Linkage analysis of candidate regions for coeliac disease genes

Abstract

A strong HLA association is seen in coeliac disease [specifically to the DQ(alpha1*0501,beta1*0201 heterodimer], but this cannot entirely account for the increased risk seen in relatives of affected cases. One or more genes at HLA-unlinked loci also predispose to coeliac disease and are probably stronger determinants of disease susceptibility than HLA. A recent study has proposed a number of candidate regions on chromosomes 6p23 (distinct from HLA), 6p12, 3q27, 5q33.3, 7q31.3, 11p11, 15q26, 19p13.3, 19q13.1, 19q13.4 and 22cen for the location of a non-HLA linked susceptibility gene. We have examined these regions in 28 coeliac disease families by linkage analysis. There was excess sharing of chromosome 6p markers, but no support for a predisposition locus telomeric to HLA. No significant evidence in favour of linkage to coeliac disease was obtained for chromosomes 3q27, 5q33.3, 7q31.3, 11p11, 19p13.3, 19q13.1, 19q13.4 or 22cen. There was, however, excess sharing close to D15S642. The maximum non-parametric linkage score was 1.99 (P = 0.03). Although the evidence for linkage of coeliac disease to chromosome 15q26 is not strong, the well established association between coeliac disease and insulin dependent diabetes mellitus, together with the mapping of an IDDM susceptibility locus (IDDM3) to chromosome 15q26, provide indirect support for this as a candidate locus conferring susceptibility to coeliac disease in some families.

Genome-wide linkage analysis of Scandinavian affected sib-pairs supports presence of susceptibility loci for celiac disease on chromosomes 5 and 11

“…X X Sib-pair* (Naluai et al) X X Extended and sib-pairs (Zhong, 1996) 10 X X X X X Extended King, 2000) 9 X X X Extended (Houlston, 1997) 12 X *Our study.…”

“…These regions were subsequently genotyped in all families (Group A and B). In addition all families were genotyped for chromosomes 5, 11 and 15 detected in previous genome-wide scans, 8,10,12,24 the HLA region on chromosome 6, the region 2q33 containing CTLA-4 and chromosome 20 containing the gene for tissue transglutaminase. Mean spacing of the microsatellite markers was 10 cM except for within the HLA and CTLA4 regions where several markers were typed over a 2 ± 5 cM region.…”

“…Also a few regions have been replicated in two independent extended pedigree studies each. 10,12 (Table 3) …”

“…First, chromosomes implicated by the previously published CD genome-wide screens: chromosomes 5, 11 and 15. 8,10,12,24 Second, novel chromosomes identified from Group A that showed NPL-values of 2.0 or more and third, chromosome 2 and 20 because of the location of two candidate genes, suggested to be involved in CD: cytotoxic T-lymphocyte associated protein (CTLA4) and tissue transglutaminase (TG2). (Figure 1).…”

Genetic linkage and association studies of Type I diabetes: challenges and rewards

“…Recent research indicates that several of the non-HLA regions linked to Type I diabetes also show linkage to other autoimmune diseases, suggesting common pathogenic pathways shared by Type I diabetes and these other disorders [127,128]. For example, the IDDM3 region on chromosome 15q26 has been reported to be linked to coeliac disease [129,130], the IDDM6 region on chromosome 18q21 has been reported to be linked to Graves disease [131] as well as multiple sclerosis and rheumatoid arthritis [69], the IDDM8 region on chromosome 6q27 has been reported to be linked to rheumatoid arthritis [132], the IDDM12 (CTLA4) region on chromosome 2q33 has been reported to be linked to coeliac disease [133,134], Graves disease [78,135], multiple sclerosis [136] and rheumatoid arthritis [137,138], the IDDM16 region on chromosome 14q32 has been reported to be linked to multiple sclerosis [139], and the chromosome 1q42 region containing an unnamed diabetes locus has been reported to be linked to systemic lupus erythematosus [140,141] (for additional examples, see [128]). Although some of these co-localizations could be coincidental, the possibility remains that at least a few IDDM loci would be more accurately called autoimmunity susceptibility loci.…”