Evidence for a dominant gene mechanism underlying coeliac disease in the West of Ireland

Abstract

Although coeliac disease (CD) is strongly associated with the HLA alleles B8 and DR3, the genetic basis of this illness remains obscure. Recent studies show that at least two unlinked loci are involved. Most studies agree on recessivity at the HLA-unlinked locus but differ with respect to dominance or recessivity at the HLA-linked disease susceptibility locus. To address this controversy, we examined the association of CD with HLA in 39 families from the West of Ireland. Previous studies have shown that the prevalence of CD and the frequencies of the HLA antigens associated with it are higher in this population than in most others. Analysis of the data revealed a significant excess of concordant sib-pairs with two HLA haplotypes in common and an excess of discordant pairs with no haplotype in common. Chi-square tests confirmed a highly significant association between HLA-B8 and CD. Both heterozygotes and homozygotes for B8 had a significantly increased risk of CD. The risk for homozygotes was slightly higher than for heterozygotes, although not significantly so. The segregation ratio for disease occurrence among sibs of probands was estimated to be 0.185 when neither parent is affected. We estimated a gene frequency of 0.003 for the disease allele (C) at the HLA-linked locus and of 0.648 for the disease allele (d) at the HLA-unlinked locus. Assuming that CCdd homozygotes are always affected and that only carriers of C who are homozygous dd can be affected, the disease was found to be completely penetrant in Ccdd heterozygotes. These results support dominance at the HLA-linked locus conferring susceptibility to CD. Possible reasons for the discrepancy between the West of Ireland and other populations are discussed.

Genome‐wide linkage analysis for celiac disease in North American families

“…However, there is likely to be at least one other gene contributing to CD [Greenberg et al, 1982;Pena et al, 1984;Risch, 1987;Hernandez et al, 1991]. In addition, because CD is an autoimmune disorder, environmental components contributing to the disease cannot be ruled out.…”

Genome screening of coeliac disease

“…On the basis of segregation studies, homozygosity at an HLA unlinked locus is a perquisite for developing coeliac disease. [24][25][26] Hence, there is a possibility that in any large family two copies of a mutation may be segregating if the population frequency of the disease allele is high. Practically, the composition of families used in linkage analysis will always depend on what can efficiently be collected.…”

HLA‐DR, DQ genotypes of celiac disease patients and healthy subjects from the West of Ireland

“…Our data reaffirm the observation that CD has one of the strongest class I1 HLA associations of any illness. At least one other gene (not linked to HLA) is required, and this gene appears to have a recessive genetic expression (29,30). When the additional gene(s) has been identified (perhaps by genome screening using microsatellite polymorphisms), CD may take its place as a uniquely well-characterized HLA associated immune-mediated disease (i.e.…”