RESUMO
OBJECTIVES: Homozygous C1q deficiency is an extremely rare condition and strongly associated with systemic lupus erythematosus. To assess and characterize C1q deficiency in an African-American lupus pedigree, C1q genomic region was evaluated in the lupus cases and family members. METHODS: Genomic DNA from patient was obtained and C1q A, B and C gene cluster was sequenced using next generation sequencing method. The identified mutation was further confirmed by direct Sanger sequencing method in the patient and all blood relatives. C1q levels in serum were measured using sandwich ELISA method. RESULTS: In an African-American patient with lupus and C1q deficiency, we identified and confirmed a novel homozygote start codon mutation in C1qA gene that changes amino acid methionine to arginine at position 1. The Met1Arg mutation prevents protein translation (Met1Arg). Mutation analyses of the patient's family members also revealed the Met1Arg homozygote mutation in her deceased brother who also had lupus with absence of total complement activity consistent with a recessive pattern of inheritance. CONCLUSION: The identification of new mutation in C1qA gene that disrupts the start codon (ATG to AGG (Met1Arg)) has not been reported previously and it expands the knowledge and importance of the C1q gene in the pathogenesis of lupus especially in the high-risk African-American population.
Assuntos
Complemento C1q/deficiência , Complemento C1q/genética , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/genética , Mutação Puntual , Adulto , Negro ou Afro-Americano/genética , Substituição de Aminoácidos , Sequência de Bases , Códon de Iniciação/genética , Análise Mutacional de DNA , Feminino , Genes Recessivos , Homozigoto , Humanos , Masculino , Linhagem , Adulto JovemRESUMO
Eosinophilic esophagitis (EoE) is a chronic, allergic disease associated with marked mucosal eosinophil accumulation. EoE disease risk is multifactorial and includes environmental and genetic factors. This review will focus on the contribution of genetic variation to EoE risk, as well as the experimental tools and statistical methodology used to identify EoE risk loci. Specific disease-risk loci that are shared between EoE and other allergic diseases (TSLP, LRRC32) or unique to EoE (CAPN14), as well as Mendellian Disorders associated with EoE, will be reviewed in the context of the insight that they provide into the molecular pathoetiology of EoE. We will also discuss the clinical opportunities that genetic analyses provide in the form of decision support tools, molecular diagnostics, and novel therapeutic approaches.
Assuntos
Calpaína/genética , Citocinas/genética , Esofagite Eosinofílica/genética , Proteínas de Membrana/genética , Mucosa/imunologia , Animais , Tomada de Decisão Clínica , Eosinófilos , Interação Gene-Ambiente , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Polimorfismo Genético , Linfopoietina do Estroma do TimoRESUMO
Population substructure is a well-known confounder in population-based case-control genetic studies, but its impact in family-based studies is unclear. We performed population substructure analysis using extended families of admixed population to evaluate power and Type I error in an association study framework. Our analysis shows that power was improved by 1.5% after principal components adjustment. Type I error was also reduced by 2.2% after adjusting for family substratification. The presence of population substructure was underscored by discriminant analysis, in which over 92% of individuals were correctly assigned to their actual family using only 100 principal components. This study demonstrates the importance of adjusting for population substructure in family-based studies of admixed populations.