Characterization of CD28, CTLA4, and ICOS Polymorphisms in Three Brazilian Ethnic Groups
Introduction
Costimulatory molecules CD28, cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and inducible costimulator (ICOS) genes lie in this order in a 300-kb region on chromosome 2q33 [1]. CD28, ICOS, and CTLA-4 are important regulators of the immune system. CD28 and ICOS enhance T-cell functions for effective antigen-specific immune responses, whereas CTLA-4 counterbalances the CD28 mediated signals and thus prevents overstimulation of the lymphoid system [2]. 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. Another important point to consider in these association studies is the ethnic homogeneity of the groups being compared because differences in allelic frequencies have been observed among different ethnic groups [5, 6].
In the current study, our purpose was to analyze ethnic variations in allelic frequencies and LD patterns regarding CD28, CTLA4, and ICOS genes in Brazilian white, mulatto, and black ethnic groups. The Brazilian population has been estimated to be composed of approximately 55% European-derived, 6% African-derived, 38% mixed ancestry (mainly mulattos, i.e., black and white admixture), 0.4% Asiatic, and 0.2% Amerindian individuals.
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Materials and methods
We analyzed DNA samples from 279 Brazilian healthy unrelated individuals from southeastern Brazil. The subjects were subdivided by ethnic groups: 103 white (predominantly of Portuguese, Spanish, and Italian origin), 97 mulatto (mixed white-black), and 79 black (predominantly of West African origin) individuals. The racial groups were classified by evaluation of phenotypical features, i.e., skin color, type and color of the hair, and nose and lip characteristics [7]. This study was approved by
Results
Allelic and genotypic distributions for each polymorphism were stratified by ethnicity as listed in Table 2. The frequency of CD28 +17 C (27%) observed in whites was similar to that referred in the literature for other white populations [9, 10, 11] and was higher than the frequency observed in Brazilian mulattos (15%) (p = 0.005) and blacks (13%) (p = 0.001). No deviation from the Hardy-Weinberg equilibrium was observed for any polymorphism. LD between CD28 +17 C and CTLA4 −319 T alleles was
Discussion
To confirm the existence of this LD, a new sample group consisting of 100 healthy white individuals was genotyped for the SNPs CD28 +17 intron 3 and CTLA4 −319 and the LD (p < 0.0001) was confirmed. The different racial distribution of frequencies of some of the polymorphisms of CD28, CTLA4, and ICOS genes described in this study further emphasizes the importance of ethnical matching in disease association studies.
Acknowledgments
Research was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
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