RESUMO
Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant disease characterized by progressive cerebellar ataxia and macular degeneration causing progressive blindness. It accounts for 1 to 11.6 % of spinocerebellar ataxias (SCAs) cases worldwide and for 7.4 % of SCA7 cases in Mexico. We identified a cluster of SCA7 families who resided in a circumscribed area of Veracruz and investigated whether the high incidence of the disease in this region was due to a founder effect. A total of 181 individuals from 20 families were studied. Four microsatellite markers and one SNP flanking the ATNX7 gene were genotyped and the ancestral origin and local ancestry analysis of the SCA7 mutation were evaluated. Ninety individuals from 19 families had the SCA7 mutation; all were found to share a common haplotype, suggesting that the mutation in these families originated from a common ancestor. Ancestral origin and local ancestry analysis of SCA7 showed that the chromosomal segment containing the mutation was of European origin. We here present evidence strongly suggesting that the high frequency of SCA7 in Veracruz is due to a founder effect and that the mutation is most likely of European origin with greatest resemblance to the Finnish population.
Assuntos
Efeito Fundador , Proteínas do Tecido Nervoso/genética , Ataxias Espinocerebelares/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Ataxina-7 , Criança , Pré-Escolar , Mapeamento Cromossômico , Análise Mutacional de DNA , Progressão da Doença , Saúde da Família , Marcadores Genéticos , Genótipo , Geografia , Haplótipos , Humanos , México , Repetições de Microssatélites/genética , Pessoa de Meia-Idade , Mutação , Análise de Sequência com Séries de Oligonucleotídeos , Análise de Componente Principal , Ataxias Espinocerebelares/etnologia , População Branca , Adulto JovemRESUMO
OBJECTIVE: The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic beta-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS: The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20-69 years (121 with onset =45 years), and 202 nondiabetic control subjects aged >50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS: R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis =45 years) (OR 3.776, P = 3.3 x 10(-6)). Both associations remained significant after adjusting for admixture (P = 0.0008 and P = 8.1 x 10(-6), respectively). Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P = 7.6 x 10(-6) and 9.4 x 10(-8), respectively). CONCLUSIONS: The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Diabetes Mellitus Tipo 2/genética , Variação Genética , Transportador 1 de Cassete de Ligação de ATP , Adulto , Idade de Início , Idoso , Idoso de 80 Anos ou mais , Genótipo , Humanos , México , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Valores de ReferênciaRESUMO
Although ATP-binding cassette transporter A1 (ABCA1) is well known for its role in cholesterol efflux and HDL formation, it is expressed in various tissues, where it may have different functions. Because hypoalphalipoproteinemia is highly prevalent in Mexico, we screened the ABCA1 coding sequence in Mexican individuals with low and high HDL cholesterol levels to seek functional variants. A highly frequent nonsynonymous variant (R230C) was identified in low-HDL cholesterol but not in high-HDL cholesterol individuals (P = 0.00006). We thus assessed its frequency in the Mexican-Mestizo general population, seeking possible associations with several metabolic traits. R230C was screened in 429 Mexican Mestizos using Taqman assays, and it was found in 20.1% of these individuals. The variant was significantly associated not only with decreased HDL cholesterol and apolipoprotein A-I levels but also with obesity (odds ratio 2.527, P = 0.005), the metabolic syndrome (1.893, P = 0.0007), and type 2 diabetes (4.527, P = 0.003). All of these associations remained significant after adjusting for admixture (P = 0.011, P = 0.001, and P = 0.006, respectively). This is the first study reporting the association of an ABCA1 variant with obesity and obesity-related comorbidities as being epidemiologically relevant in the Mexican population.