To the Editor:

Liver fibrosis is a complex genetic trait that is affected by multiple exogenous (i.e., environmental) and endogenous (i.e., genetic) factors. Two recent reports in Hepatology have associated a single-nucleotide polymorphism (rs738409, I148M) in the gene encoding adiponutrin/patatin-like phospholipase domain-containing 3 (PNPLA3) with the development of liver fibrosis and cirrhosis in hepatitis C virus (HCV)-infected patients.1, 2 In the study by Trepo et al., carriers of the PNPLA3 rs738409 GG genotype also showed a higher rate of fibrosis progression, compared to subjects carrying wild-type alleles.2 Liver transplantation (LT) for HCV liver disease is a special clinical setting in which fibrosis progression strongly determines the patient's prognosis. Reinfection of the graft with HCV is a universal event and leads to the accelerated development of severe (i.e., ≥F3) fibrosis in 40%-50% of patients with 5-10 years.3

Based on this background, we assessed whether the common PNPLA3 I148M polymorphism would be associated with early recurrence of severe fibrosis or other clinical parameters after LT for end-stage HCV infection. In total, 176 subjects (112 male; mean age at LT, 54.4 ± 8.1 years) were included into the study who underwent protocol biopsies for the evaluation of fibrosis progression for at least 5 years during follow-up. When applying severe fibrosis recurrence in the graft as the main outcome parameter, the rs738409 genotype was not associated with the development of F3 fibrosis in the protocol biopsies at years 1, 3, and 5 after LT (Table 1). We also assessed whether the PNPLA3 variant would be associated with hepatocellular carcinoma (HCC), acute rejections, or diverse laboratory parameters (including alanine aminotransferase, gamma-glutamyl transferase, alkaline phosphatase, bilirubin, glucose, creatinine, and International Normalization Ratio) within the first 5 years after LT. However, we could not detect any significant associations of all of these parameters with the rs738409 genotypes or alleles. Limitations of our study were that we only genotyped the recipient, but not the donor, and that we did not directly assess histological steatosis grade in the biopsies. Although we cannot exclude a contribution of the donor rs738409 genotype to the outcome after LT, the steatosis grade in the graft was dependent on various parameters (including the type of immunosuppression4) and might, therefore, be difficult to genetically ascertain in the post-LT setting. In summary, we conclude that, contrary to nonimmunosuppressed HCV-infected individuals, the recipient's PNPLA3 genotype is not a strong risk factor for the outcome after LT.

Table 1. Association of rs738409 With Progression to F3 Fibrosis in Protocol Biopsies at Years 1, 3, and 5
 rs738409 CCrs738409 CGrs738409 GGP Value
  1. Data are given as n (%) of patients with available biopsy at indicated time. P value was calculated by Armitage's trend test.

F3 at year 111 (6.3)11 (6.3)0 (0)0.46
No F3 at year 177 (43.8)60 (34.1)17 (9.7) 
F3 at year 315 (8.5)18 (10.2)5 (2.8)0.13
No F3 at year 373 (41.5)53 (30.1)12 (6.8) 
F3 at year 524 (13.6)27 (15.3)7 (3.9)0.11
No F3 at year 564 (35.9)44 (25.0)10 (5.6) 


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  • 1
    Valenti L, Rumi M, Galmozzi E, Aghemo A, Del Menico B, De Nicola S, et al. Patatin-like phospholipase domain-containing 3 I148M polymorphism, steatosis, and liver damage in chronic hepatitis C. HEPATOLOGY 2011; 53: 791-799.
  • 2
    Trepo E, Pradat P, Potthoff A, Momozawa Y, Quertinmont E, Gustot T, et al. Impact of PNPLA3 (rs738409 C>G) polymorphism on fibrosis progression and steatosis in chronic hepatitis C. HEPATOLOGY 2011; 54: 60-69.
  • 3
    Berres ML, Trautwein C, Schmeding M, Eurich D, Tacke F, Bahra M, et al. Serum chemokine CXC ligand 10 (CXCL10) predicts fibrosis progression after liver transplantation for hepatitis C infection. HEPATOLOGY 2011; 53: 596-603.
  • 4
    Tarantino G, Palmiero G, Polichetti G, Perfetti A, Sabbatini M, Basile V, et al. Long-term assessment of plasma lipids in transplant recipients treated with tacrolimus in relation to fatty liver. Int J Immunopathol Pharmacol 2010; 23: 1303-1308.

Nicole T. do O*, Dennis Eurich‡, Christian Trautwein*, Peter Neuhaus‡, Ulf P. Neumann†, Hermann E. Wasmuth‡, * Medical Department III, University Hospital Aachen, Aachen, Germany, † Department of General and Transplantation Surgery, Charité University Hospital, Berlin, Germany, ‡ Department of Surgery, University Hospital Aachen, Aachen, Germany.