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 and data from 1000 Genomes consortium we observed that the variant is associated with lower expression of HLA-C in individuals carrying the ligand HLA-C2 ( = 0.0059). Using flow cytometry, we demonstrated that this variant is also associated with higher expression of KIR2DL1 on the NK cell surface ( = 0.0002). Next, we applied next generation sequencing to analyze sequence variation in 109 Euro and 75 Japanese descendants. Analyzing the extended haplotype homozygosity, we show signals of positive selection for and , which are in linkage disequilibrium with . 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 and .