A pedigree-based linkage study of coeliac disease: Failure to replicate previous positive findings

Georgetown University, Washington, Washington, D.C., United States
Annals of Human Genetics (Impact Factor: 2.21). 02/1998; 62(Pt 1):25-32. DOI: 10.1046/j.1469-1809.1998.6210025.x
Source: PubMed


Coeliac Disease (CD) is a gluten sensitive enteropathy characterised by villous atrophy and crypt cell hyperplasia. There is a tight HLA association between CD and the HLA DQ alleles DQA1*0501, DQB1*0201 (DQ2), arranged in either cis- or trans- configuration, are found in 98.9% of cases in Northern European populations and 80% in Greeks and Ashkenazi Jews resident in Israel. We have previously shown that the HLA alleles and CD do not co-segregate in families multiply affected with CD, suggesting that the HLA association is entirely due to the necessity to have these normal DQ alleles for CD to manifest, and that the main genetic predisposition lies at a locus other than the MHC. It is therefore possible to conduct genetic linkage studies in order to isolate the non HLA genes which predispose to CD. Recently a group conducted a genome screen for the non HLA genes in an affected sib-pair analysis and identified four non HLA loci with positive lod scores. We examined these loci using a pedigree based linkage study. Our pedigree sample consisted of a cohort of 21 families with 60 affected individuals and 125 unaffected family members. We used 11 microsatellite markers at the loci implicated and analysed the genotype data using both MLINK and MFLINK to detect linkage. The MLINK and MFLINK analyses did not provide any evidence to support the earlier findings, although the difficulties involved in analysing complex diseases mean that one cannot be certain that these regions do not harbour susceptibility loci, at least in some families.

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Available from: Peter Mark Brett, Sep 25, 2014
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    • "In addition to the HLA region that demonstrated strong linkage to CD, six other regions—a secondary region on 6p, as well as 7q31, 11p11, 15q26, 19q, and 22cen—were reported to yield suggestive evidence for linkage. Subsequently, the non-HLA regions that were implicated from the Irish study were reexamined by Houlston et al. (1997) and Brett et al. (1998), by use of independent sample sets. Although the former study showed moderate evidence for linkage in the 15q26 region, the latter study did not find any evidence for linkage from these regions. "
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    ABSTRACT: Celiac disease (CD), or gluten-sensitive enteropathy, is a common multifactorial disorder resulting from intolerance to cereal prolamins. The only established genetic susceptibility factor is HLA-DQ, which appears to explain only part of the overall genetic risk. We performed a genomewide scan of CD in 60 Finnish families. In addition to strong evidence for linkage to the HLA region at 6p21.3 (Z(max)>5), suggestive evidence for linkage was found for six other chromosomal regions--1p36, 4p15, 5q31, 7q21, 9p21-23, and 16q12. We further analyzed the three most convincing regions--4p15, 5q31, and 7q21--by evaluation of dense marker arrays across each region and by analysis of an additional 38 families. Although multipoint analysis with dense markers provided supportive evidence (multipoint LOD scores 3.25 at 4p15, 1.49 at 5q31, and 1.04 at 7q21) for the initial findings, the additional 38 families did not strengthen evidence for linkage. The role that HLA-DQ plays was studied in more detail by analysis of DQB1 alleles in all 98 families. All but one patient carried one or two HLA-DQ risk alleles, and 65% of HLA-DQ2 carriers were affected. Our study indicates that the HLA region harbors a predominant CD-susceptibility locus in these Finnish families.
    Full-text · Article · Jan 2002 · The American Journal of Human Genetics
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    • "These associations may be explained by common gene(s) responsible for both diseases or the diseases may share a similar autoimmune pathogenic mechanism [19]. There have been several European studies to localize genes for CD, but no significant evidence for linkage has been reported other than at HLA [20-29]. "
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    ABSTRACT: Background Celiac disease has a strong genetic association with HLA. However, this association only explains approximately half of the sibling risk for celiac disease. Therefore, other genes must be involved in susceptibility to celiac disease. We tested for linkage to genes or loci that could play a role in pathogenesis of celiac disease. Methods DNA samples, from members of 62 families with a minimum of two cases of celiac disease, were genotyped at HLA and at 13 candidate gene regions, including CD4, CTLA4, four T-cell receptor regions, and 7 insulin-dependent diabetes regions. Two-point and multipoint heterogeneity LOD (HLOD) scores were examined. Results The highest two-point and multipoint HLOD scores were obtained in the HLA region, with a two-point HLOD of 3.1 and a multipoint HLOD of 5.0. For the candidate genes, we found no evidence for linkage. Conclusions Our significant evidence of linkage to HLA replicates the known linkage and association of HLA with CD. In our families, likely candidate genes did not explain the susceptibility to celiac disease.
    Full-text · Article · Feb 2001 · BMC Medical Genetics
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    • "A 70-100 % disease concordance in monozygotic twins and 10 % prevalence in ®rstdegree relatives (Sollid & Thorsby, 1993) can be linked strongly to the HLA locus on chromosome 6, an observation attributable to the very high prevalence (590 %) of DQ2 positive individuals in the celiac patient population. Since 20-25 % of normal individuals possess the HLA-DQ2 allele, some have proposed that celiac disease is initiated by a non-HLA disease gene(s) in a DQ2-positive environment (Petronzelli et al., 1997; Houlston et al., 1997; Brett et al., 1998; Greco et al., 1998; Bevan et al., 1999). This is in keeping with weaker apparent linkage to proposed non-HLA risk factors in the terminal portions of chromosomes 5 and 11 (Greco et al., 1998), or on chromosome 2 (Holopainen et al., 1999) among other proposed risk factors (chromosomes 6p, 11p, 7q, 22, 15q, 19; Zhong et al., 1996). "
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    ABSTRACT: Celiac disease is a wheat gliadin-promoted disorder that displays a complex genetic susceptibility associated with HLA-DQ2, and one or more unknown factor(s), possibly gliadin-like. The presence of mammalian proteins with partial gliadin similarity was suggested by transglutaminase-independent multi-tissue reactivity of gliadin-immunopurified antibodies from celiac patients. No non-plant sequence, however, was identified in gliadin peptide epitope searches of non-redundant and EST databanks via TBLASTN, BLASTP and FASTA, even at E values as high as 20. Therefore, an alpha-gliadin cDNA screen of human cDNA and genomic libraries was undertaken, an approach in keeping with positive human Northern and Southern analyses with the same probe. Four distinct cDNA clones were obtained, the most stringent of which (3.2 and 5.1 kb) were novel, and featured potential open reading frames with high gliadin domain II and domain IV homologies (BestFit quality scores >/=295 and 322, respectively, versus random value 126-127). Both were also homologous to ESTs. An additional 5' gliadin oligonucleotide screen identified the widely distributed cytoplasmic protein acyl coA hydrolase whose homology was restricted to the oligonucleotide probe (BestFit quality=215 versus 100 for random); and achaete-scute homologous protein, which displays particularly high gliadin domain II homology (BestFit quality 316 versus 111 for random). Genomic screening uncovered 16 positives, one of which was the ALR gene, whose similarity to three of gliadin's five domains (I, II and IV; BestFit quality 322-473 versus 121-154 for random) was remarkable. More extensive was novel genomic clone 2, with fragments hybridizing to cDNA probes approximating gliadin domains I, II+IV, V and the gliadin 5' untranslated region, and mapping by FISH to 19q13.11-13. 12. Two fragments were sequenced; one was exonic, as predicted by four different programs; and test oligonucleotides suggested widespread 4 and/or 2 kb mRNA expression, even at high stringency (t(m)-8.8 deg. C). Taken together, it is apparent that several genes with partial gliadin homology exist in the human genome. Many bear gliadin-like T-cell epitopes, are expressed in intestine and, like transglutaminase, are cytoplasmic. Glutamine to glutamic acid or other mutation within such epitopes followed by injury or infection-related release could explain enhanced disease susceptibility in affected families.
    Full-text · Article · Jul 2000 · Journal of Molecular Biology
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