Celiac Disease and HLA in a Bedouin Kindred

Abstract

We report the prevalence of celiac disease (CD) and its relationship with other autoimmune diseases and HLA haplotypes in a Bedouin kindred. Of 175 individuals sampled and typed for autoantibodies and HLA class II genotypes, six (3.4%) members had CD and an additional ten (5.7%) members tested positive for autoantibodies to transglutaminase (TgAA+). Several CD/TgAA+ relatives also had islet cell antigen or adrenal autoimmunity. Affected relatives are more closely related than expected from the pedigree relationships of all family members and were more often the offspring of consanguineous marriages. Individuals with CD or TgAA+ were enriched for DRB1 * 0301-DQA1 * 0501-DQB1 * 0201, a haplotype previously reported as high risk for celiac disease. There was also an increased frequency of DQB1 * 0201/DQB1 * 0201 homozygotes among affected relatives. We found no evidence that DRB1 * 0701-DQA1 * 0201-DQB1 * 0201/DRB1 * 11-DQA1 * 0501-DQB1 * 0301 is a high risk genotype, consistent with other studies of Arab communities. In addition, a nonparametric linkage analysis of 376 autosomal markers revealed suggestive evidence for linkage on chromosome 12p13 at marker D12S364 (NPL=2.009, p=0.0098). There were no other significant results, including the HLA region or any other previously reported regions. This could reflect the reduced power of family-based linkage and association analyses in isolated inbred populations.Correspondence information for E. Eller:,Barbara Davis Center for Childhood Diabetes, Campus Box B-140, University of Colorado Health Sciences Center, P.O. 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. Chromosome region 2q33, which contains a cluster of immune system-related genes including CTLA-4, was originally implicated by Holopainen and colleagues [9] and confirmed in a large linkage study of European families [19] and subsequent association studies [20,21]. With 11p11, the initial finding occurred in a study of Irish CD patients [22] and was confirmed in two subsequent studies of multiplex families from the UK [10,11]. Evidence for the 5q31-33 region is suggestive in two studies of Italians and of Scandinavians [8,12], but when a meta-analysis was performed of data pooled from four linkage studies the evidence for 5q31-33 reached significance [16].In this paper we describe the relationship of celiac disease, type 1 diabetes (T1D) and HLA DRB1-DQA1-DQB1 haplotypes and present t...

Differential effects of DRB1*0301 and DQA1*0501-DQB1*0201 on the activation and progression of islet cell autoimmunity

“…12,[34][35][36] We previously reported significant clustering and coclustering of islet and celiac autoimmunity in the kindred, explained in part by a common association with DR3-DQ2, which was present in all of 16 relatives with celiac autoimmunity. 37 Interestingly, the frequency of DR3-DQ5 was higher among relatives with celiac autoimmunity compared to unaffected relatives with DR3-DQ2 (0.19 vs 0.05 among DR3-DQ2 relatives with and without celiac autoimmunity), although the difference was not statistically significant (Po0.10) and there was no difference in the distribution of class II haplotypes between relatives with celiac disease and relatives with celiac-related autoantibodies without celiac disease. Nevertheless, the results are consistent with the hypothesis that DR3 is primarily responsible for the association of celiac and islet autoimmunity in the kindred whereas DQ2 determines more specific aspects of phenotypic expression including the manifestation, age of onset and severity of autoimmune disease.…”

An autosomal genome-wide screen for celiac disease in Bedouin families

“…40 However, in this analysis, we saw no evidence for linkage to HLA across the 18 pedigrees. Eller et al 15 performed a genome-wide linkage analysis of one large Bedouin pedigree with CD and also did not find evidence of linkage to the HLA region. They hypothesized that the high frequency of the CDassociated haplotypes resulted in an inability to determine alleles that are identical by descent versus by state, reducing the power to detect linkage.…”

Variants within protectin (CD59) and CD44 genes linked to an inherited haplotype in a family with coeliac disease

“…Conversely, individual III: 10 carried both the high-risk HLA-DQ2.5 and the CD59 variant, but still he was phenotypically normal. This suggests that other genetic and/or environmental factors, besides HLA and the CD59 A recent study performed in Bedouin kindred also reported absence of linkage to the HLA locus, where a higher frequency of high-risk HLA alleles was observed in affected members, thus negative linkage was probably because of a lack of distinction between alleles that were identical by descent from those that were identical by state (5). Besides this, there could be various reasons why we failed to detect linkage at the HLA locus including low marker density (closest marker D6S1051 being approximately 4 cM away), no difference in the inheritance pattern of HLA alleles between affected/nonaffected members and because in this family risk for disease was increased by HLA alleles being in trans and not in cis.…”

“…A number of linkage and association studies have been carried out to try to identify genes that might increase the individual's susceptibility for CD. The human leukocyte antigen (HLA) locus on chromosome 6 was the most commonly reported locus (2)(3)(4), although, recently, linkage to this region was not confirmed in a large Bedouin family (5). Other chromosomal loci were identified by genomewide linkage scans including 5q31-q33 (6), 10q23, 15q26, 16q23, 19p13.1, 6p12, 2q and 11p11 (7)(8)(9), with the latter being further confirmed in a later study (10).…”