Assuntos
Varíola Bovina/história , Fazendeiros/história , Imunização/história , Vacina Antivariólica/história , Varíola/história , Animais , Bovinos , Varíola Bovina/imunologia , Inglaterra , Feminino , História do Século XVIII , História do Século XIX , Humanos , Mitologia , Orthopoxvirus/imunologia , Varíola/prevenção & controleRESUMO
The Fcgamma receptors play important roles in the initiation and regulation of many immunological and inflammatory processes, and genetic variants (FCGR) have been associated with numerous autoimmune and infectious diseases. The data in rheumatoid arthritis (RA) are conflicting and we previously demonstrated an association between FCGR3A and RA. In view of the close molecular proximity with FCGR2A, FCGR2B and FCGR3B, additional polymorphisms within these genes and FCGR haplotypes were examined to refine the extent of association with RA. Biallelic polymorphisms in FCGR2A, FCGR2B and FCGR3B were examined for association with RA in two well characterized UK Caucasian and North Indian/Pakistani cohorts, in which FCGR3A genotyping had previously been undertaken. Haplotype frequencies and linkage disequilibrium were estimated across the FCGR locus and a model-free analysis was performed to determine association with RA. This was followed by regression analysis, allowing for phase uncertainty, to identify the particular haplotype(s) that influences disease risk. Our results reveal that FCGR2A, FCGR2B and FCGR3B were not associated with RA. The haplotype with the strongest association with RA susceptibility was the FCGR3A-FCGR3B 158V-NA2 haplotype (odds ratio 3.18, 95% confidence interval 1.13-8.92 [P = 0.03] for homozygotes compared with all genotypes). The association was stronger in the presence of nodules (odds ratio 5.03, 95% confidence interval 1.44-17.56; P = 0.01). This haplotype was also more common in North Indian/Pakistani RA patients than in control individuals, but not significantly so. Logistic regression analyses suggested that FCGR3A remained the most significant gene at this locus. The increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants within FCGR3A or FCGR3B, or in linkage disequilibrium with this haplotype, may additionally contribute to disease pathogenesis.
Assuntos
Antígenos CD/genética , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Cromossomos Humanos Par 1 , Receptores de IgG/genética , Sequência de Bases , Mapeamento Cromossômico , Estudos de Coortes , Proteínas Ligadas por GPI , Predisposição Genética para Doença , Variação Genética , Genótipo , Humanos , Desequilíbrio de Ligação , Reação em Cadeia da Polimerase , Polimorfismo de Nucleotídeo Único , Valores de Referência , Reino Unido , População Branca/genéticaRESUMO
Previous work has shown that a single haplotype of the T-cell antigen receptor beta-subunit (TCRB) locus is predominant in African populations. This is likely to be due to selection pressure for gene(s) that protect children against disease. This study has tested the hypothesis that malaria is the responsible selection pressure, due to its impact on child mortality. The haplotypes of BV8S3, BV2S1, BV15S1, and BV3S1 were determined in children suffering from severe malaria and unaffected adult controls. No significant difference between cases and controls was shown for any of the haplotypes studied. In addition, an insertion/deletion (INDEL) haplotype in the 5' region of the TCRB locus was investigated. Again no differences between the two groups were detected. Therefore, the evidence suggests that malaria is not responsible for haplotype selection in The Gambia.
Assuntos
Regiões Determinantes de Complementaridade/genética , Genes Codificadores da Cadeia beta de Receptores de Linfócitos T/genética , Haplótipos/genética , Malária/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Seleção Genética , Adulto , Criança , Feminino , Gâmbia/epidemiologia , Frequência do Gene , Variação Genética/genética , Humanos , Malária/epidemiologia , Malária/imunologia , Masculino , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de RestriçãoRESUMO
This study investigated polymorphisms of genes in two regions of the T-cell antigen receptor beta-subunit (TCRB) locus, including BV9S2P, and BV6S7 in a 5' linkage group, and BV8S3, BV24S1, BV25S1, BV18S1, BV2S1, BV15S1 and BV3S1 in a 3' linkage group. These loci have been genotyped in individuals from five regions in Africa, including The Gambia, Nigeria, Cameroon, Tanzania, and Zambia, and in individuals from northern Britain, northern India, and Papua New Guinea (PNG). In the 3' linkage group, 11 unique haplotypes were identified in the combined African populations; two equally frequent haplotypes represent the majority of African chromosomes. One haplotype was found in all four regions studied. This is the most frequent haplotype in the northern British, northern Indian and PNG populations. Although present, it is infrequent in the African populations. A North-South gradient in the frequency of a common African haplotype was observed. The distribution did not represent that of a known disease. Evidence suggests that malaria is not responsible for selection of these haplotypes. Overall, this study highlights large differences in the genetic constitution of the TCRB locus between Africans and other populations.