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. 2010 Dec;62(11-12):729-40.
doi: 10.1007/s00251-010-0478-4. Epub 2010 Sep 29.

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

Pierre-Antoine Gourraud  1 , Ashley Meenagh, Anne Cambon-Thomsen, Derek Middleton
Affiliations

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

Pierre-Antoine Gourraud et al. Immunogenetics. 2010 Dec.

Abstract

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.

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Figures

Fig. 1
Fig. 1
Pairwise linkage disequilibrium between the presence or absence of 13 KIR genes. Lewontin’s pairwise standardized metrics describe linkage disequilibrium (LD) between all KIR genes but KIR3DL2 and KIR3DL3 which were thought to be always present. KIR genes are considered at the structural variation level (the presence or absence level; copy number variant). Computations were double-checked using Haploview software (a SNP-oriented software) as well as the combined use of Gold software for graphical display and Stata ver. 10.0 SE for computing the LD metrics. KIR3DL1 and KIR3DS1 are considered as two different genes. The physical gene position is a consensus map, and another order may better reflect the reality of a given haplotype. Although LD computations do not use the physical positions of the genes and their alleles, LD measures are not necessarily independent of gene order. For example, this is the case when one considers the possibility of 2DS3 and 2DS5 being present on either side or both sides of 2DL4
Fig. 2
Fig. 2
Compact illustration of the KIR genes framework haplotype using centromeric and telomeric regions. Lines indicate associations of telomeric and centromeric regions. Thin lines connect haplotypes whose frequency is between 0.3% and 10%. Thick lines connect haplotype whose frequency is greater than 10%. Rectangles indicate presence of the KIR gene, and lines represent absence of the KIR gene. All haplotype structures within the sample are displayed. This figure also presents a specific D′: the Hedrick’s multiallelic D′, which represents the degree of LD between two regions, treating each haplotype within a region as an allele. The display is adapted from the Haploview software haplotype blocks display. KIR3DL2 is always present at the telomeric end. (*) KIR3DL3 is assumed to be always present but was not typed at the allelic level in the families. All founders and offspring were positive for KIR3DL3. Because KIR3DL3 and KIR3DL2 appear to be always present, it is not possible to study LD for these genes in terms of their presence or absence. The physical gene position is a consensus map, and another order may better reflect the reality of a given haplotype. Although LD computations do not use the physical positions of the genes and their alleles, LD measures are not necessarily independent of gene order. For example, this is the case when one considers the possibility of 2DS3 and 2DS5 being present on either side or both sides of 2DL4. Frequencies and membership in the A or B haplotype are displayed on the side of the haplotypes. For example, in the centromeric region, the haplotype KIR3DL3–KIR2DL3–KIR2DL1 can belong to both A and B haplotypes and its frequency in our data is 0.648 (64.8%), it combines in more than 10% of the cases with KIR2DL4–KIR3DS1–KIR2DL5A–KIR2DS1–KIR3DL2 telomeric haplotype, which is found in B haplotypes and whose frequency is 15.8%
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