CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family‐based association study
- 1 May 1999
- journal article
- research article
- Published by Wiley in Tissue Antigens
- Vol. 53 (5), 470-475
- https://doi.org/10.1034/j.1399-0039.1999.530503.x
Abstract
Celiac disease (CD) is a common small intestinal injury caused by sensitivity to gliadin in genetically‐predisposed individuals. The only susceptibility locus established is the HLA‐DQ. We tested whether the chromosomal region of the CD28/CTLA4 genes on 2q33 is linked to CD. These genes encode receptors regulating the T‐lymphocyte activation. Recently, this gene region was reported to be linked to the susceptibility to many autoimmune diseases, including insulin‐dependent diabetes (IDDM12locus). It is thus an obvious candidate locus also for CD, since the intestinal injury is mediated by the immune system. Genetic linkage between seven marker loci in this gene region and CD was studied in 69 Finnish families. In the multipoint linkage analysis, the highest non‐pararametric linkage score (NPL) was 1.75 (P=0.04) for D2S116, suggesting weak linkage for this candidate locus. To evaluate this finding, an additional 31 families were typed for all markers. In the combined set of 100 families the NPL score for marker D2S116 was 2.55 (P=0.006) and for other markers 1.90–2.47 (P=0.029–0.007), supporting genuine linkage at this region. Significantly, locus D2S116 also showed a clear allelic association in these 100 families (P=0.0001). The transmission/disequilibrium test (TDT) for locus D2S116 gave preliminary evidence for preferential maternal non‐transmission of allele *136 to patients (TDTmax=8.3; P<0.05). No paternal deviation was found suggesting that the effect of the locus might be mediated by a sex‐dependent factor protective against CD. Our results indicate that the CD28/CTLA4 gene region can contain a novel susceptibility locus for CD and support the hypothesis that CD has an immune system‐mediated component. Like the HLA, the CD28/CTLA4 genes appear to be associated with genetic susceptibility to various autoimmune diseases.Keywords
This publication has 27 references indexed in Scilit:
- The Emerging Role of CTLA-4 as an Immune AttenuatorImmunity, 1997
- Genetic contribution of the HLA region to the familial clustering of coeliac diseaseAnnals of Human Genetics, 1997
- A CTLA‐4 gene polymorphism is associated with both Graves' disease and autoimmune hypothyroidismClinical Endocrinology, 1997
- The Complexities of T‐Cell Co‐stimulation: CD28 and BeyondImmunological Reviews, 1996
- The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes RegistryHuman Molecular Genetics, 1996
- Genetic dissection of complex traits: guidelines for interpreting and reporting linkage resultsNature Genetics, 1995
- B7-1 and B7-2 costimulatory molecules activate differentially the Th1/Th2 developmental pathways: Application to autoimmune disease therapyCell, 1995
- CTLA-4 gene polymorphism associated with Graves' disease in a Caucasian populationJournal of Clinical Endocrinology & Metabolism, 1995
- Gliadin-specific, HLA-DQ(alpha 1*0501,beta 1*0201) restricted T cells isolated from the small intestinal mucosa of celiac disease patients.The Journal of Experimental Medicine, 1993
- Intestinal gluten sensitivity: snapshots of an unusual autoimmune-like diseaseImmunology Today, 1992