Genetic predisposition to coeliac disease (CD) is determined primarily by alleles at the HLA-DQB locus, and evidence exists implicating other major histocompatibility complex-linked genes (6p21) and the CTLA4 locus on chromosome 2q33. In addition, extensive family studies have provided strong, reproducible evidence for a susceptibility locus on chromosome 5q (CELIAC2). However, the gene responsible has not been identified. We have assayed genetic variation at the IL4, IL5, IL9, IL13, IL17B and NR3C1 (GR) loci, all of which are present on chromosome 5q and have potential or demonstrated involvement in autoimmune and/or inflammatory disease, in a sample of 409 CD cases and 355 controls. Thirteen single nucleotide polymorphisms were chosen on the basis of functional relevance, prior disease association and, where possible, prior knowledge of the haplotype variation present in European populations. There were no statistically significant allele or haplotype frequency differences between cases and controls. Therefore, these results provide no evidence that these loci are associated with CD in this sample population.

Chromosomal region 2q33 encodes the immune regulatory genes, CTLA4, ICOS and CD28, which are involved in regulation of T-cell activity and has been studied as a candidate gene locus in autoimmune diseases, including coeliac disease (CD). We have investigated whether an association exists between this region and CD in the Irish population using a comprehensive analysis for genetic variation. Using a haplotype-tagging approach, this gene cluster was investigated for disease association in a case–control study comprising 394 CD patients and 421 ethnically matched healthy controls. Several SNPs, including CTLA4_CT60, showed association with disease; however, after correction for multiple-testing, CTLA4−658C/T was the only polymorphism found to show significant association with disease when allele, genotype, or carrier status frequency were analysed (carrier status (Allele C), P=0.0016). Haplotype analysis revealed a haplotype incorporating the CD28/CTLA4 and two 5′ ICOS polymorphisms to be significantly associated with disease (patients 24.1%; controls 31.5%; P=0.035), as was a shorter haplotype composed of the CTLA4 markers only (30.9 vs 34.9%; P=0.042). The extended haplotype incorporating CD28/CTLA4 and 5′ ICOS is more strongly associated with disease than haplotypes of individual genes. This suggests a causal variant associated with this haplotype may be associated with disease in this population.

In addition to the well-established association of coeliac disease (CD) with HLA-DQ (6p21) and possibly CTLA4 (2q33), there is considerable evidence for a susceptibility locus on chromosome 5q, which contains many potential candidates for inflammatory disease, including a cluster of cytokine genes in 5q31. CD cases and controls were genotyped for four single-nucleotide polymorphism (SNP) markers that together characterize >90% of the haplotype variation at the IBD5 locus encoding, among others, the SLC22A4 gene. IBD5 and SLC22A4 map to 5q31 and have recently been associated with Crohn's disease and rheumatoid arthritis. Haplotype frequencies do not differ significantly between CD cases and controls in the Irish population, and therefore the chromosome 5 CD susceptibility locus most likely lies elsewhere on 5q.