Single Nucleotide Polymorphism in KIR2DL1 Is Associated With HLA-C Expression in Global Populations.

Regulation of NK cell activity is mediated through killer-cell immunoglobulin-like receptors (KIR) ability to recognize human leukocyte antigen (HLA) class I molecules as ligands. Interaction of KIR and HLA is implicated in viral infections, autoimmunity, and reproduction and there is growing evidence of the coevolution of these two independently segregating gene families. By leveraging KIR and HLA-C data from 1000 Genomes consortium we observed that the KIR2DL1 variant rs2304224*T is associated with lower expression of HLA-C in individuals carrying the ligand HLA-C2 (p = 0.0059). Using flow cytometry, we demonstrated that this variant is also associated with higher expression of KIR2DL1 on the NK cell surface (p = 0.0002). Next, we applied next generation sequencing to analyze KIR2DL1 sequence variation in 109 Euro and 75 Japanese descendants. Analyzing the extended haplotype homozygosity, we show signals of positive selection for rs4806553*G and rs687000*G, which are in linkage disequilibrium with rs2304224*T. Our results suggest that lower expression of HLA-C2 ligands might be compensated for higher expression of the receptor KIR2DL1 and bring new insights into the coevolution of KIR and HLA.

Association of killer cell immunoglobulin-like receptors and human leukocyte antigen-C genotypes in South Brazilian with type 1 diabetes.

Type 1 diabetes mellitus (T1D) is a multifactorial and chronic autoimmune disease caused by the deficiency of insulin synthesis and or by its secretion or action defects. Genetic and environmental factors are known to be involved in its pathogenesis. The human leukocyte antigen complex (human leukocyte antigen (HLA)) constitutes the most relevant region contributing with 50% of the inherited risk for T1D. Natural killer cells (NK) are part of the innate immune system recognizing class I HLA molecules on target cells through their membrane receptors, called killer immunoglobulin-like receptors (KIR). The aim of our study is to evaluate the association between the KIR genes and HLA alleles in patients with T1D and healthy controls. Two hundred forty-eight T1D patients and 250 healthy controls were typed for HLA and KIR genes by PCR-SSP. Our results showed an increase of C2 in controls (p = 0.002). The genotype 2DL1/C2+ was also more common in controls (p = 0.001), as well as haplotype association KIR2DL2/DR3/DR4+ and the combination with only DR3+ (p < 0.001; p < 0.001). The maximum protection was seen when KIR2DL2/DR3-were absent when the combination of KIR2DL1/C2+ were present (p < 0.001) and the maximum risk was observed when KIR2DL2/DR3/DR4+ were present in the absence of KIR2DL1/C2- (p = 0.005). Our results confirmed the association of the KIR2DL2/DR3 increasing risk for T1D and suggest a protective role of KIR2DL1/C2.