Single Nucleotide Polymorphism Analysis of the NKG2D Ligand Cluster on the Long Arm of Chromosome 6: Extensive Polymorphisms and Evidence of Diversity Between Human Populations

NKG2D is an important activating receptor on NK cells and T-cells and has a diverse panel of ligands (NKG2DL) which include the ULBP and RAET1 proteins. Several NKG2DL exhibit a considerable degree of genetic polymorphism, and although the functional significance of such allelic variation remains unclear, genetic variants have been implicated in susceptibility to infection and auto-immune disease. We used sequence-specific primer polymerase chain reaction to determine the frequency of 25 single nucleotide polymorphisms (SNPs) in the promoter and coding regions of genes of the RAET1/ULBP cluster in 223 Euro-Caucasoid, 60 Afro-Caribbean, and 52 Indo-Asian individuals to determine NKG2DL allele and haplotype frequencies within these populations. We show marked differences in the frequency of NKG2DL SNPs and haplotypes among the three ethnic groups, and certain haplotypes were observed almost exclusively in Afro-Caribbean compared with the Euro-Caucasoid and Indo-Asian populations. Interestingly, variation was focused within the RAET1E (ULBP4), RAET1L, and ULBP3 genes, whereas the ULBP1, ULBP2 and RAET1G (ULBP5) genes were highly conserved. These findings suggest that individual NKG2DL alleles have been subject to divergent selective pressures during the migration of Homo sapiens. This information will be of importance in understanding the biology and clinical significance of NKG2DL polymorphism.