Association between a gain-of-function variant of PTPN22 and rejection in liver transplantation.

Abstract

The protein tyrosine phosphatase nonreceptor 22 gene (PTPN22) encodes a strong T-cell regulator called lymphoid protein tyrosine phosphatase. Previously, PTPN22 was described as a susceptibility gene for autoimmunity because it contains single nucleotide polymorphisms (SNPs) associated with several autoimmune diseases. One SNP (rs2476601; 1858G>A) has emerged as a particularly potent risk factor for autoimmunity. We address the question whether PTPN22 polymorphisms are also associated with acute rejection after liver transplantation. We investigated the influence of six PTPN22 SNPs on the susceptibility to acute liver allograft rejection. Consequently, we carried out a retrospective study genotyping 345 German liver recipients at six SNP loci, which include rs2488457 (-1123G>C), rs33996649 (788C>T), rs2476601 (1858G>A), rs1310182 (-852A>G), rs1217388 (-2200G>A), rs3789604 (64434T>G). Our study enrolled 165 recipients who did not develop rejection, 123 who showed one rejection episode, and 57 patients who suffered from multiple acute rejections after transplantation. The 1858A allele containing genotypes (GA+AA) and the 1858A allele had a significantly higher frequency in the group of patients with multiple rejection episodes (35.1% and 18.4%) compared to rejection-free patients (15.8% and 7.9%; P=0.022 and 0.023). In contrast, we could not detect any association between rejection and the other tested SNPs. Additionally, we identified one haplotype contributing to risk of multiple rejections, however, exhibiting no stronger impact than the 1858A allele alone. We conclude that the 1858G>A SNP may confer susceptibility to multiple acute liver transplant rejections in the German population.