Association of HLA-G Low Expressor Genotype with Severe Acute Graft-Versus-Host Disease after Sibling Bone Marrow Transplantation

Abstract

Background: Human leukocyte antigen-G (HLA-G) molecules play a prominent role in immune tolerance. Structurally similar to their classical HLA homologs, they are distinct by having high rate of polymorphism in the non-coding regions including a functionally relevant 14-base pair (bp) insertion/deletion (Ins/Del) allele in the 3′ untranslated region (3′UTR), rarely examined in a hematopoietic stem cell transplantation (HSCT) setting. Here, we analyzed the potential impact of HLA-G Ins/Del dimorphism on the incidence of acute graft-versus-host disease (aGvHD), transplant-related mortality (TRM), overall survival (OS), and incidence of relapse after HSCT using bone marrow (BM) as stem cell source from HLA-matched donors. Methods: One hundred fifty-seven sibling pairs, who had undergone HSCT, were studied for the distribution of the HLA-G 14 bp Ins/Del polymorphism using a polymerase chain reaction (PCR)-based technique. Potential genetic association with the incidence of aGvHD, TRM, and OS was analyzed by monovariate and multivariate analyses. Results: Monovariate analysis showed that the homozygous state for the 14-bp Ins allele is a risk factor for severe aGvHD (grade III and IV; P = 0.008), confirmed subsequently by multivariate analysis [hazard ratio (HR) = 3.5; 95% confidence interval (95%CI) = 1.3–9.5; P = 0.012]. We did not find any association between HLA-G polymorphism and the other studied complications. Conclusion: Our data suggest that the HLA-G low expressor 14 bp Ins allele constitutes a risk factor for the incidence of severe aGvHD in patients who received BM as stem cell source.

Role of major histocompatibility complex variation in graft-versus-host disease after hematopoietic cell transplantation

“…In an independent study, however, the 14 bp insertion was found to be a risk factor for acute GVHD 83 . No correlation of the 14 bp insertion was found for acute GVHD, but an association with lower overall survival and disease-free survival was observed 84 .…”

Genetic association between the HLA-G 14-bp insertion/deletion polymorphism and the recurrent spontaneous abortions in Saudi Arabian women

“…Thus, several reports have indicated that this indel polymorphism is related to HLA-G mRNA stability and splicing patterns involved in generating HLA-G isoforms (Hviid et al, 2003;Rousseau et al, 2003;Chen et al, 2008). Moreover, the 14-bp insertion allele was reported to be associated with low levels of both HLA-G mRNA and circulating soluble HLA-G (sHLA-G) isoforms (Chen et al, 2008;Boukouaci et al, 2011). It was also reported that plasma levels of sHLA-G were dramatically lower with the genotype +14-bp/+14-bp than with +14-bp/-14-bp and -14-bp/-14-bp genotypes (Chen et al, 2008;Martelli-Palomino et al, 2013).…”

Genetics of graft-versus-host disease: The major histocompatibility complex

“…Studies that have investigated the relationship between GVHD and the 14 bp sequence have yielded heterogeneous results. The 14 bp deletion was associated with an increased risk of acute GVHD after unrelated donor HCT 38 and with lower survival and disease-free survival (DFS) 39 , however in another analysis, the 14 bp insertion most closely predicted risk of clinically severe acute GVHD 40 . These results likely reflect population differences and complex mechanisms that involve splice variants of HLA-G 41-43 .…”