs738409 CC variant was present in 56% of donors and 57% of recipients. The median follow-up period was 620 days. A total of 39 patients developed the primary outcome of ≥stage 3 fibrosis or HCV-related mortality/graft loss, the time to which differed by donor (

P

= 0.019) but not recipient (

P

= 0.89) genotype. In the multivariate model, donor GC or GG variants had 2.53 times the risk (95% confidence interval [CI] 1.25–5.02,

P

= 0.008) compared to CC variants. In the alternative endpoint: stage 3 fibrosis or all-cause mortality/graft loss, the effect of donor genotype was attenuated but remained significant at 1.98 (95% CI 1.11–3.53).

Conclusions

: The rs738409 genotype is an important predictor of posttransplant outcome in HCV. Liver, and not adipocytes, is the site at which this effect occurs. Our finding may be useful in donor selection for liver transplantation with HCV, and may guide decisions regarding early antiviral treatment. (Hepatology 2014;59:453–460)