Polymorphism of the promoter region and exon 1 of the CTLA4 gene in endemic pemphigus foliaceus (fogo selvagem)

Abstract

Endemic pemphigus foliaceus (EPF) is an autoimmune bullous skin disease characterized by acantholysis and antibodies against a desmosomal protein, desmoglein 1. Genetic and environmental factors contribute to development of this multifactorial disease. HLA class II and some cytokine gene polymorphisms are the only genetic markers thus far known to be associated with susceptibility to or protection from EPF. The cytotoxic T-lymphocyte antigen-4 gene (CTLA4) encodes a key immunoreceptor molecule that regulates and inhibits Tcell proliferation. It participates in the regulatory process controlling autoreactivity and therefore has been considered a strong candidate gene in autoimmune diseases. In the search for genes that might influence EPF pathogenesis, we analyzed variants of the CTLA4 gene in a sample of 118 patients and 291 controls from a Brazilian population. This is the first study investigating the possible role of polymorphisms of the 2q33 chromosomal region in differential susceptibility to pemphigus foliaceus. Promoter region and exon 1 single nucleotide polymorphisms -318 (C,T) and 49 (A,G) were genotyped using sequence-specific oligonucleotide probes after amplification by the polymerase chain reaction. The allelic and genotypic frequencies did not differ significantly between the patient and the control groups (-318T: 9.8 and 10.9%, 49G: 33.0 and 35.2% were the allelic frequencies in patients and controls, respectively). In addition, no significant difference was found when the patient and control population samples were stratified by the presence of HLA-DRB1 alleles. We conclude that the CTLA4 -318 (C,T) and 49 (A,G) polymorphisms do not play a major role in EPF development.

Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases

“…Several studies have confirmed that CTLA-4 polymorphism is associated with MG [18 -20]. Recently, Pavoni et al studied the influence of CTLA4 Ϫ318 and ϩ49 polymorphisms in the pathogenesis of PF; however, no statistically significant association between PF and variants of the CTLA4 gene was observed [21], similar to our results. On the other hand, in our study the frequency of the G/G ϩ49 genotype, associated with a reduced control of T-cell activation and in this way probably contributing to the pathogenesis, was increased in PV patients compared with healthy individuals.…”

Polymorphisms in the 2q33 and 3q21 chromosome regions including T-cell coreceptor and ligand genes may influence susceptibility to pemphigus foliaceus

“…However the absence of significant associations has been reported in a previous study of -318CϾT and 49AϾG SNPs in a cohort of 118 PF patients and 291 control subjects [28]. In a recent study of pemphigus, the CTLA4 49*G allele and G/G genotype frequencies were slightly increased among 48 patients, of whom 37 had pemphigus vulgaris, but no association was found either [45].…”

“…To improve efficacy and specificity, we performed a nested PCR using the same forward primer and oligonucleotide 5=-TTTTAGGG-TACATGTGCACAACA-3= as reverse primer, resulting in a fragment of 367 bp. The segment, including the SNPs -318CϾT (rs5742909) and 49AϾG (rs231775), was amplified by PCR and hybridized with the sequence-specific oligonucleotide probes (PCR-SSOP) as described by Pavoni et al [28]. The 6230GϾA (or CT60 SNP, rs3087243) in the 3=UTR was typed in the same population samples in a previous study [29].…”

Individual and epistatic effects of genetic polymorphisms of B-cell co-stimulatory molecules on susceptibility to pemphigus foliaceus

“…[22][23][24] Associations were found also with interleukin 6, interleukin 4 25 and programmed cell death 1 genotypes 26 but not with the TNF, lymphotoxin-a, DSG1 polymorphisms, cytotoxic T-lymphocyte antigen-4 gene, BAX and TP53 polymorphisms. [27][28][29][30] This is typical for multifactorial (complex) diseases, with several genetic and environmental factors involved in etiology and pathogenesis, and justifies the search for other genes modulating the susceptibility to PF.…”