Analysis of candidate genes on chromosome 19 in coeliac disease: an association study of the KIR and LILR gene clusters

Abstract

Coeliac disease is strongly heritable, with more than half of the genetic susceptibility estimated to come from genes outside the HLA region. Several candidate regions have been suggested from genome-wide linkage studies including chromosome 19q13.4 where linkage has been replicated between populations. The natural killer (NK) cell immunoglobulin-like receptors (KIRs) and leukocyte immunoglobulin-like receptor (LILR, also known as ILT and LIR) gene clusters lie within this region in the leukocyte receptor cluster (LRC). KIR molecules are involved in cytotoxic lymphocyte function and expressed by intraepithelial T and NK cells in the duodenum. We studied 132 unrelated UK Caucasian coeliac patients and their parents together with a control group of 171 UK Caucasians. PCR-SSP for KIR2DL1, KIR2DL2, KIR2DL3, KIR2DL5, LILRA3 (ILT6), LILRA3 deletion and an LILRA3 exon 3 single nucleotide polymorphism (SNP) allowed classification of KIR genotypes into five categories and determination of homozygosity or heterozygosity for the common A and B type KIR haplotypes (as defined in the text) and for the LILRA3 deletion. Case-control analysis found no association of the five KIR genotype categories, the A or B KIR haplotypes, the LILRA3 gene deletion or the LILRA3 exon 3 SNP with coeliac disease. A transmission disequilibrium test also found no association of the A and B KIR haplotypes or the LILRA3 gene deletion with coeliac disease.

Paired Ig-Like Receptors Bind to Bacteria and Shape TLR-Mediated Cytokine Production

“…ILTs are encoded by multiple genes with many polymorphisms (22,36,37), some of which may affect individual susceptibility to bacteria infection. Interestingly, several recent reports suggest that ILT polymorphisms are associated with some autoimmune diseases including rheumatoid arthritis (42)(43)(44). Thus, alteration of immune homeostasis by disruption of one member of an ILT pair may contribute to an increased risk for autoimmune disease.…”

Analysis of β-defensin and Toll-like receptor gene copy number variation in celiac disease

“…During the last few years, however, a growing interest has focused on the possible implication of the innate immune response, based on the fact that gliadin peptides are also able to trigger a non-T-cell-dependent response that could establish the proinflammatory environment necessary for subsequent T-cell activation and tissue destruction [8]. Different innate immune gene families have been proposed as putative susceptibility candidates to autoimmune disorders, and there is conflicting evidence implicating killer immunoglobulin-like receptor (KIR) gene content with increased CD [9,10] or type 1 diabetes risk [11,12]. Several coding and noncoding SNPs in Toll-like receptor (TLR) 4 and TLR2 have also been analyzed, but no consistent association between these allelic variants and the disease has been detected so far [13,14].…”

Association of KIR2DL5B gene with celiac disease supports the susceptibility locus on 19q13.4

“…14,16 However, a subsequent study in Caucasians from the UK has failed to prove association of KIR genes with CD and confirm the locus on 19q13.4. 32 In the present study, we analyzed the contribution of KIR genes to the genetic predisposition to celiac disease in Basques, an ancient European population that has been isolated in the past and maintains certain genetic characteristics distinctive from other Caucasians, including KIR gene frequencies. [33][34][35][36] We have studied KIR gene content, genotype and haplotype frequencies, as well as combinations with known ligands (HLA-C80) in Basque patients with the disease, and compared them to the general population of the same ethnic origin.…”