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. 2017 Oct 23;153(3):380–386. doi: 10.1111/imm.12847

Novel KIR genotypes and gene copy number variations in northeastern Thais

Suwit Chaisri 1,2, James A Traherne 3, Jyothi Jayaraman 3, Amornrat Romphruk 2,4, John Trowsdale 3, Chanvit Leelayuwat 2,5,✉
PMCID: PMC5795178  PMID: 28950036

Summary

KIR (Killer Immunoglobulin‐like Receptor) variants influence immune responses and are genetic factors in disease susceptibility. Using sequence‐specific priming PCR, we have previously described the diversity of KIR genes in term of presence/absence in northeastern Thais (NETs). To provide additional resolution beyond conventional methods, quantitative PCR was applied to determine KIR copy number profiles. Novel expanded and contracted KIR copy number profiles were identified at cumulatively high frequencies. These all comprise haplotypes with duplication (6·9%) or deletion (2·7%) of KIR3DL1/S1 along with adjacent genes. Five expanded KIR profiles comprised haplotypes with duplications of KIR2DP1, 2DL1, 3DP1, 2DL4, 3DL1/S1 and 2DS1/4, whereas two contracted profiles contained only a single copy of KIR3DP1, 3DL1/S1 and 2DL4. Using a KIR haplotype prediction program (KIR Haplotype Identifier), 14% of NET haplotypes carried atypical haplotypes based on the gene copy number data.

Keywords: haplotypes, KIR copy number, quantitative PCR

Introduction

Killer Immunoglobulin‐like Receptors (KIRs) are expressed on natural killer (NK) cells and subsets of T cells. KIRs play an important role in mediating self‐tolerance and facilitating the cytotoxic activity of NK cells against pathogenic cells. Interactions of KIRs and HLA class I molecules on target cells can modulate the function of NK cells. The KIR gene family is located within the leucocyte receptor cluster on chromosome 19q13.4.1, 2 The KIR nomenclature reflects the number of extracellular immunoglobulin‐like domains: two domains (KIR2D), three domains (KIR3D), followed by short (S) or long (L) cytoplasmic tail. Seventeen KIRs have been characterized, of which 15 are functional as activating or inhibitory KIRs (KIR2DL1–4, 2DL5A, 2DL5B, 3DL1–3, 2DS1–5 and 3DS1) and two pseudogenes (KIR2DP1, 3DP1). Extensive polymorphism of KIR has been reported worldwide,3 including allelic polymorphisms, gene content (presence/absence polymorphism) and copy number variations. KIR haplotypes can be classified into groups A and B. The number of genes in group A haplotypes is fixed by the presence of four framework genes (KIR3DL3, 3DP1, 2DL4 and 3DL2), pseudogene (KIR2DP1) and inhibitory (KIR2DL3, 2DL1, 3DL1), as well as one activating gene, KIR2DS4. Conversely, group B haplotypes consist of variable numbers of KIR genes and one or more activating KIR genes. However, A and B haplotypes with distinctive gene content may be generated by shuffling of centromeric and telomeric motifs. The centromeric motif is defined by all KIR located between 3DL3 and 3DP1, and the telomeric motif by KIR located between 2DL4 and 3DL2. A recombination hotspot sited between KIR3DP1 and KIR2DL4 delineates centromeric and telomeric haplotype motifs of the KIR gene cluster.4 Most haplotypes comprise pairings between three common centromeric (cA01, cB01, cB02) and two telomeric (tA01, tB01) motifs.5 In addition, the expression of KIRs may be subject to epigenetic regulation through the promoter region6, 7 as well as pre‐ and post‐transcriptional regulation,8 resulting in variegated expression of KIRs on NK cells.9 Genetic variations of KIR are clearly involved in disease susceptibility and resistance, including infectious diseases,10, 11 autoimmune diseases,12 pregnancy disorders13, 14 and cancers,15, 16 and they influence haematopoietic stem cell transplantations.17, 18

To understand the influence of KIR in immune responses, the presence and absence of individual KIR genes has been investigated in normal populations19 as well as disease cohorts.20 Different KIR distributions in different geographical regions may have been selected through NK cell control of local diseases.21 KIR genes are highly homologous and are closely arranged head‐to‐tail, facilitating unequal crossing over during meiosis and generation of novel KIR haplotypes, including gene duplications and hybrid genes.22, 23 Several studies have linked genetic associations of diseases to KIR copy number.24, 25, 26, 27

Recently, genetic variation of KIR and their HLA ligands in northeastern Thais (NETs) was reported,28, 29, 30, 31 by conventional methods [sequence‐specific priming–PCR (PCR‐SSP) typing]. However, gene copy number variations of KIR have not previously been reported in Thais. Hence, to better understand the KIR diversity in NETs, KIR copy number was ascertained by quantitative PCR (qPCR).

Materials and methods

Study population

Seventy‐three healthy blood donors were obtained from the Blood Transfusion Centre, Faculty of Medicine, Khon Kaen University, Thailand. Interviews were conducted for volunteers; they were confirmed to be of Thai ancestry living in the northeastern part of Thailand for at least two generations.32, 33 Ethical permission was obtained for the investigation from the Human Research Ethics Committee of Thammasart University No. 1 (COA 057/59).

KIR genotyping and copy number identification

The salting‐out method34 was used to extract DNA from peripheral blood. To prepare genomic DNA for KIR copy number identification, 10‐ng samples of genomic DNA (2·5 μl of 4 ng/μl) were aliquoted into 384‐well plates using the Hydra 96 microdispenser (Art Robbins, San Jose, CA). KIR copy number typing was performed using a quantitative multiplex PCR assay described by Jiang et al.35

The typing results of 17 KIR genes obtained using PCR‐SSP were previously reported28 and compared with those obtained with the qPCR method.35 Copy numbers for all KIR genes (KIR2DL1–5, 2DS1–5, 2DP1, 3DP1, 3DL1, 3DL2, 3DL3 and 3DS1) were determined in the Thai samples using a Roche LightCycler 480 at Cambridge Institute for Medical Research (CIMR), University of Cambridge, UK. Using multiplex assays, the copy number was measured by relative quantification analysis of the target gene (KIR) and reference gene (signal transducer and activator of transcription 6; STAT6) using the comparative Cq method.36 Cq value is the qPCR cycle at which fluorescence from amplification exceeds the background fluorescence (also referred to as threshold cycle, Ct). The ∆∆Cq was used to calculate KIR copy number. The first ∆Cq was calculated by the cycle threshold difference between the target and reference assay of the same sample. The second ∆Cq was calculated by the difference of ∆Cq values from a test sample and a calibrator sample with known copy number of the target. Two assays for both 3DL1 and 3DL2 genes that target different exons were included. These assays were designed to help detect a known fusion gene of 3DL1, 3DL1/2v,37 which is carried on a truncated haplotype (with 2DS4 completely deleted) seen in individuals of African descent. There is a drop in copy number for exon 9 of 3DL1 and exon 4 of 3DL2 (i.e. discordance between the exon 4 and exon 9 copy numbers in the same gene) when the fusion gene is present. Assays for 2DS4 variants, 2DS4D (a 22‐bp deletion in exon 5 that causes a frameshift mutation) and 2DS4F (full‐length gene), were also included.

copycaller software from Applied Biosystems (Foster City, CA) was used to score KIR copy number. When the Cq of the reference gene was greater than 32 or where a data point was more than 4 SD from the mean ∆Cq of four replicates, the reaction was not analysed. KIR copy number frequencies were calculated from the 73 NET samples.

KIR genotypes and predicted haplotypes

The KIR genotypes (IDs) were ascertained according to the Allele Frequency Net Database (http://www.allelefrequencies.net)3. The KIR haplotypes (centromeric–telomeric motif pairings) in NETs were predicted by the KIR Haplotype Identifier program (www.bioinformatics.cimr.cam.ac.uk/haplotypes/) using the determined copy number for each KIR gene.35 KIR haplotypes were predicted in samples (n = 73) that had copy number typing for all KIR genes.

Results

KIR genotypes in NETs

KIR genotypes were identified based on quantitative PCR data. Twenty genotypes were characterized in the NET samples (n = 73) that had copy number typing for all KIR genes as shown in Fig. 1. Genotypes 1, 2, 3, 4, 5, 7 and 8 were commonly found (> 5% frequency) as seen in previous studies28, 38 of the Thai population. To compare KIR genotype with other populations, the genotype frequencies of Asians (Chinese Han, Mongolian and north Indian), Europeans (Italian and English) and Amerindian (north Brazilian) were included,28, 38, 39, 40, 41, 42, 43, 44 showing that genotype IDs 1 and 2 were the most common genotypes (> 10% frequency) in Amerindian, Europeans and most Asians (NETs, Thais, Chinese Han and Mongolian), whereas other genotypes varied among populations. Individually, the frequencies of all KIR genotypes in north Indians were < 10%, with the most common genotype found at 9·3%. Eighty per cent of the genotypes, based on qPCR, were in accordance with those obtained using the PCR‐SSP typing method. However, inconsistent data between PCR‐SSP typing and quantitative PCR were found in KIR2DS1. Originally, we thought that the discordances could probably be explained by allelic polymorphisms of KIR2DS1 that affected PCR‐SSP primer binding sites. Subsequently, we have performed DNA sequencing and DNA sequence analysis of the samples (n = 4). The discordances of the samples were typing errors of the PCR‐SSP method because of high homology sequences between KIR2DL1 and KIR2DS1 as well as low quality of the DNA templates. Accordingly, there is no variant of KIR2DS1 in this population.

Figure 1.

Figure 1

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Killer immunoglobulin‐like receptor gene (KIR) genotypes in 73 northeastern Thais (NETs) and other populations. Twenty KIR genotypes were identified with genotype ID assigned based on The Allele Frequency Net Database. Filled and opened boxes represent presence and absence of KIR genes, respectively. Hap. refers to KIR haplotype group.3 Carrier frequency (CF) and genotype frequencies (%) are given.

KIR copy number frequency in NETs

Copy numbers of 17 KIR genes, including KIR3DL3, 2DS2, 2DL2, 2DL3, 2DP1, 2DL1, 3DP1, 2DL4, 3DL1, 3DS1, 2DS3, 2DS5, 2DL5, 2DS1, 2DS4F, 2DS4D and 3DL2, were determined in 73 NETs as shown in Table 1. Copy number data for most samples matched standard centromeric/telomeric haplotype configurations but copy number characteristics of expanded and contracted haplotypes, i.e. unusual structural variation, was also observed. These data are consistent with an earlier study that reported expanded haplotypes in Thais.37 For example, the central framework genes, KIR3DP1 and 2DL4, that typically present with two copies, were found at one, three or four copies in 1·4–5·5% of NETs. Duplication of other genes was also identified with three copies of 2DP1, 2DL1, 3DL1 or 3DS1 observed in approximately 1% of NETs (Fig. 2).

Table 1.

Killer immunoglobulin‐like receptor gene (KIR) copy number frequencies in 73 northeastern Thais

KIR copy number Framework and pseudogenes A haplotype member B haplotype‐specific
3DL3 2DP1 3DP1 2DL4 3DL2 2DL1 2DL3 3DL1 2DS4WT 2DS4DEL 2DS2 2DL2 3DS1 2DL5 2DS3 2DS5 2DS1
0 0·0 6·8 0·0 0·0 0·0 5·5 12·3 9·6 45·2 45·2 42·5 42·5 45·2 31·5 61·6 58·9 45·2
1 0·0 35·6 2·7 2·7 0·0 37·0 46·6 46·6 45·2 38·4 45·2 45·2 41·1 50·7 37·0 37·0 43·8
2 100·0 56·2 90·4 90·4 100·0 56·2 41·1 42·5 9·6 16·4 12·3 12·3 12·3 17·8 1·4 4·1 11·0
3 0·0 1·4 5·5 5·5 0·0 1·4 0·0 1·4 0·0 0·0 0·0 0·0 1·4 0·0 0·0 0·0 0·0
4 0·0 0·0 1·4 1·4 0·0 0·0 0·0 0·0 0·0 0·0 0·0 0·0 0·0 0·0 0·0 0·0 0·0
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Figure 2.

Figure 2

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Killer immunoglobulin‐like receptor gene (KIR) copy number profiles in northeastern Thais (NETs). Seventy‐three individuals were characterized for KIR copy number profiles. Thirty‐six copy number profiles were found; (a) usual KIR copy number, (b) expanded copy number profiles,26, 40 (c) contracted copy number profiles.26, 40 [Colour figure can be viewed at wileyonlinelibrary.com]

KIR copy number profiles in NETs

To provide additional resolution beyond conventional methods, KIR copy number profiles were constructed from the copy number data. Thirty‐six copy number profiles were identified (Fig. 2). A variation at 2DS4 (2DS4F/2DS4D) subdivided into nine genotypes (Genotypes 1, 2, 3, 4, 5, 7, 8, 71 and 76) and was largely responsible for the expansion of genotypes from the 20, identified by PCR‐SSP, to 36 KIR copy number profiles. Genotypes 7 and 8 were further subdivided by copy number of 2DL1 and 2DP1, varying between one or two copies for each gene. Unusual KIR genotypes displaying expanded and contracted copy number profiles were identified, and are listed as novel genotypes 1–7 (Fig. 2). Novel genotypes 1–5 included expanded copy number profiles comprising three or four copies of KIR3DP1, 2DL4 and 3DL1/S1. Individuals carrying four copies of these genes probably carry two expanded haplotypes. Copy number variation of novel genotypes 1–3 included three copies of 2DS1/4. Novel genotype 4 included three copies of 2DP1 and 2DL1. Novel genotypes 6 and 7 comprised contracted copy numbers, which were defined by only one copy of KIR3DP1 and 2DL4 along with one copy of 2DS1/S4 for novel genotype 7, which also misses a copy of 2DP1 (Fig. 2). Copy number data were concordant between exons 4 and 9 of 3DL1 and 3DL2. The contracted haplotype carrying 3DL1/2v 37 was, therefore, not seen in NETs. Together, expanded or contracted copy number profiles, representing non‐standard structural variations, included 9·6% of all KIR genotypes (6·9% expanded and 2·7% contracted). Linkage disequilibrium between KIR genes was constructed using Cramer's V statistics (Wn*) to investigate the non‐random association between KIR genes, as shown in the Supplementary material (Fig S1).

KIR haplotype prediction in NETs

Haplotypes in the NET samples were imputed using the KIR Haplotype Identifier program (see Materials and methods). Eighty‐six per cent of NET haplotypes were predicted to be common haplotypes that comprised pairing of standard centromeric (CA01, CB01, CB02) and telomeric (TA01, TB01) motifs. The remaining 14% of haplotypes were classified as having non‐standard structural variations that do not fit the standard motif structures (Fig. 3), accounting for the expanded and contracted profiles described above.

Figure 3.

Figure 3

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Prediction of killer immunoglobulin‐like receptor (KIR) haplotype in northeastern Thais (NETs). KIR haplotypes were predicted by the KIR Haplotype Identifier program. The most haplotypes (86%) were generated by pairings between three centromeric motifs (cA01, cB01, cB02) and two telomeric motifts (tA01, tB01). The remaining (14%) were classified as carrying at least one haplotype with non‐typical structure. [Colour figure can be viewed at wileyonlinelibrary.com]

Discussion

Recently, genetic variations of KIR and their ligands in NETs were reported by presence and absence of 17 KIRs.28 To better understand the complexity of KIR, qPCR was used to investigate copy number of KIR genes in NETs. To compare with conventional methods, the KIR genotype, copy number and haplotype were analysed. Variations of KIR copy number ranged from zero to four copies. Individuals who were previously classified as having the same genotype by PCR‐SSP typing, were subdivided by KIR copy number variations (Fig. 2). Twenty KIR genotypes (Fig. 1) and 36 copy number profiles (Fig. 2) were identified. Most haplotypes could be considered to have arisen from three common centromeric (cA01, cB01, cB02) and two common telomeric (tA01, tB01) motifs. However, seven expanded and contracted KIR profiles were identified in the NET population (Fig. 2). Remarkably, five expanded KIR profiles (novel genotypes 1–5) comprised haplotypes with duplications of centromeric and telomeric genes including 2DP1, 2DL1, 3DP1, 2DL4, 3DL1/S1 and 2DS1/S4. Two contracted profiles (novel genotypes 6 and 7) contained one copy of KIR3DP1, 2DL4 and 3DL1/S1. All the unusual copy number profiles comprised haplotypes with deletion/duplication of 3DL1/S1 and 2DL4 located in the central region of the KIR cluster.37, 45 Similar haplotypes have been described in Caucasians. Our data indicate that these haplotypes could be more frequent in the NET population at 9·6%, but this requires further verification in a larger set of samples. The frequencies of these haplotypes could relate to population history or a region‐specific selective advantage for particular expanded/deleted haplotypes, for example. In this regard, KIR2DS1/S4 contributes to successful pregnancy in humans46 and KIR3DL1/S1 copy number is linked to retroviral control.24 Furthermore, this study could provide useful information for identifying NK alloreactive donors for haploidentical hematopoietic stem cell transplantation (HSCT) to improve clinical outcome, in KIR–disease association studies and imputation analyses of NETs.47

A study of KIR copy number in families from the UK and USA, indicated that B haplotypes were subject to gene duplication or deletion and the data here are consistent with this observation.48

Disclosures

The authors declare that they have no conflict of interest.

Supporting information

Figure S1. Linkage disequilibrium distribution in northeastern Thais.

Click here for additional data file. (243.4KB, tif)

Acknowledgements

This work was supported by the Thailand Research Fund under the Grant for New Researcher (No.TRG5880208) and Thammasat University under the TU New Research Scholar (Contract No. 23/2559) to SC. JAT and JJ are supported by the European Research Council under the European Union's Horizon 2020 research and innovation programme (Grant agreement No 695551). We also wish to acknowledge the support of the Centre for Research and Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand and the Cambridge Institute of Medical Research, Cambridge University, UK.

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Associated Data

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Supplementary Materials

Figure S1. Linkage disequilibrium distribution in northeastern Thais.

Click here for additional data file. (243.4KB, tif)

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