Nistico et al. (1996) identified a 49A-G transition polymorphism in exon 1 of the CTLA4 gene, resulting in a thr17-to-ala (T17A) substitution. Among 529 Belgian control individuals, the frequencies for the 49A and 49G alleles were 68% and 32%, respectively.
In 48 Italian families in which at least 2 sibs were affected with type 1 diabetes mellitus (T1D12; 601388), Nistico et al. (1996) found evidence for preferential transmission of the 49G allele to affected offspring. Similar findings were obtained for 44 Spanish IDDM families, but not for families from the United Kingdom, Sardinia, or the US. Marron et al. (1997) found highly significant transmission of the 49G allele in patients with IDDM in 3 Mediterranean European populations (Italian, Spanish, and French), a Mexican American population, and Korean population. However, significant heterogeneity was observed; datasets of British, Sardinian, and Chinese populations did not show any deviation for the A/G polymorphism, whereas the Caucasian American dataset showed a weak transmission deviation. The results suggested that a true IDDM susceptibility locus is located near CTLA4.
Donner et al. (1997) found that patients with Hashimoto thyroiditis (140300) had a significantly higher number of the 49G allele compared to controls, both as homozygotes (22% vs 15%) and heterozygotes (53% vs 46%), and less of the A allele compared to controls as homozygotes (25% vs 39%; P less than 0.04). They also found that the phenotypic frequency for the G allele was significantly higher in patients (75%), compared with controls (61%), P less than 0.03. Whereas Addison disease (240200) subjects did not differ significantly from controls, those carrying the susceptibility marker, human leukocyte antigen DQA1*0501, had a significantly higher frequency of the G allele than controls with the same DQA1 allele (P less than 0.05). Donner et al. (1997) concluded that the 49G allele (ala17) of the CTLA4 gene conferred genetic susceptibility to Hashimoto thyroiditis, whereas this finding only applied to the subgroup of patients with Addison disease carrying DQA1*0501+.
Vaidya et al. (1999) presented evidence that the alanine-17 allele also confers susceptibility to thyroid-associated orbitopathy in patients with Graves disease.
Rau et al. (2001) analyzed the CTLA4 49A/G polymorphism in 300 Caucasian patients with type 2 diabetes (125853) and 466 healthy controls. All patients were negative for glutamate decarboxylase and islet cell antibodies. The distribution of alleles and the genotypic and phenotypic frequencies were similar among patients and controls. However, analysis of clinical and biochemical parameters revealed a tendency of GG (alanine/alanine) toward younger age at disease manifestation, lower body mass index, and basal C-peptide level, as well as earlier start of insulin treatment and higher portion of patients on insulin. Patients with the AA genotype were significantly less likely to develop microangiopathic lesions. The authors concluded that CTLA4 ala17 does not represent a major risk factor for type II diabetes.
Zalloua et al. (2004) evaluated the role of the CTLA4 exon 1 A49G polymorphism as a risk factor for type 1 diabetes in the Lebanese population. The CTLA4 G allele was found to be more frequently present in patients with type 1 diabetes (32.4%) than in control individuals (24.5%). The GG genotype was also significantly higher among patients (12.6%) than in controls (4.2%). Furthermore, in HLA-DQB1*0201-positive patients with type 1 diabetes, the GG and AA genotypes were higher and lower, respectively, than those found in control individuals.
In a metaanalysis of 7 published studies and their own study, Barreto et al. (2004) examined the association between the 49A-G SNP and systemic lupus erythematosus (152700). The authors found that individuals with the GG genotype were at significantly higher risk of developing SLE; carriers of the A allele had a significantly lower risk of developing the disease, and the AA genotype acted as a protective genotype for SLE.
In a metaanalysis of 14 independent studies testing association between CTLA4 polymorphisms and SLE, Lee et al. (2005) confirmed that the 49A-G polymorphism is significantly associated with SLE susceptibility, particularly in Asians.
Djilali-Saiah et al. (1998) found a significantly increased frequency of the 49A allele in 101 French Caucasian patients with celiac disease compared to controls (82.2% vs 65.8%, p less than 0.0001), reflecting the increased frequency of A/A homozygotes among patients compared with controls (68.3% vs 47.7%, p = 0.002). The effect remained after stratification of patients according to their DR-DQ phenotype. The authors concluded that the A allele of the CTLA4 position 49 polymorphism conferred an HLA-independent predisposition to celiac disease.
Naluai et al. (2000) analyzed the 49A/G polymorphism in 107 Swedish and Norwegian families with celiac disease and found a significant association, with preferential transmission of the 49A allele by the transmission disequilibrium test (p less than 0.007). Nonparametric linkage analysis yielded a score of 2.1 (p = 0.018), suggesting that the CTLA4 region is a susceptibility region in celiac disease. Naluai et al. (2000) noted that, of several chronic inflammatory diseases exhibiting associations to the CTLA4 49A/G polymorphism, celiac disease is the only one associated with the A allele, suggesting that the 49A/G alleles of CTLA4 are in linkage disequilibrium with 2 distinct disease-predisposing alleles with separate effects.
