P. Holopainen et al., CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family-based association study, TISSUE ANTI, 53(5), 1999, pp. 470-475
Celiac disease (CD) is a common small intestinal injury caused by sensitivi
ty to gliadin in genetically-predisposed individuals. The only susceptibili
ty locus established is the HLA-DQ. We tested whether the chromosomal regio
n of the CD28/CTLA4 genes on 2q33 is linked to CD. These genes encode recep
tors regulating the T-lymphocyte activation. Recently, this gene region was
reported to be linked to the susceptibility to many autoimmune diseases, i
ncluding insulin-dependent diabetes (IDDM12locus). It is thus an obvious ca
ndidate locus also for CD, since the intestinal injury is mediated by the i
mmune system. Genetic linkage between seven marker loci in this gene region
and CD was studied in 69 Finnish families. In the multipoint linkage analy
sis, 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 combi
ned 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 as
sociation in these 100 families (P=0.0001). The transmission/disequilibirum
test (TDT) for locus D2S116 gave preliminary evidence for preferential mat
ernal 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 in
dicate that the CD28/CTLA4 gene region can contain a novel susceptibility l
ocus for CD and support the hypothesis that CD has an immune system-mediate
d component Like the HLA, the CD28/CTLA4 genes appear to be associated with
genetic susceptibility to various autoimmune diseases.