Defining the contribution of the HLA region to cis DQ2-positive coeliac disease patients

Abstract

The major genetic susceptibility to coeliac disease is contributed by the human leukocyte antigen (HLA) region. The primary association is with the HLA-DQ2 molecule, encoded by the DQA1*05 and DQB1*02 alleles, which is expressed by over 90% of patients. The aim of our study was to perform an extensive scan of the entire HLA region to determine whether there is evidence for the presence of additional HLA susceptibility genes for coeliac disease in the Dutch population, acting independently of DQ2. In all, 16 microsatellite markers and the DQA1 and DQB1 genes were genotyped in simplex cis DQ2-positive coeliac disease families and cis DQ2-positive control families. Allele frequencies of markers on phase-known DQ2-positive haplotypes transmitted to patients were compared to a combined group of DQ2-positive nontransmitted and control haplotypes, thereby controlling for the DQ2 contribution. No significant differences at any of the marker loci were detected, suggesting that DQ2 is the major HLA risk factor for coeliac disease. Individuals homozygous for DQ2 or heterozygous for DQA1*05-DQB1*02/DQA1*0201-DQB1*02 were found to be at five-fold increased risk for development of coeliac disease (Po10 À8 ). This risk seems to be conferred by the presence of a second DQB1*02 allele next to one DQA1*05-DQB1*02 haplotype, independently of the second DQA1 allele.

Genetics in coeliac disease

“…DQ2.5 in cis or trans) confers the primary increased risk of coeliac disease. Interestingly, however, several studies 15,16 have shown that this risk is further increased 4-6! by homozygosity for the cis haplotype or a second DQB1*02 allele on the other haplotype (i.e.…”

“…Unfortunately, however, inadequate control for the strong linkage disequilibrium across the HLA is responsible for at least some of these claims. 23 Two recent studies using larger cohorts and careful methodology did not find significant evidence for additional HLA risk factors, 15,24 however, the question of HLA risk factors in addition to DQ2 remains unresolved.…”

HLA and disease

“…Heterodimer DQA1*0501-DQB1*0201/02 Dutch [65] DQ2 Homozygotes, DQA1*05-DQB1*02/DQA1*0201-DQB1*02 heterozygotes France [66] HLA-DQ2 (DQA1*0501/DQB1*0201) and DR53 Italy [67] HLA-DQ2 Netherlands [68] HLA-DQ2.5/2.5 homozygotes, HLA-DQ2.5/2.2 heterozygotes Norway [69] HLA-DQ2 (DQA 1*0501, DQB 1*0201) Spain [70] HLA-DRB1*04 (DR4) *These are some of the representative population studies from various continents.…”

Shared genetics in coeliac disease and other immune-mediated diseases

“…Approximately 95% of patients with CD carry the HLA-DQ2 allele and the remaining 5% carry HLA-DQ8 [4]. HLA genes are responsible for approximately 40% of the genetic risk for CD [5]. The other 60% of the genetic susceptibility to CD is shared between an unknown number of non-HLA genes, each of which is estimated to contribute only a small effect [6].…”