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The killer-cell immunoglobulin-like receptor ( KIR ) region comprises a fast-evolving family of genes that encode receptors for natural killer (NK) cells and have crucial role in host defense. Evolution of KIR was examined in the context of the human genome. Gene-content diversity and single nucleotide polymorphisms (SNP) in the KIR genes and flanking regions were compared to >660,000 genome-wide SNPs in over 800 individuals from 52 populations of the human genome diversity panel (HGDP). KIR allelic diversity was further examined using next generation sequencing in a subset of 56 individuals. We identified the SNP rs587560 located in KIR3DL3 as a marker of KIR2DL2 and KIR2DL3 and, consequently, Cen A and Cen B haplotypes. We also show that combinations of two KIR2DL4 SNPs ( rs35656676 and rs592645 ) distinguish KIR3DL1 from KIR3DS1 and also define the major KIR3DL1 high- and low-expressing alleles lineages. Comparing the diversity of the SNPs within the KIR region to remainder of the genome, we observed a high diversity for the centromeric KIR region consistent with balancing selection ( p < 0.01); in contrast, centromeric KIR diversity is significantly reduced in East Asian populations ( p < 0.01), indicating purifying selection. By analyzing SNP haplotypes in a region spanning ~500 kb that includes the KIR cluster, we observed evidence of strong positive selection in Africa for high-expressing KIR3DL1 alleles, favored over the low-expressing alleles ( p < 0.01). In sharp contrast, the strong positive selection ( p < 0.01) that we also observed in the telomeric KIR region in Oceanic populations tracked with a high frequency of KIR3DS1 . In addition, we demonstrated that worldwide frequency of high-expression KIR3DL1 alleles was correlated with virus with virus (r = 0.64, p < 10 -6 ) and protozoa (r = 0.69, p < 10 -6 ) loads, which points to selection globally on KIR3DL1 high-expressing alleles attributable to pathogen exposure.

Pemphigus foliaceus (PF) is a blistering autoimmune skin disease rare in most of the world but endemic in certain regions of Brazil. PF is characterized by the detachment of epidermal cells and the presence of autoantibodies against desmoglein 1. In previous studies, we have shown that genetic polymorphisms and variable expression levels of certain leucocyte receptor complex (LRC) genes were associated with PF. However, the role of the LRC on PF susceptibility remained to be investigated. Here, we analysed 527 tag single nucleotide polymorphisms (SNPs) distributed within the 1·5 Mb LRC. After quality control, a total of 176 SNPs were analysed in 229 patients with PF and 194 controls. Three SNPs were associated with differential susceptibility to PF. The intergenic variant rs465169 [odds ratio (OR) = 1·50; P = 0·004] is located in a region that might regulate several immune-related genes, including VSTM1, LILRB1/2, LAIR1/2, LILRA3/4 and LENG8. The rs35336528 (OR = 3·44; P = 0·009) and rs1865097 (OR = 0·57; P = 0·005) SNPs in LENG8 and FCAR genes, respectively, were also associated with PF. Moreover, we found four haplotypes with SNPs within the KIR3DL2/3, LAIR2 and LILRB1 genes associated with PF (P < 0·05), which corroborate previously reported associations. Thus, our results confirm the importance of the LRC for differential susceptibility to PF and reveal new markers that might influence expression levels of several LRC genes, as well as candidates for further functional studies., (© 2018 John Wiley & Sons Ltd.)

Killer cell immunoglobulin-like receptor (KIR) genes encode cell surface molecules that recognize HLA molecules and modulate the activity of natural killer (NK) cells. KIR genes exhibit presence and absence polymorphism, which generates a variety of gene-content haplotypes in worldwide populations. KIR gene-content variation is implicated in many diseases and is also important for placentation and transplantation. Because of the complexity of KIR polymorphism, variation in this family is still mostly studied at the gene-content level, even with the advent of next-generation sequencing (NGS) methods. Gene-content determination is generally expensive and/or time-consuming. To overcome these difficulties, we developed a method based on multiplex polymerase chain reaction with specific sequence primers (PCR-SSP) followed by melting curve analysis that allows cost-effective, precise and fast generation of results. Our method was 100% concordant with a gel-based method and 99.9% concordant with presence and absence determination by NGS. The limit of detection for accurate typing was 30 ng of DNA (0.42 μM) with 260/230 and 260/280 ratios as low as 0.19 and of 0.44. In addition, we developed a user-friendly Java-based computational application called killerPeak that interprets the raw data generated by Viia7 or QuantStudio 7 quantitative PCR machines and reliably exports the final genotyping results in spreadsheet file format. The combination of a reliable method that requires low amount of DNA with an automated interpretation of results allows scaling the KIR genotyping in large cohorts with reduced turnaround time., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The KIR (killer cell immunoglobulin-like receptors) gene family codifies a group of receptors that recognize human leukocyte antigens (HLA) and modulate natural killer (NK) cells response. Genetic diversity of KIR genes and HLA ligands has not yet been deeply investigated in South East Asia. Here, we characterized KIR gene presence and absence polymorphism of 14 KIR genes and two pseudogenes, as well as the frequencies of the ligands HLA-Bw4, HLA-C1 and HLA-C2 in a Vietnamese population from Hanoi (n = 140). Genotyping was performed by polymerase chain reaction with specific sequence primers (PCR-SSP). We compared KIR frequencies and performed principal component analysis with 43 worldwide populations of different ancestries. KIR carrier frequencies in Vietnamese were similar to those reported for Thai and Chinese Han, but differed significantly from other geographically close populations such as Japanese and South Korean. This similarity was also observed in KIR gene-content genotypes and is in accordance with the origin from Southern China and Thailand proposed for the Vietnamese population. The frequencies of HLA ligands observed in Vietnamese did not differ from those reported for other East-Asian populations (p > .05). Studies regarding KIR-HLA in populations are of prime importance to understand their evolution, function and role in diseases., (Copyright © 2017 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)