The human leukocyte antigen (HLA) are the most polymorphic genes in the human genome. Because of their importance for antigen recognition, HLA molecules play a central role in host defense and graft rejection upon transplantation. The aim of this study was to characterize allelic diversity of the classical HLA genes HLA‐A, ‐B, ‐C, ‐DRA, ‐DRB1, ‐DQA1, ‐DQB1, ‐DPA1, ‐DPB1, and the non‐classical class I genes HLA‐E, ‐F and ‐G at high‐resolution for a population of predominantly European ancestry from Curitiba, Brazil. Genotyping of 108 individuals was performed by next‐generation sequencing on the MiSeq platform and also by Sanger sequencing. The genotype distributions of all loci were in accordance with Hardy‐Weinberg equilibrium (P > 0.05) and a total of 202 HLA variants at second field resolution were observed for the 12 loci. The strongest linkage disequilibrium (r2 = 1.0, P < 10−5) was observed for the following pairs of alleles: HLA‐B*42:01:01 ~ HLA‐DRB1*03:02:01; HLA‐B*14:02:01 ~ HLA‐C*08:02:01; B*42:01:01 ~ HLA‐C*17:01:01; HLA‐DRB1*03:01:01 ~ HLA‐DQB1*02:01:01 ~ DRB1*03:01:01 ~ HLA‐DQB1*02:01:01; DRB1*13:01:01~ HLA‐DQB1*06:03:01 and HLA‐DRB1*09:01:02 ~ HLA‐DQA1*03:02. This is the first study to characterize all 12 HLA genes at high resolution in a single population. On the basis of the allelic frequencies of worldwide populations and principal component analysis, we confirmed the similarity of the study population to European and other Euro‐descendant populations.

The HLA-G and MICA genes are stimulated under inflammatory conditions and code for soluble (sMICA and sHLA-G) or membrane-bound molecules that exhibit immunomodulatory properties. It is still unclear whether they would have a synergistic or antagonistic effect on the immunomodulation of the inflammatory response, such as in chronic kidney disease (CKD), contributing to a better prognosis after the kidney transplantation. In this study, we went from genetic to plasma analysis, first evaluating the polymorphism of MICA , NKG2D and HLA-G in a cohort from Southern Brazil, subdivided in a control group of individuals (n = 75), patients with CKD (n = 94), and kidney-transplant (KT) patients (n = 64). MICA , NKG2D and HLA-G genotyping was performed by polymerase chain reaction with specific oligonucleotide probes, Taqman and Sanger sequencing, respectively. Levels of soluble forms of MICA and HLA-G were measured in plasma with ELISA. Case-control analysis showed that the individuals with haplotype HLA-G*01 : 01/ UTR-4 have a lower susceptibility to develop chronic kidney disease (OR = 0.480; p = 0.032). Concerning the group of kidney-transplant patients, the HLA-G genotypes +3010 GC ( rs1710 ) and +3142 GC ( rs1063320 ) were associated with higher risk for allograft rejection (OR = 5.357; p = 0.013 and OR = 5.357, p = 0.013, respectively). Nevertheless, the genotype +3010 GG (OR = 0.136; p = 0.041) was associated with kidney allograft acceptance, suggesting that it is a protection factor for rejection. In addition, the phenotypic analysis revealed higher levels of sHLA-G ( p = 0.003) and sMICA ( p < 0.001) in plasma were associated with the development of CKD. For patients who were already under chronic pathological stress and underwent a kidney transplant, a high sMICA ( p = 0.001) in pre-transplant proved to favor immunomodulation and allograft acceptance. Even so, the association of genetic factors with differential levels of soluble molecules were not evidenced, we displayed a synergistic effect of sMICA and sHLA-G in response to inflammation. This increase was observed in CKD patients, that when undergo transplantation, had this previous amount of immunoregulatory molecules as a positive factor for the allograft acceptance.

HLA-E, a class I nonclassical HLA molecule, is expressed in all tissues and is involved in the regulation of both innate (by interaction with the CD94/NKG2 receptor expressed mainly in NK cells) and adaptive immunity (by interaction with T CD8 + cells), suggesting a possible role in the solid organ transplantation context. Transplanted patients with chronic kidney disease and their respective donors (N = 107 pairs) were genotyped for exons 2 and 3 of the HLA-E locus by sequence-based typing (SBT). Groups' genotype frequencies were compared regarding episodes of clinical rejection by global G test, and binary logistic regression was made to demonstrate the contribution of genetic variables vs epidemiological variables. Comparisons of donors' genotype frequencies showed significant differences (P = .0230), revealing a protective profile of E*01:01/*01:01 compared to the other genotypes (P = .0099; OR = 0.3088; CI [95%] = 0.1333-0.7157). The same happened when the aforementioned genotype was combined with the E*01:01/*01:01 recipients' genotype (P = .0065; OR = 0.1760; CI [95%] = 0.0517-0.5987). A binary logistic regression analysis was performed, and, of all variables considered, only two were included in the resulting model (P = .007; R 2 Cox and Snell = 0.243; R 2 Nagelkerke = 0.328)-"End-Stage