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. Author manuscript; available in PMC: 2025 Jan 1.
Published in final edited form as: HLA. 2023 Aug 2;103(1):e15177. doi: 10.1111/tan.15177

Exceptional Diversity of KIR and HLA class I in Egypt

Gonzalo Montero-Martin 1, Katherine M Kichula 2, Maneesh K Misra 3,4, Luciana B Vargas 2, Wesley M Marin 3, Jill A Hollenbach 3, Marcelo A Fernández-Viña 1, Sally Elfishawi 5, Paul J Norman 2,6,#
PMCID: PMC11068459  NIHMSID: NIHMS1984209  PMID: 37528739

Abstract

Genetically determined variation of killer cell immunoglobulin like receptors (KIR) and their HLA class I ligands affects multiple aspects of human health. Their extreme diversity is generated through complex interplay of natural selection for pathogen resistance and reproductive health, combined with demographic structure and dispersal. Despite significant importance to multiple health conditions of differential effect across populations, the nature and extent of immunogenetic diversity is under-studied for many geographic regions. Here, we describe the first high-resolution analysis of KIR and HLA class I combinatorial diversity in Northern Africa. Analysis of 125 healthy unrelated individuals from Cairo in Egypt yielded 186 KIR alleles arranged in 146 distinct centromeric and 79 distinct telomeric haplotypes. The most frequent haplotypes observed were KIR-A, encoding two inhibitory receptors specific for HLA-C, two that are specific for HLA-A and -B, and no activating receptors. Together with 141 alleles of HLA class I, 75 of which encode a KIR ligand, we identified a mean of six distinct interacting pairs of inhibitory KIR and HLA allotypes per individual. We additionally characterize 16 KIR alleles newly identified in the study population. Our findings place Egyptians as one of the most highly diverse populations worldwide, with important implications for transplant matching and studies of immune-mediated diseases.

Keywords: KIR, HLA class I, Immunogenetic diversity, Egypt, Africa

Introduction

Interactions of killer cell immunoglobulin-like receptors (KIR) with HLA class I ligands modulate effector activities of natural killer (NK) cell and T cell subsets [1, 2]. Through this role, the extreme genetic diversity of KIR and HLA class I influences success rates of infection or cancer control, placentation, and transplantation [3–5]. Due in part to the importance for human health and survival, combinatorial diversity of KIR and HLA class I is highly differentiated across human populations [6]. It is therefore critical to establish the extent and characteristics of this diversity across ethnicities and geographic regions.

Key components of innate immunity are germline encoded receptors that allow immune cells to respond to any changes in HLA class I expression that may occur when tissue cells become diseased [7]. Through differential interactions with HLA-A, -B, -C, highly polymorphic KIR provide diversity to this response, where genetic variation directly affects the immune effector functions of any KIR expressing cells [8]. Inhibitory KIR prevent NK cells from killing tissue cells that express normal levels of HLA class I [1]. These interactions also educate NK cells, allowing them to respond to changes in HLA class I expression that may occur upon infection or tumorigenesis [9, 10]. Although KIR diversity has evolved to combat diverse pathogen threats, the receptors also have critical role mediating extravillous trophoblast invasion during early placentation [11, 12]. All human populations therefore maintain both inhibitory KIR, which tend to be beneficial towards infection control, and activating KIR, which promote adequate placentation [13].

Humans are unique in possessing two broad families of KIR haplotype [14]. KIR-A haplotypes encode four inhibitory receptors and up to two activating receptors specific for HLA class I, and KIR-B encode up to five activating and fewer inhibitory receptors for HLA class I [15]. Although present in all populations, the relative proportion of KIR-A haplotypes and the compositions of KIR-B haplotypes underly substantial KIR gene content diversity worldwide [16]. Allelic polymorphism enhances this diversity, with a total 1,617 known variants (Dec 2022, [17]) of the 13 expressible KIR genes, having demonstrable impact on immune cell function and disease [18]. High-resolution studies have revealed enormous KIR allelic diversity across human populations, likely rivalling that of HLA [19–29]. Although this diversity is especially evident in groups representing the deep population structure of the African continent, previous studies have focused on sub-Saharan Africa [24–26].

To counter lack of knowledge concerning immunogenomic diversity in Northern Africa, we focus here on a population from Egypt. Egypt is the third largest country in Africa, with a population of over 100 million people [30]. The country extends from Northeast Africa to Southwest Asia via the Sinai Peninsula, which serves as a land bridge between the two continents. As one of the principal routes for human migration to and from Africa, Egypt maintains a unique genetic ancestry [31–33]. Egypt is thus a critical population for understanding human migrations and evolution, having ancestral influences derived from African, Persian, Arab and Ottoman cultures [30]. Although the greatest ancestral component of the current Egyptian population is estimated to be of Eurasian origin [34–36], the genetic architecture is distinct, such that European genomes and other data serve as inadequate references for this population [37]. Here, we use high-throughput sequencing to analyze KIR and HLA class I diversity to full resolution in a population of healthy Egyptians from Cairo.

Materials and Methods:

Study population

DNA samples were obtained from 125 healthy unrelated donors from the National Cancer Institute blood bank. All donors were from the Cairo greater area, with Egyptian parents and grandparents. All donors gave written informed consent. The study was approved by the institutional review board of the Egyptian National Cancer Institute (approval number 2101-2P03-003).

High-resolution KIR and HLA allele genotyping

The entire KIR locus and individual HLA genes were targeted for DNA sequencing using a biotinylated DNA probe-based capture method [38], with modifications as described [25]. Sequencing was performed using a MiSeq instrument (Illumina) using V3 chemistry, and the sequencing read length was 2 x 300 bp.

Sequence data analysis

KIR gene content, copy numbers, and allele genotypes were determined using the Pushing Immunogenetics to the Next Generation (PING) pipeline as previously reported [38]. The copy number was obtained according to the ratio of reads mapping to each KIR gene to those mapping to KIR3DL3, a reference gene present as one copy on each haplotype [39]. Genes analyzed were KIR2DL1-4, KIR2DL5A and B, KIR2DS1-5, KIR3DL1-3, and pseudogenes KIR2DP1 and KIR3DP1. KIR2DL2 and KIR2DL3 are alleles of one gene (KIR2DL2/3), as are KIR2DS3 and KIR2DS5 (KIR2DS3/5), and KIR3DL1 and KIR3DS1 (KIR3DL1/S1). KIR3DL3 alleles were corroborated using PHASE 2.1 [40]. The following parameters for PHASE 2.1 were used: −f1, −x5, and −d1, and the ‘best pairs’ result was used. The PING pipeline generates a high-resolution KIR gene content and allele level genotype [38]. It can also identify previously unreported single nucleotide polymorphisms (SNPs) and recombinant alleles. Novel allele sequences were first validated by eliminating read mapping errors. Reads specific to the relevant gene were isolated by bioinformatics filtering, aligned to the closest reference allele using MIRA 4.0.2, and inspected using Gap4 of the Staden package [41, 42]. Finally, the newly identified alleles were confirmed using Sanger sequencing, starting from the original gDNA sample, using gene and exon specific primers as described [26]. Sequences were deposited in GenBank and the ImmunoPolymorphism Database [17]. The HLA class I alleles were determined using NGSengine 2.10.0 (GenDX, Utrecht, the Netherlands) and Omixon HLA Explore (Omixon Biocomputing Ltd., Budapest, Hungary) with any discrepancies resolved using HLA*LA v1.01 [43].

KIR3DP1 genotyping

To supplement PING output, we used text-based virtual probes specific for the full-length and exon 2 deletion forms of KIR3DP1. We used the ‘grep’ function of Linux to count their occurrence in the forward or reverse complement orientation in the sequence files for each sample. A threshold of 10 total reads was considered positive. The text-based probe sequences used are described in Supplementary Fig. 1A. The results from the virtual probe analysis were used to determine genotypes that were ambiguous from analysis of the sequence data using PING (e.g. KIR3DP*001 vs *00302). To validate these results, we used PCR-SSP, as previously described by Vilches et al. [44] on each of the 125 DNA samples. We performed the PCR as described, with the exception that we used separate reactions for the deletion and full length primer combinations (Supplementary Fig. 1A).

Frequencies of genotypes, alleles and haplotypes

Allele frequencies were calculated by direct counting, and the number observed divided by 2N (alleles duplicated on a single haplotype were included as distinct loci, and gene absence was counted as a distinct allele). KIR haplotypes include a centromeric motif and a telomeric motif. The centromeric motif is defined as all genes from KIR3DL3 through KIR3DP1. The telomeric motif encompasses all genes present from KIR2DL4 to KIR3DL2 on the telomeric side of the KIR locus. The centromeric and telomeric haplotypes were designated based on linkage disequilibrium among KIR genes and the copy number of each KIR gene in an individual. In cases containing deleted or duplicated segments of the KIR locus, the distinction between centromeric or telomeric location of a given gene may be ambiguous. Here we adopted the ‘align left’ strategy, with centromeric being left. For example, KIR2DS5 can occur either in the centromeric or telomeric KIR segment. The allele KIR2DS5*002 is often found in the telomeric segment, but can also be present on haplotypes having the center portion deleted; in this case we designate KIR2DS5*002 as centromeric. HLA haplotype composition and frequencies were determined using ‘Arlequin 3.5 [45]. Hardy Weinberg tests were also performed using ‘Arlequin 3.5. Principal components analysis was performed using the using the ade4 R package [46].

HLA/KIR interactions

We use ‘allele’ to denote each distinct coding sequence for a given gene, and ‘allotype’ to denote each distinct amino acid sequence. The numbers of viable interactions between distinct pairs of HLA and KIR allotypes were counted from the individual KIR and HLA genotypes. Broadly, HLA-B or -C allotypes possessing asparagine at position 80 (C1+ HLA class I) are ligands for KIR2DL2/3; HLA-C carrying lysine at this position (C2+ HLA class I) are ligands for KIR2DL1 and KIR2DL2; HLA-A and HLA-B allotypes that carry the Bw4 motif at residues 77-83 are ligands for KIR3DL1, HLA-A*03 and HLA-A*11 are ligands for KIR3DL2 [47–50]. There are established exceptions and refinements to these broad rules [51–54], and the full matrix of interactions that were counted is given in the Supplementary Figure 2 of Deng et al. 2021 [21]. KIR2DL5 and KIR3DL3 are not receptors for HLA class I [55], with the latter characteristic of tissue-resident T cells rather than NK cells [56].

Results

To assess the immunogenetic diversity of the Egyptian population, we analyzed a cohort of 125 healthy individuals from Cairo by sequencing their KIR and HLA class I genes. This high resolution analysis identified 186 distinct alleles of the 13 KIR genes and two pseudogenes (Fig. 1). The KIR allele frequencies are given in Fig. 1A–C and Supplementary Fig. S2A, and the number of alleles observed for each gene are summarized in Fig. 1D. The genotype frequencies for each KIR gene were consistent with Hardy Weinberg equilibrium. As observed in other populations, KIR3DL3 is the most polymorphic KIR gene [39], with 46 alleles detected in the cohort (Fig. 1A). A substantially greater number of alleles for inhibitory KIR (135, Fig. 1A) than activating KIR (24, Fig. 1B) were observed, and we detected 27 alleles of the KIR2DP1 and KIR3DP1 pseudogenes (Fig. 1C). The alleles we detected encode a total of 130 distinct polypeptide sequences (allotypes, Fig. 1D). Of particular note, six allotypes of KIR2DS5 are encoded in the Egyptian cohort (Fig. 1D), whereas populations outside Africa tend to possess only one KIR2DS5 allotype, which does not function as a receptor for HLA class I [57]. Together, these findings indicate the Egyptian population has substantial functional diversity of NK cells.

Figure 1. KIR Allele frequencies in Egyptians from Cairo.

Figure 1.

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Shown are the KIR alleles and their frequencies identified in 125 Egyptians. Red text indicates alleles not expressed on the cell surface.

A. Inhibitory KIR

B. Activating KIR (KIR3DS1 alleles are shown in panel A, as alleles of KIR3DL1/S1)

C. KIR pseudogenes

D. Summary of the number of alleles per KIR gene and pseudogene. Note KIR2DS3*00102, S3*002 and S5*002 can each be located in the centromeric or telomeric portion of the KIR locus. The alleles present in instances of gene duplication (e.g. KIR3DP1*004) are given in Supplementary Figure 2B–C.

Comparison with populations representing major global groups shows Egyptians likely have one of the highest levels of KIR diversity worldwide (Fig. 2A). In comparing randomly selected population subsamples of 75 individuals genotyped to the same resolution as described here, the Egyptian cohort has greater diversity than Europeans, and resembles sub-Saharan African groups. In this comparison, the only population that exceeds the KIR diversity of Egyptians is the Nama. The Nama represent the KhoeSan from Southern Africa who have the greatest genome wide diversity of any human population [58]. Despite the similarity in allele number to other Africans, the KIR genotypes of Egyptians cluster with those of Europeans by principal components analysis of worldwide populations (Fig. 2B).

Figure 2. Egyptians have high KIR diversity.

Figure 2.

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A. Shows a comparison of the total number of alleles detected from the 13 KIR genes across eight populations genotyped to the same resolution and representing major global groups. For each population, 75 individuals were chosen at random, and the number of alleles counted, as described [19, 21].

B. Principal Component analysis drawn from the KIR allele frequencies of all populations currently tested to the same high resolution [19–28].

In the Egyptian population sample, we identified a further 16 previously uncharacterized alleles, which were independently validated and submitted to the IPD (Fig. 3). Thirteen of these alleles encode unique amino acid sequences, and three are characterized by synonymous nucleotide changes. That ten of these substitutions occur in the D0-D2 Ig domains suggests cumulative effect on ligand binding and subsequent NK cell function [52]. Many of the novel alleles were identified only once in the sample of 125 individuals. By contrast, two of the alleles (KIR2DL4*59 and KIR2DL5A*042) were each observed in three or more individuals and often together, notably also with KIR3DS1*014 (Supplementary Fig. S2). Suggesting these alleles are specific to North African, KIR3DS1*014 has been observed previously at low frequency in Morocco, and no other population [59, 60].

Figure 3. KIR alleles first discovered in the Egyptian population.

Figure 3.

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Shown are the KIR alleles discovered in this study. From left to right: the KIR gene, GenBank ID, new allele name, the closest match to previously identified alleles, nucleotide and corresponding amino acid substitutions compared to the closest match, and number of individuals in which the novel allele was observed. D0-D1: Ig-like domains, Cyt: cytoplasmic domain.

Analyzing the KIR alleles from 125 Egyptian individuals, we identified 146 distinct centromeric KIR haplotypes (Supplementary Fig. S2B), with 23 of them each observed in three or more individuals (Fig. 4A). We also identified 78 distinct telomeric KIR haplotypes (Supplementary Fig. S2C), and 20 of these were each observed in three or more individuals (Fig. 4B). KIR-A comprise 60% of the centromeric haplotypes by frequency (Fig. 4C), with 81 distinct cen-A haplotypes observed (Supplementary Fig. S2B). Similarly, KIR-A comprise 71% of the telomeric haplotypes by frequency (Fig. 4C), with 51 distinct tel-A haplotypes observed (Supplementary Fig. S2C). The most frequent centromeric (3DL3*00901-2DL3*00101-2DL1*00302) and telomeric (2DL4*00801-3DL1*00101-2DS4*003-3DL2*001) motifs are of the KIR-A configuration. Both haplotype motifs are common across populations worldwide (Fig. 5). A median within-population frequency rank of 2 and 4, respectively, indicates they are also among the most frequent centromeric and telomeric KIR haplotypes in those populations (Fig. 5). Because KIR2DL4*008 and KIR2DS4*003 are not expressed at the cell surface [61, 62], this cen-A tel-A configuration expresses the maximum number of inhibitory receptors and no activating receptors specific for HLA class I. Individuals possessing both these haplotype motifs therefore have maximal NK cell education potential.

Figure 4. KIR haplotype diversity in the Egyptian population.

Figure 4.

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A. Shown are any centromeric KIR haplotypes identified in three or more individuals from the cohort of 125 Egyptians. KIR-A haplotypes are shaded pink and KIR-B haplotypes are blue. The haplotype frequencies are shown at the right. The complete list of haplotypes is given in Supplementary Fig. S1.

B. Telomeric KIR haplotypes observed in three or more individuals.

C. Shows the relative proportions of KIR-A and KIR-B haplotypes in the centromeric (left) and telomeric (right) portions of the KIR locus, and (right) KIR-AA genotypes vs other full-locus KIR genotypes.

Figure 5. Haplotypes that confer maximum NK cell educating potential are common worldwide.

Figure 5.

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Shows the rank and frequency across worldwide populations of the centromeric and telomeric KIR haplotypes most frequent in Egypt. The number in parentheses indicates the number of populations analyzed within the respective group (in which case the rank across all subpopulations and the mean frequency is shown). The populations are from Iran [19], West Africa [24, 26], Malaysia [29], USA [20], Southern Africa (KhoeSan) [25], Central Africa [24], South America [28], Oceania [23] and East Asia [21, 27]. Grey shading indicates allele not expressed on the cell surface.

Although haplotypes characterized by large-scale insertions encompassing complete KIR genes have been observed in up to 10% individuals in many populations worldwide, they are rare or absent in sub-Saharan Africans [63–67]. The duplicated genes can be expressed, broadening the repertoire of NK cell diversity per individual [63, 64]. In the Egyptian cohort, we observed two KIR haplotypes possessing large-scale insertions of three or more genes, and these were found in a total of eight individuals (Fig. 6). The first duplication haplotype is characterized by an insertion of seven genes (KIR2DL4, 3DL1/S1, 2DL5A, 2DS3/5, 2DP1, 2DL1, 3DP1). This seven-gene insertion was observed five times in the cohort, with three having identical alleles, and the remaining two differing by one and two alleles, respectively. The insertion is present in context with two distinct telomeric configurations, and a different cen-A motif in each example (Fig. 6). Similar haplotypes have been identified in Europeans and Southeast Asians, but with differing KIR2DL1 alleles [29, 67]. The second insertion comprises three genes (KIR2DL4, 3DL1/S1, 3DP1), and is identical in allele sequence for all three observed cases. The haplotypes having three gene insertions are further characterized by possession of KIR3DP1*004, whereas those having seven additional KIR are characterized by KIR3DP1*010 (Fig. 6). Consistent with previous descriptions of KIR gene duplication haplotypes [63, 68], these KIR3DP1 alleles may serve as markers for the structural variants. The inserted segment of the Egyptian haplotype is distinguished by replacement of KIR3DS1 with KIR3DL1. As a result, the Egyptian haplotype encodes two distinct inhibitory allotypes specific for Bw4+HLA, KIR3DL1*001 and *005. The ability to express both KIR3DL1*001 and *005 likely broadens the efficiency of NK cells to interact with tissue cells expressing Bw4+HLA-A or -B [69], in addition any third KIR3DL1 allotype present in the respective individual.

Figure 6. Large scale KIR duplications observed in the Egyptian population sample.

Figure 6.

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Shows two large structural variations observed. Cyan shading indicates the additional segment in relation to more frequent haplotypes. The order of the insertion is deduced based on the preceding alleles: e.g. the first five all have centromeric KIR-A configuration, and the additional alleles (such as 2DL1*004 and 2DL1*007 [20]) are of the KIR-B configuration. Each of the complete haplotypes indicated was observed only once in the population sample of 125 Egyptians.

To estimate the KIR ligand diversity of the Egyptian population we next determined the HLA class I alleles present. In the cohort of 125 individuals, we observed 40 alleles (encoding 35 allotypes) of HLA-A, 58 (50 allotypes) of HLA-B and 43 (29 allotypes) of HLA-C (Table 1 and Supplementary Figure 1D). Included are nine distinct KIR ligands carried by HLA-A, and 23 by HLA-B (Fig. 7A). By frequency, 62% of the HLA-C allotypes are C1+ and 38% are C2+, with an additional C1 ligand carried by B*73:01 (0.01%). The frequency of C2+HLA-C is substantially lower than sub-Saharan Africans [59]. We detected 185 distinct HLA class I haplotypes (Supplementary Figure 1E). Of these haplotypes, 177 are distinct at the allotype level, and 15 were observed in three or more individuals each (Fig. 7B). In Egyptians we observed a mean of 1.8 KIR ligands encoded per HLA class I haplotype (Fig. 7C). Taken together with the KIR alleles, we observed a mean of six distinct inhibitory receptor/ligand interactions per individual (Fig. 8A), where on average, four are of KIR with HLA-C and two with HLA-A or -B (Fig. 8B). Previous analyses of HLA class I frequencies in Egypt have tended to rely on serological typing and are thus difficult to compare directly to our high-resolution data. Nevertheless, we observe good correlation of the major serological frequencies with these studies [70–73]. Moreover, although the descriptions of HLA class I alleles at high-resolution in Egyptians are limited in number [74, 75], we observe almost complete correlation both in the alleles detected and their frequencies.

Table 1.

HLA class I allele frequencies of 125 Egyptians from Cairo, shown at two-field resolution.

HLA-A Freq. HLA-B Freq. HLA-C Freq.
A*01:01 0.124 B*07:02 0.028 C*01:02 0.008
A*01:02 0.004 B*07:05 0.008 C*02:02 0.028
A*01:03 0.016 B*07:96 0.004 C*03:02 0.02
A*01:43 0.004 B*08:01 0.024 C*03:03 0.004
A*02:01 0.156 B*13:02 0.024 C*03:04 0.024
A*02:02 0.032 B*14:01 0.004 C*04:01 0.112
A*02:05 0.028 B*14:02 0.048 C*05:01 0.012
A*02:14 0.004 B*15:01 0.004 C*05:37 0.004
A*03:01 0.072 B*15:03 0.004 C*06:02 0.08
A*03:02 0.024 B*15:10 0.008 C*07:01 0.112
A*03:05 0.004 B*15:16 0.008 C*07:02 0.044
A*11:01 0.04 B*15:22 0.028 C*07:04 0.008
A*23:01 0.044 B*18:01 0.052 C*07:06 0.012
A*23:17 0.004 B*27:02 0.004 C*07:18 0.02
A*24:02 0.052 B*27:03 0.02 C*08:02 0.06
A*24:03 0.02 B*27:07 0.012 C*12:02 0.088
A*26:01 0.028 B*35:01 0.028 C*12:03 0.096
A*29:01 0.004 B*35:02 0.016 C*12:05 0.004
A*29:02 0.012 B*35:03 0.02 C*12:13 0.004
A*29:10 0.004 B*35:08 0.032 C*14:02 0.02
A*30:01 0.036 B*37:01 0.004 C*15:02 0.036
A*30:02 0.036 B*38:01 0.06 C*15:05 0.02
A*30:04 0.044 B*40:01 0.02 C*16:01 0.04
A*30:99 0.004 B*40:06 0.004 C*16:02 0.044
A*31:01 0.016 B*41:01 0.072 C*16:04 0.012
A*31:04 0.004 B*41:02 0.004 C*17:01 0.076
A*32:01 0.064 B*42:01 0.016 C*17:02 0.004
A*33:01 0.032 B*44:02 0.024 C*17:03 0.004
A*33:03 0.008 B*44:03 0.028 C*18:02 0.004
A*34:02 0.016 B*44:25 0.004
A*66:01 0.004 B*45:01 0.024
A*68:01 0.008 B*47:01 0.004
A*68:02 0.02 B*49:01 0.064
A*69:01 0.024 B*50:01 0.044
A*74:01 0.008 B*51:01 0.044
B*51:07 0.008
B*51:08 0.016
B*52:01 0.084
B*52:19 0.004
B*53:01 0.004
B*53:05 0.004
B*55:01 0.008
B*56:01 0.004
B*57:01 0.004
B*57:03 0.012
B*58:01 0.028
B*58:02 0.008
B*73:01 0.012
B*78:01 0.004
B*82:02 0.008
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Figure 7. KIR ligand composition of HLA class I in Egyptians.

Figure 7.

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A. Shown are the HLA-A, -B, and -C allele frequency spectra observed from 125 Egyptian individuals. Each pie segment represents a distinct allele, colored according to the expressed KIR binding motif: Yellow - A3/11 (HLA-A3 and -A11); Green - Bw4 epitope (subsets of HLA-A and -B); Red - C1 (HLA-C allotypes, plus HLA-B*73); Blue - C2 (HLA-C allotypes that do not carry C1); White - allotypes that are not KIR ligands. Supplementary Fig. S1 lists all the HLA-A, -B and -C allotypes present in the study population and shows which KIR ligand motifs they carry.

B. Shows all the HLA class I haplotypes detected in three or more individuals in the Egyptian population sample of 125 individuals. The frequencies are shown at the right. Colored shading indicates HLA class I alleles that encode KIR ligands, as described in panel A. The complete list of haplotypes is given in Supplementary Fig. S1.

C. Pie charts show the combined frequencies of HLA class I haplotypes encoding one (gold), two (purple) or three (cyan) KIR ligands.

Figure 8. Combinatorial diversity of KIR and HLA class I allotypes in Egyptians.

Figure 8.

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A. Shows the number of distinct interacting ligand/receptor allotype pairs observed per individual in the Egyptian sample of N=125.

B. Shows the mean number of distinct ligand/receptor allotype pairs per individual for HLA-C (upper) and HLA-A and -B combined (lower) across representative populations. The populations are ordered from least to greatest interaction diversity. In the populations shown, KIR and HLA class I have been analyzed to similar high-resolution as described here for Egyptians. These populations comprise the Yucpa Amerindians, Chinese Southern Han, Japanese, Māori, Europeans, Ghanaians and Nama, as described [21].

Summary

We analyze the combinatorial diversity of KIR and HLA class I allotypes in a population sample from Cairo, Egypt. Our findings indicate that the Egyptian population has an exceptionally high level of KIR diversity, with 186 alleles identified across 13 KIR genes and two pseudogenes. This diversity is among the highest levels reported for any human population worldwide, comparable to that seen in sub-Saharan African populations such as the Nama from Southern Africa who have been shown to possess some of the greatest genome wide diversity. Despite this similarity in the level of diversity to sub-Saharan Africans, the KIR allele composition clusters with Europeans by principal components analysis of worldwide populations. The difference likely reflects the unique genetic ancestry of Egyptians, having a major Eurasian component of ancestry, influenced by multiple cultures [34–36]. One consequence of this admixture is the lower frequency of C2+HLA-C, which may contribute to the lower incidence of preeclampsia in Egypt than in Sub-Saharan Africa, representing an intermediate incidence in relation to Europeans [76]. Overall, our findings demonstrate the exceptional diversity of KIR and HLA class I in the Egyptian population, which is likely to have a significant impact on the immune response of individuals in this population. This study provides a valuable resource for understanding the immunogenetic diversity in Egypt and will be useful for further studies into the role of KIR and HLA class I in disease susceptibility and progression.

Supplementary Material

Supplementary 1

Supplementary Fig. S1. KIR3DP1 exon 2 in/del genotyping

A. (upper) Shows text-based virtual probes used to determine the genotype of the KIR3DP1 exon 2 in/del polymorphism. (lower) shows example counts for each of the four major genotypes.

B. Shows example PCR gels from the individuals genotyped in panel A.

Supplementary 2

Supplementary Fig. S2. Allele and Haplotype frequencies

(Excel Spreadsheet)

Shows the frequencies in Egyptians (2N = 250) of:

A. KIR alleles ordered by frequency

B. Centromeric KIR haplotypes

C. Telomeric KIR haplotypes

D. HLA class I alleles at four-field resolution

E. HLA class I haplotypes at four-field and two-field (allotype) resolution

Acknowledgements

This work was supported by NIH grant U01 AI090905 (PJN), and by Joint Egyptian Academy of Scientific Research & Technology and Bibliotheca Alexandrina (ASRT-BA) post-doctoral research grants program, number 1492. Thanks to the Barbara Davis Diabetes Research Center for help with Sanger sequencing for novel allele validation (NIH P30 DK116073).

Footnotes

Conflict of Interest Statement

The authors declare no conflicts of interest.

Ethics statement: The study was approved by the institutional review board of the Egyptian National Cancer Institute (approval number 2101-2P03-003).

Data availability

All data are given in the main and supplementary figures and any newly-identified sequences deposited in GenBank and IPD, with accession numbers given in Figure 3.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary 1

Supplementary Fig. S1. KIR3DP1 exon 2 in/del genotyping

A. (upper) Shows text-based virtual probes used to determine the genotype of the KIR3DP1 exon 2 in/del polymorphism. (lower) shows example counts for each of the four major genotypes.

B. Shows example PCR gels from the individuals genotyped in panel A.

NIHMS1984209-supplement-Supplementary_1.docx (51.3KB, docx)
Supplementary 2

Supplementary Fig. S2. Allele and Haplotype frequencies

(Excel Spreadsheet)

Shows the frequencies in Egyptians (2N = 250) of:

A. KIR alleles ordered by frequency

B. Centromeric KIR haplotypes

C. Telomeric KIR haplotypes

D. HLA class I alleles at four-field resolution

E. HLA class I haplotypes at four-field and two-field (allotype) resolution

NIHMS1984209-supplement-Supplementary_2.xlsx (52.7KB, xlsx)

Data Availability Statement

All data are given in the main and supplementary figures and any newly-identified sequences deposited in GenBank and IPD, with accession numbers given in Figure 3.

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