HLA-G∗01:04∼UTR3 Recipient Correlates with Lower Survival and Higher Frequency of Chronic Rejection after Lung Transplantation

Abstract

Lung transplantation (LTx) is a valid therapeutic option for selected patients with end-stage lung disease. Soluble HLA-G (sHLA-G) has been associated with increased graft survival and decreased rejection episodes in solid organ transplantation. HLA-G haplotypes named UTRs, defined by SNPs from both the 5′URR and 3′UTR, have been reported to reliably predict sHLA-G level. The aim of this retrospective study was to determine the impact of HLA-G alleles and UTR polymorphism from LTx recipients on anti-HLA allo-immunization risk, overall survival and chronic rejection (CLAD). HLA-G SNPs were genotyped in 124 recipients who underwent LTx from 1996 to 2010 in Marseille, 123 healthy individuals and 26 cystic fibrosis patients not requiring LTx. sHLA-G levels were measured for 38 LTx patients at D0, M3 and M12 and for 123 healthy donors. HLA-G∗01:06∼UTR2 was associated with a worse evolution of cystic fibrosis (p=0.005) but not of long-term survival post-LTx. HLA-G∗01:04∼UTR3 haplotype was associated with lower levels of sHLA-G at D0 and M3 (p=0.03), impaired long-term survival (p=0.001), increased CLAD occurrence (p=0.03) and the production of de novo donor-specific antibodies (DSA) at M3 (p=0.01). This study is the first to show the deleterious association of different HLA-G alleles and UTRs in LTx. Focusing on HLA-G genotype and dosage in patients after lung tr ansplantation, this study finds that a specific HLA-G genotype is correlated with a lower survival rate and a h igher frequency of chronic rejection.