Genetic polymorphisms of the T-cell coreceptors CD28 and CTLA-4 in Afro- and Euro-Brazilians.

CD28 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are two receptors that have complementary functions in control of T-cell activation. Polymorphisms of their genes, CD28 and CTLA4, might confer differential susceptibility to diseases resulting from unbalanced or inefficient immune responses. Thus far, little is known about the CD28 polymorphism in populations and even for CTLA4 just one or two single nucleotide polymorphisms (SNPs) are usually analysed. To assess the allelic and haplotypic diversity and linkage disequilibrium in the Brazilian population, two samples differing according to predominant ancestry - African or European - have been analysed for seven SNPs, CD28 -372(G>A), and int3 17(T>C); CTLA4 -1722(T>C), -1577(G>A) -318(C>T), 49(A>G), 6230(G>A) also named CT60, and three microsatellites, CD28 (CAA)n, CTLA4 (AT)n and D2S72 (CA)n. The two population strata show little differentiation, the only significant differences being the allele frequencies of the CTLA4 -1577(G>A) SNP and the CTLA4 (AT)n microsatellite (P = 0.018 and P = 0.007, respectively). Linkage disequilibrium is high, especially between the CTLA4 polymorphisms. However, low r(2) values indicate that none of the markers is a tag SNP in these populations. These results provide valuable information for optimal selection of markers for use in future association studies. We conclude that disease association studies and functional studies addressing the possible consequences of polymorphisms of the 2q33 genomic region should consider haplotypic data besides analysis of individual polymorphisms.

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

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 T-cell 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.

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

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 T-cell 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 percent, 49G: 33.0 and 35.2 percent 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.

Polymorphisms within the tumor necrosis factor and lymphotoxin-alpha genes and endemic pemphigus foliaceus--are there any associations?

The purpose of this study was to analyze the possible influence of the TNF and LTA loci polymorphisms on the susceptibility/resistance to endemic pemphigus foliaceus, also named fogo selvagem (FS), an autoimmune disease characterized by blisters due to acantholysis of the superficial-most epidermal cells. Autoantibodies, mainly of the IgG4 subclass, are directed against a desmosomal glycoprotein known as desmoglein 1. FS shares clinical, histological and immunological features with nonendemic pemphigus foliaceus. Most residents of the endemic regions do not develop the disease, and familial clustering has been documented, suggesting that host factors play a role in susceptibility. In fact, strong positive and negative associations with HLA class II genes have been reported. The TNF and LTA genes are located in the class III region of the Human Major Histocompatibility Complex. Their location, the function of their products, which are cytokines and pluripotent immunomodulators, as well as their genetic variability make them candidate genes for complex diseases with an altered immune response. A total of 162 patients and 191 controls were enrolled in this study. No significant associations were found with any one of the three LTA single nucleotide polymorphisms (SNP) analyzed (at nucleotides 249, 365, 720), nor with the TNF SNP located at positions -863 and -308. The frequency of allele TNF*238A was slightly decreased in patients (OR = 0.45). In conclusion, the results of this study indicate that genetic variability of the TNF and LTA genes does not play a major role in susceptibility/resistance to pemphigus foliaceus.

Dissecting the associations of endemic pemphigus foliaceus (Fogo Selvagem) with HLA-DRB1 alleles and genotypes.

Endemic pemphigus foliaceus (EPF) is a blistering skin disease characterized by autoantibodies against the desmosomal protein desmoglein 1. Genetic and environmental factors influence its pathogenesis. A total of 128 patients and 402 controls from an ethnically admixed Brazilian population were analyzed for associations by allele and genotype with HLA-DRB1. The alleles DRB1(*)0101, (*)0102, (*)0103, (*)0404, (*)0406, (*)0410, (*)1406 and (*)1601 are significantly more frequent among patients, while DRB1(*)0301, (*)0701, (*)0801, (*)1101, (*)1104 and (*)1402 are negatively associated to EPF. Results of association analysis with protein motifs composed of polymorphic amino-acid residues do not add much to comprehension of the molecular basis of the HLA-DRB1/EPF associations. Interactions between susceptible (SU), protective (PR) and neutral (NE) alleles clearly deviate from the codominant model. Protection is dominant, since the PR/NE and PR/PR genotypes are both equally (P=0.95) and strongly protective (odds ratio OR=0.07 and 0.05, respectively; P<10(-6) for both). The SU/SU genotype confers a higher (P=0.012) risk than genotype SU/NE (OR=8.7 and 4.0; P<10(-6) for both), an evidence of a semi-dominant effect of SU alleles relative to NE alleles. The OR for the SU/PR genotype (statistically close to 1) is consistent with semi-dominance between PR and SU alleles. Knowledge of these allelic interactions is relevant for understanding the mechanisms underlying autoimmune disease pathogenesis.