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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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References

  • Agresti A (2002) Categorical data analysis, 2nd edn. Wiley, New York

    Google Scholar 

  • Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, Kwiatkowski DP, McCarthy MI, Ouwehand WH, Samani NJ, Todd JA, Donnelly P, Barrett JC, Davison D, Easton D, Evans DM, Leung HT, Marchini JL, Morris AP, Spencer CC, Tobin MD, Attwood AP, Boorman JP, Cant B, Everson U, Hussey JM, Jolley JD, Knight AS, Koch K, Meech E, Nutland S, Prowse CV, Stevens HE, Taylor NC, Walters GR, Walker NM, Watkins NA, Winzer T, Jones RW, McArdle WL, Ring SM, Strachan DP, Pembrey M, Breen G, St Clair D, Caesar S, Gordon-Smith K, Jones L, Fraser C, Green EK, Grozeva D, Hamshere ML, Holmans PA, Jones IR, Kirov G, Moskivina V, Nikolov I, O’Donovan MC, Owen MJ, Collier DA, Elkin A, Farmer A, Williamson R, McGuffin P, Young AH, Ferrier IN, Ball SG, Balmforth AJ, Barrett JH, Bishop TD, Iles MM, Maqbool A, Yuldasheva N, Hall AS, Braund PS, Dixon RJ, Mangino M, Stevens S, Thompson JR, Bredin F, Tremelling M, Parkes M, Drummond H, Lees CW, Nimmo ER, Satsangi J, Fisher SA, Forbes A, Lewis CM, Onnie CM, Prescott NJ, Sanderson J, Matthew CG, Barbour J, Mohiuddin MK, Todhunter CE, Mansfield JC, Ahmad T, Cummings FR, Jewell DP et al (2007) Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants. Nat Genet 39:1329–37

    Article  PubMed  CAS  Google Scholar 

  • Canavez F, Young NT, Guethlein LA, Rajalingam R, Khakoo SI, Shum BP, Parham P (2001) Comparison of chimpanzee and human leukocyte Ig-like receptor genes reveals framework and rapidly evolving genes. J Immunol 167:5786–94

    PubMed  CAS  Google Scholar 

  • Cargill M, Schrodi SJ, Chang M, Garcia VE, Brandon R, Callis KP, Matsunami N, Ardlie KG, Civello D, Catanese JJ, Leong DU, Panko JM, McAllister LB, Hansen CB, Papenfuss J, Prescott SM, White TJ, Leppert MF, Krueger GG, Begovich AB (2007) A large-scale genetic association study confirms IL12B and leads to the identification of IL23R as psoriasis-risk genes. Am J Hum Genet 80:273–90

    Article  PubMed  CAS  Google Scholar 

  • Carrington M, Martin MP (2006) The impact of variation at the KIR gene cluster on human disease. Curr Top Microbiol Immunol 298:225–57

    Article  PubMed  CAS  Google Scholar 

  • Cereb N, Maye P, Lee S, Kong Y, Yang SY (1995) Locus-specific amplification of HLA class I genes from genomic DNA: locus-specific sequences in the first and third introns of HLA-A, -B, and -C alleles. Tissue Antigens 45:1–11

    Article  PubMed  CAS  Google Scholar 

  • Devlin SM, Yang H, Ippoliti A, Taylor KD, Landers CJ, Su X, Abreu MT, Papadakis K, Vasiliauskas E, Melmed G, Fleshner P, Mei L, Rotter JI, Targan SR (2007) NOD2/CARD15 variants are significantly associated with sero-reactivity to microbial antigens in patients with Crohn’s disease and their unaffected relatives. Gastroenterology 132:576–586

    Article  PubMed  CAS  Google Scholar 

  • Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH (2006) A genome-wide association study identifies IL23R as an inflammatory bowel disease gene. Science 314:1461–3

    Article  PubMed  CAS  Google Scholar 

  • Guethlein LA, Flodin LR, Adams EJ, Parham P (2002) NK cell receptors of the orangutan (Pongo pygmaeus): a pivotal species for tracking the coevolution of killer cell Ig-like receptors with MHC-C. J Immunol 169:220–9

    PubMed  CAS  Google Scholar 

  • Houtchens KA, Nichols RJ, Ladner MB, Boal HE, Sollars C, Geraghty DE, Davis LM, Parham P, Trachtenberg EA (2007) High-throughput killer cell immunoglobulin-like receptor genotyping by MALDI-TOF mass spectrometry with discovery of novel alleles. Immunogenetics 59:525–537

    Article  PubMed  CAS  Google Scholar 

  • Jones DC, Edgar RS, Ahmad T, Cummings JR, Jewell DP, Trowsdale J, Young NT (2006) Killer Ig-like receptor (KIR) genotype and HLA ligand combinations in ulcerative colitis susceptibility. Genes Immun 7:576–82

    Article  PubMed  CAS  Google Scholar 

  • Khakoo SI, Carrington M (2006) KIR and disease: a model system or system of models? Immunol Rev 214:186–201

    Article  PubMed  CAS  Google Scholar 

  • Khakoo SI, Rajalingam R, Shum BP, Weidenbach K, Flodin L, Muir DG, Canavez F, Cooper SL, Valiante NM, Lanier LL, Parham P (2000) Rapid evolution of NK cell receptor systems demonstrated by comparison of chimpanzees and humans. Immunity 12:687–98

    Article  PubMed  CAS  Google Scholar 

  • Kim S, Poursine-Laurent J, Truscott SM, Lybarger L, Song YJ, Yang L, French AR, Sunwoo JB, Lemieux S, Hansen TH, Yokoyama WM (2005) Licensing of natural killer cells by host major histocompatibility complex class I molecules. Nature 436:709–13

    Article  PubMed  CAS  Google Scholar 

  • Kim S, Sunwoo JB, Yang L, Choi T, Song YJ, French AR, Vlahiotis A, Piccirillo JF, Cella M, Colonna M, Mohanakumar T, Hsu KC, Dupont B, Yokoyama WM (2008) HLA alleles determine differences in human natural killer cell responsiveness and potency. Proc Natl Acad Sci U S A 105:3053–8

    Article  PubMed  Google Scholar 

  • Landers CJ, Cohavy O, Misra R, Yang H, Lin YC, Braun J, Targan SR (2002) Selected loss of tolerance evidenced by Crohn’s disease-associated immune responses to auto- and microbial antigens. Gastroenterology 123:689–99

    Article  PubMed  CAS  Google Scholar 

  • Lodes MJ, Cong Y, Elson CO, Mohamath R, Landers CJ, Targan SR, Fort M, Hershberg RM (2004) Bacterial flagellin is a dominant antigen in Crohn disease. J Clin Invest 113:1296–306

    PubMed  CAS  Google Scholar 

  • Mager DL, McQueen KL, Wee V, Freeman JD (2001) Evolution of natural killer cell receptors: coexistence of functional Ly49 and KIR genes in baboons. Curr Biol 11:626–30

    Article  PubMed  CAS  Google Scholar 

  • McGovern DP, Taylor KD, Landers C, Derkowski C, Dutridge D, Dubinsky M, Ippoliti A, Vasiliauskas E, Mei L, Mengesha E, King L, Pressman S, Targan SR, Rotter JI (2009) MAGI2 genetic variation and inflammatory bowel disease. Inflamm Bowel Dis 15:75–83

    Article  PubMed  Google Scholar 

  • Mei L, Targan SR, Landers C, Dutridge D, Ippoloti A, Vasiliauskas EA, Papadakis KA, Fleshner P, Rotter JI, Yang H (2006) Familial expression of anti-Escherichia coli outer membrane porin C (OmpC) in relatives of patients with Crohn’s disease. Gastroenterology 130:1078–1085

    Article  PubMed  CAS  Google Scholar 

  • Middleton D, Gonzalez A, Gilmore PM (2007) Studies on the expression of the deleted KIR2DS4*003 gene product and distribution of KIR2DS4 deleted and nondeleted versions in different populations. Hum Immunol 68:128–34

    Article  PubMed  CAS  Google Scholar 

  • Mizuki M, Eklund A, Grunewald J (2000) Altered expression of natural killer cell inhibitory receptors (KIRs) on T cells in bronchoalveolar lavage fluid and peripheral blood of sarcoidosis patients. Sarcoidosis Vasc Diffuse Lung Dis 17:54–9

    PubMed  CAS  Google Scholar 

  • Momot T, Koch S, Hunzelmann N, Krieg T, Ulbricht K, Schmidt RE, Witte T (2004) Association of killer cell immunoglobulin-like receptors with scleroderma. Arthritis Rheum 50:1561–5

    Article  PubMed  CAS  Google Scholar 

  • Moretta A, Bottino C, Mingari MC, Biassoni R, Moretta L (2002) What is a natural killer cell? Nat Immunol 3:6–8

    Article  PubMed  CAS  Google Scholar 

  • Mow WS, Lo SK, Targan SR, Dubinsky MC, Treyzon L, Abreu-Martin MT, Papadakis KA, Vasiliauskas EA (2004) Initial experience with wireless capsule enteroscopy in the diagnosis and management of inflammatory bowel disease. Clin Gastroenterol Hepatol 2:31–40

    Article  PubMed  Google Scholar 

  • Nelson GW, Martin MP, Gladman D, Wade J, Trowsdale J, Carrington M (2004) Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 173:4273–6

    PubMed  CAS  Google Scholar 

  • Rajalingam R, Hong M, Adams EJ, Shum BP, Guethlein LA, Parham P (2001) Short KIR haplotypes in pygmy chimpanzee (Bonobo) resemble the conserved framework of diverse human KIR haplotypes. J Exp Med 193:135–46

    Article  PubMed  CAS  Google Scholar 

  • Sandborn WJ, Loftus EV Jr, Colombel JF, Fleming KA, Seibold F, Homburger HA, Sendid B, Chapman RW, Tremaine WJ, Kaul DK, Wallace J, Harmsen WS, Zinsmeister AR, Targan SR (2001) Evaluation of serologic disease markers in a population-based cohort of patients with ulcerative colitis and Crohn’s disease. Inflamm Bowel Dis 7:192–201

    Article  PubMed  CAS  Google Scholar 

  • Shilling HG, Lienert-Weidenbach K, Valiante NM, Uhrberg M, Parham P (1998) Evidence for recombination as a mechanism for KIR diversification. Immunogenetics 48:413–6

    Article  PubMed  CAS  Google Scholar 

  • Sutton CL, Yang H, Li Z, Rotter JI, Targan SR, Braun J (2000) Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn’s disease. Gut 46:58–63

    Article  PubMed  CAS  Google Scholar 

  • Takedatsu H, Taylor KD, Mei L, McGovern DPB, Landers CJ, Gonsky R, Cong Y, Vasiliauskas EA, Ippoliti A, Elson CO, Rotter JI, Targan SR (2009) Linkage of CD-related serological phenotypes: NFKB1 haplotypes are associated with anti-CBir1 and ASCA, and show reduced NF-kB activation. Gut 58:60–67

    Article  PubMed  CAS  Google Scholar 

  • Targan SR, Shanahan F, Karp LC (2003) Inflammatory bowel disease: from bench to bedside. Kluwer, Dordrecht

    Google Scholar 

  • Taylor KD, Yang H, Rotter JI (2007) Inflammatory bowel disease. Emery and Rimoin’s principles and practice of medical genetics. Churchill Livingstone, London, pp 1549–1582

    Google Scholar 

  • Team R. D. C.: R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria, 2008

  • Trachtenberg E, Yang H, Hayes E, Vinson M, Li S, Targan S, Tyan D, Erlich H, Rotter J (2000) HLA class II haplotype associations with Inflammatory Bowel Disease in Jewish (Ashkenazi) and non-Jewish Caucasian populations. Hum Immunol 61:326–333

    Article  PubMed  CAS  Google Scholar 

  • Trowsdale J (2001) Genetic and functional relationships between MHC and NK receptor genes. Immunity 15:363–74

    Article  PubMed  CAS  Google Scholar 

  • Trowsdale J, Parham P (2004) Mini-review: defense strategies and immunity-related genes. Eur J Immunol 34:7–17

    Article  PubMed  CAS  Google Scholar 

  • Trowsdale J, Barten R, Haude A, Stewart CA, Beck S, Wilson MJ (2001) The genomic context of natural killer receptor extended gene families. Immunol Rev 181:20–38

    Article  PubMed  CAS  Google Scholar 

  • van der Slik AR, Roeleman PC, Verduijn W, Jan Bruining G, Roep BO, Giphart MJ (2003) KIR in type 1 diabetes: disparate distribution of activating and inhibitory natural killer cell receptors in patients versus HLA-matched control subjects. Diabetes 52:2639–2642

    Article  PubMed  Google Scholar 

  • van Heel DA, Dechairo BM, Dawson G, McGovern DP, Negoro K, Carey AH, Cardon LR, Mackay I, Jewell DP, Lench NJ (2003) The IBD6 Crohn’s disease locus demonstrates complex interactions with CARD15 and IBD5 disease-associated variants. Hum Mol Genet 12:2569–75

    Article  PubMed  CAS  Google Scholar 

  • Vermeire S, Wild G (2001) RE: development of an assay for antibodies to Saccharomyces cerevisiae: easy, cheap and specific for Crohn’s disease. Can J Gastroenterol 15:841–2

    PubMed  CAS  Google Scholar 

  • Vilches C, Parham P (2002) KIR: diverse, rapidly evolving receptors of innate and adaptive immunity. Annu Rev Immunol 20:217–51

    Article  PubMed  CAS  Google Scholar 

  • Wei B, Huang T, Dalwadi H, Sutton CL, Bruckner D, Braun J (2002) Pseudomonas fluorescens encodes the Crohn’s disease-associated I2 sequence and T-cell superantigen. Infect Immun 70:6567–75

    Article  PubMed  CAS  Google Scholar 

  • Young NT, Uhrberg M (2002) KIR expression shapes cytotoxic repertoires: a developmental program of survival. Trends Immunol 23:71–5

    Article  PubMed  CAS  Google Scholar 

  • Zhang HX, Li JC, Liu ZJ (2008) Relationship between expression of inhibitory killer cell immunoglobulin-like receptor HLA-Cw ligand and susceptibility to inflammatory bowel disease. Zhonghua Yi Xue Za Zhi 88:3108–11

    PubMed  CAS  Google Scholar 

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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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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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