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. 2008:415:49-64.
doi: 10.1007/978-1-59745-570-1_3.

KIR locus polymorphisms: genotyping and disease association analysis

Maureen P Martin  1 , Mary Carrington
Affiliations

KIR locus polymorphisms: genotyping and disease association analysis

Maureen P Martin et al. Methods Mol Biol. 2008.

Abstract

The genes encoding the killer immunoglobulin-like receptors (KIR) are situated within a segment of DNA that has undergone expansion and contraction over time due in large part to unequal crossing over. Consequently, individuals exhibit considerable haplotypic variation in terms of gene content. The highly polymorphic human leukocyte antigen (HLA) class I loci encode ligands for the KIR; thus, it is not surprising that KIR genes also show significant allelic polymorphism. As a result of the receptor-ligand relationship between KIR and HLA, functionally relevant KIR-HLA combinations need to be considered in the analysis of these genes as they relate to disease outcomes. This chapter will describe a genotyping method for identifying the presence/absence of the KIR genes and general approaches to data analysis in disease association studies.

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Figures

Fig. 1.
Fig. 1.
KIR haplotypes identified by segregation analysis. Haplotypes are derived from refs. - and unpublished observations (M.C.). Haplotypes A and B are labeled as such. White boxes represent inhibitory receptors, black boxes represent activating receptors, and hatched boxes represent pseudogenes. KIR2DL4 is shown as grey boxes. This receptor has features of both inhibitory and activating receptors, although functional data suggest that it is primarily activating (31, 32).
Fig. 2.
Fig. 2.
KIR genotyping results by PCR-SSP. (A) Gel electrophoresis showing the presence of all genes tested. (B) Gel electrophoresis results from an individual homozygous for haplotype A. (C) Gel electrophoresis of KIR2DS4 showing the 197 and 219 bp alleles. (D) A gel showing the absence of amplicon (arrow) for one of the two primer pairs for KIR3DL2. The PCR for KIR3DL2 was repeated, indicating the presence of amplicon for both pairs of primers (i.e., one pair of primers did not amplify in the initial PCR due to technical error). (E) This gel shows the absence of amplicon for one of the primer pairs for KIR2DL2 (arrow), which was confirmed after repeating the PCR. The sample was sequenced for KIR2DL2 and was found to be allele *004, which is not amplified by this primer pair (see Table 1). The order of the genes for B, D, and E is as shown in A.
Fig. 3.
Fig. 3.
Susceptibility to psoriatic arthritis. (A) Old model. NK cell activation (by KIR2DS1 in this case) is quenched when HLA ligand (HLA-C group 2) for the corresponding homologous inhibitory receptor (KIR2DL1) is present (protection), but not when ligand is absent (susceptibility). (B) New model. There is a trend in susceptibility to PsA such that genotypes conferring the most inhibition are protective, whereas those conferring the most activation are susceptible (adapted from ref. 16).
See this image and copyright information in PMC

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