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

Abstract

Celiac disease (CD) is a common chronic inflammatory disorder of the small intestine with a multifactorial aetiology. HLA is a well-known risk factor, but other genetic factors also influence disease susceptibility. To identify the genes involved in this disorder, we performed a genome-wide scan on 106 well-defined Swedish and Norwegian families with at least two affected siblings. We investigated familial segregation of 398 microsatellite markers, and utilised non-parametric linkage analysis. The strongest linkage with disease was found to the HLA locus (6p) (P50.000006). There were eight regions besides HLA with a point wise P value below 0.05. Among these eight regions were 11q and 5q, both of which have been suggested in several linkage studies of independent celiac disease families. We also performed a stratification analysis of families according to their HLA genotypes. This resulted in significant differences on chromosome 2q. These results indicate that 11q, 5q and possibly also 2q are true susceptibility regions in CD. European Journal of Human Genetics (2001) 9, 938 ± 944.

A family-based study does not confirm the association of MYO9B with celiac disease in the Italian population

“…5 Apart from the HLA region, only 5q31-33, with a maximum Zlr ¼ 4.39 (P ¼ 6 Â 10 À6 ), showed genome-wide significant linkage according to standard thresholds. 6 Linkage of CD to this region was originally identified by Greco et al 7 and was also found by Naluai et al 8 and Liu et al 9 Evidence for a risk factor in 2q33 (CELIAC3), likely corresponding to the CTLA4/ICOS genes, comes from association studies mainly in Northern Europe populations. 10 The CELIAC4 locus was mapped to 19p13.1 with a maximum logarithm of odds score ¼ 4.43 in a cohort of 101 affected sib pairs belonging to 82 Dutch families.…”

Searching for genes influencing a complex disease: the case of coeliac disease

“…Still, some linkage to the region has been reported in a few studies 68,100,74 and most published studies in CD do show signs of association as well. 100,74,101 -111 However, they are not completely congruent.…”

“…64 These were the second, third, fourth and fifth studies published. 62,66,68,69 The raw data consisted of genotypes from 442 families; 2025 individuals of whom 1056 are affected. The results pointed to chromosome 5q31 -33 as being the only significant locus in these families apart from HLA ( Figure 2 Figure 1 The HLA-DQ2 ab heterodimer encoded in cis and in trans.…”

“…Genotypes at HLA have also been suggested to influence the outcome of susceptibility to alleles in CTLA4. 68,110 Other non-HLA candidate genes potentially involved in CD We searched PubMed (www.pubmed.gov) for 'genetic AND (celiac OR coeliac) AND (associated OR association)' and the database returned 405 hits. The genes presented in Table 3 are implicated from candidate gene studies, where a reported significance was below a P-value of 0.05.…”

Celiac Disease and HLA in a Bedouin Kindred

“…Box 6511, Aurora, Colorado 80045, The fact that HLA-specific relative risk to siblings is 2.3-5.5 [1] compared to the overall relative risk to siblings of 30-60 suggests that non-HLA genes play a large role in the etiology of CD. Several linkage studies, either of candidate genes or whole genome screens, to find non-HLA genes have been performed (e.g., [2,[8][9][10][11][12][13][14][15][16][17][18]), but few regions have been replicated, and replication has occurred only in studies of European or European-derived populations. The exceptions are the HLA region, which consistently shows extremely strong evidence of linkage to CD, and three regions, 2q33, 11p11 and 5q31-33.…”