Coeliac disease: investigation of proposed causal variants in the CTLA4 gene region

Abstract

Coeliac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically predisposed individuals. Patients with CD have an increased prevalence of other autoimmune disorders, including type 1 diabetes (T1D) and Graves' disease (GD). CD shares with these conditions certain HLA susceptibility alleles. A number of studies have also shown association of autoimmune diseases, including CD, with the CD28-cytotoxic T lymphocyte antigen 4 (CTLA4)-inducible costimulator (ICOS) region of chromosome 2q33, but until recently the precise causal variant has remained unknown. Recently, it was shown that, in GD, CT60 (+6230G>A), a single nucleotide polymorphism (SNP) at the end of the CTLA4 transcript, is associated with an alteration in the ratio of splice forms of the CTLA4 gene and that this ratio affects disease susceptibility. A similar but weaker association was found with T1D. There is also an independent association of GD and T1D with the SNP MH30 (-23 327G>C), which possibly affects promoter region function. Hypothesizing that CT60 and MH30 may be causal variants in other autoimmune disorders, we investigated these SNPs in CD using 149 family trios and 100 unrelated/unaffected controls. No association was detected with either SNP using both the transmission disequilibrium test (TDT) and case-control methods. Our study appears to have good power to detect moderate genetic effects, but possibly these SNPs exert too weak an effect on risk of CD to have been detected in our sample. Alternatively, the previously noted association of CD with the CTLA4 gene region may be due to different causal variants. Unlike T1D and GD, CD is not a true autoimmune disease, and CD has different associations at the CTLA4 exon 1 SNP +49G>A from all other autoimmune disorders. MH30, CT60, and other SNPs in the region may still warrant further investigation in other CD samples.

CTLA4/CT60 polymorphism is not relevant in susceptibility to autoimmune inflammatory intestinal disorders

“…Our analyses in celiac disease case-control and familial cohorts have a 50% power to detect the effect of a polymorphism, conferring an OR of 2.0 (assuming an allele frequency of 50%). In accordance with our findings, recent studies have observed no association [20,26] or borderline significance [27] between CTLA4/ CT60 polymorphisms and celiac disease predisposition. All these observations suggest that the chromosome 2q33 linked susceptibility in celiac disease might be attributed to another genetic marker.…”

“…Table 1 lists the allelic distribution of CTLA4/CT60 polymorphism in patients with IBD and controls. The allelic distribution in controls was similar to that obtained in other Caucasian populations [20,21]. Allele frequencies were in Hardy-Weinberg equilibrium in both the patient and control groups.…”

“…Most of the studies have analyzed polymorphisms Ϫ318C/T, ϩ49A/G in exon 1 and the AT n microsatellite, without consistent findings in all populations [20]. The present study found no association between CTLA4/CT60 polymorphism and celiac disease susceptibility.…”

Celiac Disease and Autoimmune Thyroid Disease

“…89,90 Outside the HLA region, both CD and autoimmune thyroid disease are reported to be associated with the gene encoding cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), a candidate gene for conferring susceptibility to thyroid autoimmunity. [91][92][93] More recently, a study showed that 10 of 14 patients with Hashimoto's thyroiditis had genotypes compatible with CD (three patients had DQ heterodimer A1*0501, B1*0201, four had DRB1*04 and one had A1*0101, B1*0501). Six of these 14 patients showed an increased density of γδ + T-cell receptor-bearing intra-epithelial lymphocytes and signs of mucosal T-cell activation, both typical of CD.…”

Characterization of CD28, CTLA4, and ICOS Polymorphisms in Three Brazilian Ethnic Groups

“…The influence of genetic polymorphisms of these immunoregulatory molecules on immune responses, susceptibility to disease, and transplant outcome has gained increasing interest in recent years. Most association studies between autoimmune diseases and the 2q33 region have focused mainly on CTLA4 gene polymorphisms [3,4]. However, because CD28, CTLA4,and ICOS loci are in close proximity, possible linkage disequilibrium (LD) between the alleles of these genes should be taken into account.…”