Human Leukocyte Antigen-G (HLA-G) 3'UTR haplotypes in kidney transplantation

HLA-G is a non-classical HLA molecule involved in tolerance and considered an immune checkpoint in transplantation. HLA-G 14 bp ins/del, consisting of an insertion/ deletion of 14 bp in exon 8, is one of the most studied HLA-G gene polymorphisms. In organ transplantation, it was mainly associated with the onset of immunological complications, such as rejection and post-transplant infections. Recently, we have found an association of HLA-G 14 bp ins/del with post-transplant weight gain. Here, a preliminary analysis of the complete 30 untranslated regulatory region (30UTR) of the HLA-G gene was carried out in kidney transplant recipients (n = 176) and associations with the onset of post-transplant obesity, diabetes (NODAT) and chronic allograft dysfunction (CAD) were investigated. The analysis of the 30UTR region, which included HLA-G 14 bp ins/del, +3003 T/C, +3010C/G, +3027C/A, +3035C/T, +3142C/G, +3187A/G and + 3196C/G gene polymorphisms, was performed by direct sequencing. Allele and genotype frequencies were calculated and 30UTR haplotypes were estimated, recipients that did not develop obesity, NODAT or CAD for more than ten years post-transplant were used for comparisons. A significant association of HLA-G 14 bp ins/ins and + 3142G/G genotypes was confirmed in obese recipients, and a different distribution of haplotypes of the 30UTR region was evidenced between obese and non-obese recipients. In particular, the UTR-5 haplotype frequency was significantly increased in recipients with BMI > 30. A novel nucleotide variation in position +3114 (G>A) was identified in a recipient (GenBank accession n. MT040615); due to its location, this variation could have a potential interest in interactions with miRNA and in HLA-G expression. These results confirm the hypothesis of a functional role of HLA-G in metabolic regulation, until now only marginally highlighted in other pathological conditions.