Previous studies have found CD247, a T cell receptor gene, to be within genomic risk regions for celiac disease (CeD). Moreover, the CD247 SNP rs864537 has been associated with CeD risk by season of birth and with genotype-dependent CD247 mRNA expression in whole blood at 3 and 6 months. Since T cells are in the center of CeD pathogenesis, genetic variation affecting their function is of special interest in understanding the development of the disease. The aim of our study was to both identify CD247 SNPs associated with CeD and assess the functional effect of rs864537 on T cell activation.
Genotypic association studies with SNPs spanning 500 kb upstream and downstream of CD247 revealed two SNPs (rs6670426, rs863455) associated with CeD in the whole population, and six (rs864537, rs704853, rs12737372, rs12095738, rs704856, rs2982482) associated with CeD in the high HLA risk group (HLA2.5/2.5 or 2.5/2.2). For analysis of rs864537 effect on T cell activation, PBMCs from genotyped patients and controls were stimulated overnight, followed by flow cytometric analysis. There were no significant differences in CD247 protein expression in CD3+ T cells according to genotype nor between CeD and controls. Assessing T cell activation after stimulation, levels of activation marker CD69 were not significantly different according to genotype or disease status.
We found a total of eight SNPs associated with CeD, although the p-values were nominally significant, and therefore would require verification in a larger cohort. Regardless, CD247 may present a relevant candidate for risk of CeD. The functional effect of rs864537 variants on T cells may be carried out through more complex mechanisms than protein expression levels. It is also possible that the effects have a temporal dependence, asserting their effects during crucial periods development.