Genetic polymorphism analysis of killer cell immunoglobulin-like receptor genes in the Chinese Uygur population

Human killer cell immunoglobulin-like receptors are expressed in natural killer cells and subsets of T lymphocytes. They regulate these cells upon interaction with human leukocyte antigen class I molecules and other ligands presented by target cells. KIR gene frequencies and haplotype distributions have been shown to differ significantly between populations from different geographical regions and ethnic origins, which relates to functional variations in the immune response. We have investigated KIR gene frequencies and genotype diversities of 15 KIR genes (KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, ID, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) and two pseudogenes (KIR3DP1 and 2DP1) in 120 unrelated healthy individuals of the Uygur population living in the Xinjiang autonomous region of China. All individuals were typed positive for the four framework loci KIR3DL3, 2DL4, 3DL2 and KIR3DP1, while activating genes (KIR2DS1, 2DS2, 2DS3, 2DS5 and KIR3DS1) indicated some variation in this population. KIR3DS1 was found in a higher frequency in the studied population than in other groups from China. Linkage disequilibrium among KIR genes displayed a wide range. ??² analysis, conducted among non-ubiquitous genes, based on the KIR gene frequency data from our study population and previously published population data, revealed significant differences in the KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 2DS1, 2DS2, 2DS3, 2DS5, and 3DS1 genes. A neighbor-joining phylogenic tree, built using the observed carrier frequencies data of 13 KIR loci (KIR2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 3DL1, 3DL2, 3DL3, 2DS1, 2DS2, 2DS3, 2DS5, and 3DS1), showed relationships between the population studied and other previously reported populations. The present study can therefore be valuable for enriching the ethnical gene information resources of the KIR gene pool, for population origin studies and for KIR-related clinical practice.     

<Emphasis Type="Italic">KIR</Emphasis> haplotype content at the allele level in 77 Northern Irish families

There has been an explosion in population studies determining the frequency of KIR genes. However, there is still limited knowledge of allele and haplotype frequencies in different populations. The present study aims to determine the haplotype frequencies using allele information on ten genes and presence/absence of the other seven genes in the parents of 77 families. There were 26 of 154 different genotypes without using allele information and 143 of 154 different genotypes using allele information. These genotypes came from 96 of 308 different haplotypes. Of these, 41 were A and 55 were B. Forty-nine haplotypes occurred only once. In total, 181 (58.8%) of haplotypes were A and 127 (41.2%) were B. Three different haplotypes carried two copies of KIR2DL4, two different haplotypes were truncated with both KIR2DL4 and KIR3DL1/S1 missing, and three different haplotypes were negative for both KIR2DL2 and KIR2DL3; two of these haplotypes carried KIR2DS2. A further haplotype, present in two individuals, appeared to have two alleles of KIR2DL5A present. The percentages of individuals who were homozygous for the A haplotype, heterozygous for the A and B haplotype and homozygous for the B haplotype were 35.1%, 47.4% and 17.5% respectively. The genes KIR3DL1, KIR2DS4 and KIR2DL3 were present on 31, 32 and 15 different B haplotypes, respectively, and 64, 65 and 40 of the total B haplotypes, respectively. Sixty B haplotypes had both KIR3DL1 and KIR2DS4, and four haplotypes had KIR2DS4 and KIR2DL3. However, in 40 of 41 different and 180 of 181 total A haplotypes, KIR3DL1, KIR2DS4 and KIR2DL3 were all present (we did not allele-type for KIR2DL1 and therefore could not determine presence/absence on those haplotypes). At the allele level, homozygosity was found in 22.1%, 9.7% and 12.6% for KIR2DL4, KIR3DL2 and KIR3DL1 genes, respectively, but 62.6% and 53% for KIR2DL3 and KIR2DS4 genes, respectively, despite the fact that no one allele dominated the frequency in any of these genes.     

Diversity of killer cell immunoglobulin-like receptor genes in Pacific Islands populations

Killer immunoglobulin-like receptors (KIRs) regulate the activity of NK and T cells through interaction with specific HLA class I molecules on target cells. To date, 16 KIR genes and pseudogenes have been identified. Diversity in KIR gene content and KIR allelic and haplotype polymorphism has been observed between different ethnic groups. Here, we present data on the KIR gene distribution in Pacific Islands populations. Sixteen KIR genes were observed in Pacific Islands populations from the Cook Islands, Samoa, Tokelau, and Tonga. The majority of KIR genes were present at similar frequencies between the four populations with KIR2DL4, KIR3DL2, and KIR3DP1 genes observed in all individuals. Commonly observed KIR genes in Pacific Islands populations (pooled frequencies) were KIR2DL1 (0.77), KIR2DL3 (0.77), KIR3DL1 (0.65), KIR3DL3 (0.93), KIR2DS4/1D (0.78), and KIR2DP1 (0.82), compared to the less-frequently observed KIR2DL2 (0.27), KIR2DL5 (0.30), KIR2DS1 (0.19), KIR2DS2 (0.27), KIR2DS3 (0.16), KIR2DS5 (0.17), and KIR3DS1 (0.18) genes. Differences in KIR gene frequency distributions were observed between the Pacific Islands populations and when compared to other populations. Sixty-nine different genotypes were identified, with five genotypes accounting for more then 50% of all genotypes observed. The number of genotypes observed in each population was similar in the Cook Islands, Samoan, and Tokelauan populations (19, 18, and 19, respectively), but 26 different genotypes were observed in Tongans. The putative haplotype A was predominantly observed over haplotype B in all Pacific Islands populations. Significant linkage disequilibrium was observed for a number of KIR gene pairs.     

Natural Killer Cell Immunoglobulin-like Receptors (KIR) Genotypes in two Arab Populations: Will KIR become a genetic landmark between nations?

Genotypic profiles of the Natural killer cell Immunoglobulin-like Receptors (KIR) have been reported to vary among different ethnic groups and this study represents a comparative report on its distribution between two Arabic populations in the Middle East: Lebanese and Palestinians. Our compared population samples included 120 unrelated healthy Lebanese (as per Mahfouz et al.) and a Palestinian population of 105 individuals (as per Norman et al.). All had their DNA typed using Sequence Specific Primer (SSP) technique for the presence of the different KIR loci. Similar to most published data, we observed that the two framework genes 2DL4 and 3DL2 are present in 100% of individuals from both communities, while 2DL2, 2DL3, 2DS1, 2DS2, 2DS3, 2DS5, 3DL1, and 3DS1 were very similar in frequency. However, significant differences were noted in the frequencies of 2DL1 and 2DS4. This report is comparing KIR genotyping distribution in two Arab populations that sheds additional light on the importance of this gene in delineating a possible geographic genetic demarcation among different ethnicities or even different communities among the same or close ethnic groups.     

Allele-Level Haplotype Frequencies and Pairwise Linkage Disequilibrium for 14 KIR Loci in 506 European-American Individuals

The immune responses of natural killer cells are regulated, in part, by killer cell immunoglobulin-like receptors (KIR). The 16 closely-related genes in the KIR gene system have been diversified by gene duplication and unequal crossing over, thereby generating haplotypes with variation in gene copy number. Allelic variation also contributes to diversity within the complex. In this study, we estimated allele-level haplotype frequencies and pairwise linkage disequilibrium statistics for 14 KIR loci. The typing utilized multiple methodologies by four laboratories to provide at least 2x coverage for each allele. The computational methods generated maximum-likelihood estimates of allele-level haplotypes. Our results indicate the most extensive allele diversity was observed for the KIR framework genes and for the genes localized to the telomeric region of the KIR A haplotype. Particular alleles of the stimulatory loci appear to be nearly fixed on specific, common haplotypes while many of the less frequent alleles of the inhibitory loci appeared on multiple haplotypes, some with common haplotype structures. Haplotype structures cA01 and/or tA01 predominate in this cohort, as has been observed in most populations worldwide. Linkage disequilibrium is high within the centromeric and telomeric haplotype regions but not between them and is particularly strong between centromeric gene pairs KIR2DL5∼KIR2DS3S5 and KIR2DS3S5∼KIR2DL1, and telomeric KIR3DL1∼KIR2DS4. Although 93% of the individuals have unique pairs of full-length allelic haplotypes, large genomic blocks sharing specific sets of alleles are seen in the most frequent haplotypes. These high-resolution, high-quality haplotypes extend our basic knowledge of the KIR gene system and may be used to support clinical studies beyond single gene analysis.     

Killer cell immunoglobulin-like receptor gene diversity in the Saudi population

Killer cell immunoglobulin-like receptors (KIRs) influence the outcome of haematopoetic stem cell transplantation by modulating the cytotoxic ability of natural killer (NK) cells and a subset of T cells. KIRs are also highly polymorphic and could therefore be good population genetic markers, much like their human leukocyte antigen (HLA) ligands. This study represents the first report on distribution of 16 KIR genes in 162 unrelated healthy Saudi individuals. All the 16 KIR genes were observed in the studied population and the four framework genes (KIR2DL4, 3DL2, 3DL3 and 3DP1) were present in all individuals. Forty- one distinct KIR profiles were expressed in our population, 11 of which had not been previously described in other populations including the Middle Eastern population. AA1, the most common genotypic profile was observed at a frequency of 26.5%. The group A haplotype was more frequent (53%) in the Saudi population compared to the group B haplotype (47%). The pattern of the inhibitory KIR/HLA ligands were also analyzed and 52.3% of the Saudi population was found to express two pairs of the inhibitory KIR/HLA-C. The KIR gene frequencies suggests that the Saudi population shares common general features with the Middle Eastern and other populations, but still has its own unique frequencies of several KIR loci.     

A mutation in <Emphasis Type="Italic">KIR3DS1</Emphasis> that results in truncation and lack of cell surface expression

The KIR gene cluster exhibits a high degree of polymorphism in terms of gene content as well as allelic polymorphism, and data suggest that it is evolving rapidly. The KIR3DL1 locus is one of the most polymorphic loci within this cluster and is unique in that it encodes an activating receptor KIR3DS1, as well as multiple inhibitory KIR3DL1 allotypes. Because KIR3DS1 has been implicated in a number of diseases, we tested for the presence of KIR3DS1 variants that might affect its expression and activating capacity. Preliminary FACS analysis indicated that indeed some individuals with the KIR3DS1 allele showed no cell surface expression of the molecule. Sequencing analysis identified a variant with a complex deletion/substitution mutation in exon 4 (which encodes the D1 extracellular domain), resulting in a premature stop codon. We subsequently genotyped 3,960 unrelated individuals and determined the frequencies of this allele across geographically distinct world populations. The data indicate that the null KIR3DS1 allele is uncommon, arose on a single haplotype, and spread across geographically distinct populations. An erratum to this article can be found at     

Definition of gene content for nine common group B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes

The segregation of killer cell immunoglobulin-like receptor ( KIR) genes was determined for a panel of 21 Caucasoid families: 23 different KIR gene patterns were found and could be assigned to combinations of 16 different haplotypes. Four loci were held in common by all haplotypes: KIR2DL4, KIR3DL2, the putative pseudogene KIR3DL3 and KIR2DL2/KIR2DL3, the latter likely being alleles of one gene. Group A haplotypes, which have a unique combination of seven KIR genes, were found at 80% frequency in the family panel, the polygenic group B haplotypes at 65% frequency. KIR gene segregation was fully determined for the nine group B haplotypes, which occurred at highest frequencies in both the family panel and a panel of unrelated individuals. The group B haplotypes carried between seven and 11 KIR genes and encoded inhibitory KIR for one, two, or all three major HLA class I epitopes. Analysis of human leucocyte antigen (HLA) class I genotypes revealed that most, but not all, individuals possess an inhibitory KIR for a self HLA class I epitope. The number of stimulatory KIR genes in group B haplotypes varied considerably between one and five. The data show that group B haplotypes possess a broad spectrum of KIR gene patterns, which is largely complementary to the KIR gene set of group A haplotypes. The results suggest that rapid diversification of group B haplotypes is the result of pathogen-mediated selection for KIR genotypes that have more than the set of KIR genes provided by the group A haplotype.     

<Emphasis Type="Italic">KIR</Emphasis> gene content diversity in four Iranian populations

Killer cell immunoglobulin-like receptors (KIR) regulate natural killer cell response against infection and malignancy. KIR genes are variable in the number and type, thereby discriminating individuals and populations. Herein, we analyzed the KIR gene content diversity in four native populations of Iran. The KIR genomic diversity was comparable between Bakhtiari and Persian and displayed a balance of A and B KIR haplotypes, a trend reported in Caucasian and African populations. The KIR gene content profiles of Arab and Azeri were comparable and displayed a preponderance of B haplotypes, a scenario reported in the natives of America, India, and Australia. A majority of the B haplotype carriers of Azeri and Arab had a centromeric gene-cluster (KIR2DS2-2DL2-2DS3-2DL5). Remarkably, this cluster was totally absent from the American natives but occurred at highest frequencies in the natives of India and Australia in combination with another gene cluster at the telomeric region (KIR3DS1-2DL5-2DS5-2DS1). Therefore, despite having similar frequencies of B haplotypes, the occurrence of B haplotype-specific KIR genes, such as 2DL2, 2DL5, 3DS1, 2DS1, 2DS2, 2DS3, and 2DS5 in Azeri and Arab were substantially different from the natives of America, India, and Australia. In conclusion, each Iranian population exhibits distinct KIR gene content diversity, and the Indo-European KIR genetic signatures of the Iranians concur with geographic proximity, linguistic affinity, and human migrations. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A mutation in <Emphasis Type="Italic">KIR3DS1</Emphasis> that results in truncation and lack of cell surface expression

The KIR gene cluster exhibits a high degree of polymorphism in terms of gene content as well as allelic polymorphism, and data suggest that it is evolving rapidly. The KIR3DL1 locus is one of the most polymorphic loci within this cluster and is unique in that it encodes an activating receptor KIR3DS1, as well as multiple inhibitory KIR3DL1 allotypes. Because KIR3DS1 has been implicated in a number of diseases, we tested for the presence of KIR3DS1 variants that might affect its expression and activating capacity. Preliminary FACS analysis indicated that indeed some individuals with the KIR3DS1 allele showed no cell surface expression of the molecule. Sequencing analysis identified a variant with a complex deletion/substitution mutation in exon 4 (which encodes the D1 extracellular domain), resulting in a premature stop codon. We subsequently genotyped 3,960 unrelated individuals and determined the frequencies of this allele across geographically distinct world populations. The data indicate that the null KIR3DS1 allele is uncommon, arose on a single haplotype, and spread across geographically distinct populations.     

Evolutionary patterns of killer cell Ig-like receptor genes in Old World monkeys

Killer cell Ig-like receptors (KIRs) modulate the cytotoxic effects of Natural Killer cells. KIR genes are encoded in the Leucocyte Receptor Complex and are characterized by their high haplotypic diversity and polymorphism. The KIR system has been studied in only three species of Old World monkeys, the rhesus macaque, the cynomolgus macaque, and the sabaeus monkey, displaying a complexity rivaling that of hominids (human and apes). Here we analyzed bacterial artificial chromosome draft sequences spanning the KIR haplotype of three other Old World monkeys, the vervet monkey (Chlorocebus aethiops), the olive baboon (Papio anubis) and the colobus monkey (Colobus guereza). A total of 25 KIR gene models were identified in these species, predicted to encode receptors with 1, 2, and 3 extracellular Ig domains, all of them with long cytoplasmic domains having two putative ITIMs, although three had a positively charged residue in the transmembrane domain. Sequence and phylogenetic analyses showed that most Old World monkeys shared five classes of KIR loci: i) KIR2DL5/3DL20 in the most centromeric region, followed by ii) the single Ig domain-encoding locus KIR1D, iii) the pseudogene KIR2DP, iv) the conserved KIR2DL4, and v) the highly diversified KIR3DL/H loci in the telomeric half of the cluster. An exception to this pattern was the KIR haplotype of the colobus monkey that lacked the KIR1D, KIR2DP, and KIR2DL4 loci of the central region of the cluster. Thus, Old World monkeys display a broad spectrum of KIR haplotype variation that has been generated upon an ancestral haplotype architecture by gene duplication, gene deletion, and non-homologous recombination.     

Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism

KIR3DL1 and KIR3DL2 are NK cell receptors for polymorphic HLA-B and -A determinants. The proportion of NK cells that bind anti-KIR3DL1-specific Ab DX9 and their level of binding vary between individuals. To determine whether these differences are due to KIR polymorphism, we assessed KIR3D gene diversity in unrelated individuals and families. Both KIR3DL1 and KIR3DL2 are highly polymorphic genes, with KIR3DS1 segregating like an allele of KIR3DL1. A KIR haplotype lacking KIR3DL1 and KIR3DS1 was defined. The two KIR3DL1 alleles of a heterozygous donor were expressed by different, but overlapping, subsets of NK cell clones. Sequence variation in KIR3DL1 and KIR3DL2 appear distinct; recombination is more evident in KIR3DL1, and point mutation is more evident in KIR3DL2. The KIR3DL1 genotype correlates well with levels of DX9 binding by NK cells, but not with the frequency of DX9-binding cells. Different KIR3DL1 alleles determine high, low, and no binding of DX9 Ab. Consequently, heterozygotes for high and low binding KIR3DL1 alleles have distinct subpopulations of NK cells that bind DX9 at high and low levels, giving characteristic bimodal distributions in flow cytometry. The Z27 Ab gave binding patterns similar to those of DX9. Four KIR3DL1 alleles producing high DX9 binding phenotypes were distinguished from four alleles producing low or no binding phenotypes by substitution at one or more of four positions in the encoded protein: 182 and 283 in the extracellular Ig-like domains, 320 in the transmembrane region, and 373 in the cytoplasmic tail.     

Asian population frequencies and haplotype distribution of killer cell immunoglobulin-like receptor (KIR) genes among Chinese, Malay, and Indian in Singapore

Killer cell immunoglobulin-like receptors (KIR) gene frequencies have been shown to be distinctly different between populations and contribute to functional variation in the immune response. We have investigated KIR gene frequencies in 370 individuals representing three Asian populations in Singapore and report here the distribution of 14 KIR genes (2DL1, 2DL2, 2DL3, 2DL4, 2DL5, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DL1, 3DL2, 3DL3, 3DS1) with two pseudogenes (2DP1, 3DP1) among Singapore Chinese (n = 210); Singapore Malay (n = 80), and Singapore Indian (n = 80). Four framework genes (KIR3DL3, 3DP1, 2DL4, 3DL2) and a nonframework pseudogene 2DP1 were detected in all samples while KIR2DS2, 2DL2, 2DL5, and 2DS5 had the greatest significant variation across the three populations. Fifteen significant linkage patterns, consistent with associations between genes of A and B haplotypes, were observed. Eighty-four distinct KIR profiles were determined in our populations, 38 of which had not been described in other populations. KIR haplotype studies were performed using nine Singapore Chinese families comprising 34 individuals. All genotypes could be resolved into corresponding pairs of existing haplotypes with eight distinct KIR genotypes and eight different haplotypes. The haplotype A2 with frequency of 63.9% was dominant in Singapore Chinese, comparable to that reported in Korean and Chinese Han. The A haplotypes predominate in Singapore Chinese, with ratio of A to B haplotypes of approximately 3:1. Comparison with KIR frequencies in other populations showed that Singapore Chinese shared similar distributions with Chinese Han, Japanese, and Korean; Singapore Indian was found to be comparable with North Indian Hindus while Singapore Malay resembled the Thai. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Polymorphism of killer cell immunoglobulin-like receptors (KIR) and their HLA ligands in Graves’ disease

Killer immunoglobulin-like receptors (KIR) play a pivotal role in commencement of both innate and adaptive immunity. Dysregulation of KIRs is associated with an increased risk of autoimmune disorders. This study was designed to assess whether polymorphisms in KIR gene family and their respective HLA class I ligands confer protection or susceptibly to Graves’ disease (GD). Eighty patients with confirmed GD (cases) and 176 healthy unrelated subjects (controls) were recruited. Using a polymerase chain reaction sequence-specific primer directed method (PCR-SSP), presence or absence of KIR genes and their HLA ligands were determined. No significant differences were observed between case and control groups regarding individual KIR gene frequencies (p > 0.05 in all cases). The frequency of group A haplotype (the most common KIR haplotype, encompassing 2DL1/2DL3/3DL1/2DS4/2DP1/3DP1/2DL4/3DL2/3DL3), was not different between individuals with and without GD. Moreover, among all other haplotypes (group Bx), no significant differences regarding distribution of centromeric and telomeric gene clusters were identifiable. Inhibitory/activatory gene contents were also comparable between the two groups. Four models of KIR-HLA interaction (inhibition, activation, unrestrained inhibition, and unrestrained activation) were constructed. No combination proved to confer susceptibility to, or offer protection against GD. It seems that the contribution of KIR gene polymorphism to natural killer cell dysfunction and other autoimmune abnormalities observed in GD is limited.     

Distinctive KIR and HLA diversity in a panel of north Indian Hindus

HLA and KIR are diverse and rapidly evolving gene complexes that work together in human immunity mediated by cytolytic lymphocytes. Understanding their complex immunogenetic interaction requires study of both HLA and KIR diversity in the same human population. Here a panel of 72 unrelated north Indian Hindus was analyzed. HLA- A, B, C, DRB1, DQA1, and DQB1 alleles and their frequencies were determined by sequencing or high-resolution typing of genomic DNA; KIR genotypes were determined by gene-specific typing and by allele-level DNA typing for KIR2DL1, 2DL3, 2DL5, 3DL1, and 3DL2. From HLA analysis, the north Indian population is seen to have several characteristics shared either with Caucasian or East Asian populations, consistent with the demographic history of north India, as well as specific features, including several alleles at high frequency that are rare or absent in other populations. A majority of the north Indian KIR gene profiles have not been seen in Caucasian and Asian populations. Most striking is a higher frequency of the B group of KIR haplotypes, resulting in equal frequencies for A and B group haplotypes in north Indians. All 72 members of the north Indian panel have different HLA genotype and different KIR genotype.     

Linkage disequilibrium organization of the human KIR superlocus: implications for KIR data analyses

An extensive family-based study of linkage disequilibrium (LD) in the killer cell immunoglobulin-like receptors (KIR) cluster was performed. We aimed to describe the LD structure in the KIR gene cluster using a sample of 418 founder haplotypes identified by segregation in a group of 106 families from Northern Ireland. The LD was studied at two levels of polymorphism: the structural level (presence or absence of KIR genes) and the allelic level (between alleles of KIR genes). LD was further assessed using the predictive value of one KIR polymorphism for another one in order to provide an interpretative framework for the LD effect in association studies. In line with previous research, distinct patterns of KIR genetic diversity within the genomic region centromeric to KIR2DL4 (excluding KIR2DL4) and within the telomeric region including KIR2DL4 were found. In a comprehensive PPV/NPV-based LD analysis within the KIR cluster, robust tag markers were found that can be used to identify which genes are concomitantly present or absent and to further identify groups of associated KIR alleles. Several extended KIR haplotypes in the study population were identified (KIR2DS2*POS-KIR2DL2*001-KIR2DL5B*002-KIR2DS3*00103-KIR2DL1*00401; KIR2DL4*011-KIR3DL1/S1*005-KIR2DS4*003-KIR3DL2*003; KIR2DL4*00802-KIR3DL1/S1*004-KIR2DS4*006-KIR3DL2*005; KIR2DL4*00801-KIR3DL1/S1*00101-KIR2DS4*003-KIR3DL2*001; KIR2DL4*00103-KIR3DL1/S1*008-KIR2DS4*003-KIR3DL2*009; KIR2DL4*00102-KIR3DL1/S1*01502/*002-KIR2DS4*00101-KIR3DL2*002; KIR2DL4*00501-KIR3DL1/S1*013-KIR2DL5A*001-KIR2DS5*002-KIR2DS1*002-KIR3DL2*007). The present study provides a rationale for analyzing associations of KIR polymorphisms by taking into account the complex LD structure of the KIR region.     

HLA class I,KIR, and genome-wide SNP diversity in the RV144 Thai phase 3 HIV vaccine clinical trial

RV144 is the first phase 3 HIV vaccine clinical trial to demonstrate efficacy. This study consisted of more than 8,000 individuals in each arm of the trial, representing the four major regions of Thailand. Human leukocyte antigen (HLA) class I and killer cell immunoglobulin-like receptor (KIR) genes, as well as 96 genome-wide ancestry informative markers (AIMs) were genotyped in 450 placebo HIV-1-uninfected individuals to identify the immunogenetic diversity and population structure of this cohort. High-resolution genotyping identified the common HLA alleles as A*02:03, A*02:07, A*11:01, A*24:02, A*24:07, A*33:03, B*13:01, B*15:02, B*18:01, B*40:01, B*44:03, B*46:01, B*58:01, C*01:02, C*03:02, C*03:04, C*07:01, C*07:02, C*07:04, and C*08:01. The most frequent three-loci haplotype was B*46:01-C*01:02-A*02:07. Framework genes KIR2DL4, 3DL2, and 3DL3 were present in all samples, and KIR2DL1, 2DL3, 3DL1, 2DS4, and 2DP1 occurred at frequencies greater than 90 %. The combined HLA and KIR profile suggests admixture with neighboring Asian populations. Principal component and correspondence analyses comparing the RV144 samples to the phase 3 International HapMap Project (HapMap3) populations using AIMs corroborated these findings. Structure analyses identified a distinct profile in the Thai population that did not match the Asian or other HapMap3 samples. This shows genetic variability unique to Thais in RV144, making it essential to take into account population stratification while performing genetic association studies. The overall analyses from all three genetic markers indicate that the RV144 samples are representative of the Thai population. This will inform subsequent host genetic analyses in the RV144 cohort and provide insight for future genetic association studies in the Thai population.     

Thirty allele-level haplotypes centered around KIR2DL5 define the diversity in an African American population

KIR2DL5 alleles were physically linked to alleles at adjacent KIR loci to define this region of KIR haplotypes in 55 gene-positive random African Americans. The majority carried KIR2DL5B. Three KIR2DL5A and six KIR2DL5B alleles that have been previously described and 11 novel KIR2DL5 alleles were identified by DNA sequencing. Novel alleles included variation that may impact promoter activity; two alleles carried nonsynonymous coding region variation. Based on linkage with KIR2DS1, KIR2DS3, KIR2DS5, KIR2DL2, KIR2DL3, and KIR3DS1 alleles, seven haplotypes of KIR2DL5A and 23 haplotypes of KIR2DL5B were observed. The phylogenetic relationships among the KIR2DL5 alleles predicted their association with either KIR2DS3 (six alleles) or KIR2DS5 (seven alleles). All of the KIR2DL5A alleles were linked either to KIR3DS1*01301 or KIR3DS1*049N. The majority of the KIR2DL5B alleles were linked to seven KIR2DL2 alleles; two were linked to a novel allele of KIR2DL3. These findings underscore the diversity of KIR haplotypes present in this population.     

Exploring the Role of Killer Cell Immunoglobulin-Like Receptors and Their HLA Class I Ligands in Autoimmune Hepatitis

Background

Natural killer cells are involved in the complex mechanisms underlying autoimmune diseases but few studies have investigated their role in autoimmune hepatitis. Killer immunoglobulin-like receptors are key regulators of natural killer cell-mediated immune responses.

Methods and Findings

KIR gene frequencies, KIR haplotypes, KIR ligands and combinations of KIRs and their HLA Class I ligands were investigated in 114 patients diagnosed with type 1 autoimmune hepatitis and compared with a group of 221 healthy controls. HLA Class I and Class II antigen frequencies were compared to those of 551 healthy unrelated families representative of the Sardinian population. In our cohort, type 1 autoimmune hepatitis was strongly associated with the HLA-B18, Cw5, DR3 haplotype. The KIR2DS1 activating KIR gene and the high affinity HLA-C2 ligands were significantly higher in patients compared to controls. Patients also had a reduced frequency of HLA-Bw4 ligands for KIR3DL1 and HLA-C1 ligands for KIR2DL3. Age at onset was significantly associated with the KIR2DS1 activating gene but not with HLA-C1 or HLA-C2 ligand groups.

Conclusions

The activating KIR gene KIR2DS1 resulted to have an important predictive potential for early onset of type 1 autoimmune hepatitis. Additionally, the low frequency of the KIR-ligand combinations KIR3DL1/HLA-Bw4 and KIR2DL3/HLA-C1 coupled to the high frequency of the HLA-C2 high affinity ligands for KIR2DS1 could contribute to unwanted NK cell autoreactivity in AIH-1.     

Copy number variation of KIR genes influences HIV-1 control

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.00028), as does an increase in KIR3DL1 count in the presence of KIR3DS1 and appropriate ligands for both receptors (p = 0.0015). We further provide functional data that demonstrate that NK cells from individuals with multiple copies of KIR3DL1, in the presence of KIR3DS1 and the appropriate ligands, inhibit HIV-1 replication more robustly, and associated with a significant expansion in the frequency of KIR3DS1+, but not KIR3DL1+, NK cells in their peripheral blood. Our results suggest that the relative amounts of these activating and inhibitory KIR play a role in regulating the peripheral expansion of highly antiviral KIR3DS1+ NK cells, which may determine differences in HIV-1 control following infection.