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Susceptibility to Crohn’s disease is mediated by KIR2DL2/KIR2DL3 heterozygosity and the HLA-C ligand

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Abstract

In the present study, we investigated the relationship between the KIR loci and the genes encoding their HLA ligands and genetic susceptibility to Crohn’s disease (CD). Analyses of the interactions between KIR3DL1, KIR2DL1, KIR2DL2, and KIR2DL3 with their respective HLA ligands indicate that there is a protective effect for KIR2DL2 in the absence of its HLA ligand C1. Given that KIR2DL2 and KIR2DL3 segregate as alleles, we compared their genotypic distributions to expectations under Hardy–Weinberg Equilibrium (HWE) with regard to the HLA ligand C1 status. While all the genotypic distributions conform to expectations under HWE in controls, in C2 ligand homozygous cases there is significant deviation from HWE, with a reduction of KIR2DL2, KIR2DL3 heterozygotes. KIR2DL2, KIR2DL3 heterozygosity is the only genotypic combination that confers protection from CD. In addition to the protective effect (OR = 0.44, CI = 0.22–0.87; p = 0.018) observed in C2 ligand homozygotes, the KIR2DL2, KIR2DL3 genotype is predisposing (OR = 1.34, CI = 1.03–4.53; p = 0.031) in the presence of C1 ligand. A test for trend of HLA class I C ligand group genotypes with KIR2DL2, KIR2DL3 heterozygosity in cases and controls indicates that C1, C2 ligand group heterozygotes have an intermediate effect on predisposition. These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype.

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Acknowledgments

This study was supported by a National Institutes of Health research grant no. U01 AI067068 (JAH, MBL, KS, HAE, and EAT). Assay development at Children’s Hospital Oakland Research Institute was supported by National Institutes of Health grant no. R21 AI065254. Sample collection and clinical identification at Cedars–Sinai Medical Center was supported by research grants AI 067068, IBD Program Project Grant DK 046763 (KDT, LM, TH, DPBM, and JIR), General Clinical Research Center grant MO1 RR00069, Diabetes Endocrinology Research Center grant DK 063491, and the Cedars–Sinai Board of Governors’ in Medical Genetics (JIR). The authors would also like to thank Kristine Munir for her administrative assistance.

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Authors and Affiliations

  1. Center for Genetics, Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA, 94609, USA

    Jill A. Hollenbach, Martha B. Ladner, Koy Saeteurn & Elizabeth A. Trachtenberg

  2. Medical Genetics Institute and IBD Center, Cedars–Sinai Medical Center, Los Angeles, CA, USA

    Kent D. Taylor, Ling Mei, Talin Haritunians, Dermot P. B. McGovern & Jerome I. Rotter

  3. Department of Human Genetics, Roche Molecular Systems, Pleasanton, CA, USA

    Henry A. Erlich

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  1. Jill A. Hollenbach
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  2. Martha B. Ladner
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Correspondence to Elizabeth A. Trachtenberg.

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Hollenbach, J.A., Ladner, M.B., Saeteurn, K. et al. Susceptibility to Crohn’s disease is mediated by KIR2DL2/KIR2DL3 heterozygosity and the HLA-C ligand. Immunogenetics 61, 663–671 (2009). https://doi.org/10.1007/s00251-009-0396-5

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