CTLA-4 gene polymorphisms in systemic lupus erythematosus: a highly significant association with a determinant in the promoter region

Abstract

The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4; CD 152) is a negative regulator of T-lymphocyte activation. Particular genotypes of the locus encoding the CTLA-4 glycoprotein have been associated with susceptibility to various autoimmune diseases. To determine their role in susceptibility to systemic lupus erythematosus (SLE), we genotyped 130 patients and 200 ethnically matched controls for allelic determinants at four polymorphic sites, viz., three in the promoter region at positions -1722 (T/C), -1661 (A/G), and -318 (C/T), and one within the first exon at position +49 (A/G), by restriction fragment length polymorphism methods. All genotype frequencies were in Hardy-Weinberg equilibrium. The genotypes at position -1722 were significantly associated with SLE. The frequency of T/T homozygotes was higher in patients than in controls (56% vs 33%, P=0.00003). Conversely, the frequencies of C/C homozygotes and C/T heterozygotes were higher in controls than in patients (15.5% vs 7%, P=0.019; 51.5% vs 37%, P=0.009). Genotypes at positions +49, -318, or -1661 were not significantly associated with SLE. These results show that allelic variation at the -1722 site influences susceptibility to SLE. This is the first report to our knowledge implicating CTLA-4 genotypes at the -1722 locus in susceptibility to any disease.

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…Importantly elevation in CLTA-4 is not a universal feature of peripheral T cells in patients with autoimmune rheumatic diseases since T cells from RA and PsA showed normal expression levels. Additional support for a role for CTLA-4 in the pathogenesis of lupus comes from genetic studies linking CTLA-4 with SLE [20][21][22][23][24][25][26][27]. One of these polymorphisms impairs the upregulation of CLTA-4 upon T-cell activation [45].…”

“…Genetic studies linking CTLA-4 with SLE provide an additional rationale to investigate the role of CTLA-4 in the pathogenesis of this disease. Indeed, an association between CTLA-4 polymorphisms and lupus has been found in numerous studies around the world [20][21][22][23][24][25][26][27]. In addition, increased CTLA-4 expression has been noted in T cells from patients with SLE [28].…”

Association of CTLA-4 gene promoter polymorphisms with systemic sclerosis in Iranian population

“…The impact of CTLA-4 on T-cell polarization is further supported by a shifting towards Th2 polarization in germline CTLA-4-deficient mice. 18 Several studies have shown that specific CTLA-4 gene polymorphisms confer susceptibility to several autoimmune diseases, such as Graves' disease, 19 type 1 diabetes, 20 systemic lupus erythematosus 21,22 and SSc. 6,12 In a recent study, we were unable to show any association between CTLA-4 þ 49 polymorphism and SSc in Iranian population.…”

Haplotype tagging efficiency in worldwide populations in CTLA4 gene

“…þ 49 G has been related to multiple diseases, including type 1 diabetes (T1D), 9 rheumatoid arthritis, 10 multiple sclerosis, 11 Graves' disease, 12 asthma, 13 or systemic sclerosis. 14 SNP À1722 has been related to lupus erythematosus in two contradictory studies, 15,16 while the À1661 G variant has been suggested to be associated with T1D. 17 Also, SNPs 6230 G, 10 717 G, 10 242 G and 12 310 T have been related to GD, autoimmune hypothyroidism and T1D.…”