Asunto(s)
Moléculas de Adhesión Celular/genética , Lectinas Tipo C/genética , Receptores de Superficie Celular/genética , Síndrome Respiratorio Agudo Grave/fisiopatología , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/patogenicidad , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Humanos , L-Lactato Deshidrogenasa/metabolismo , Polimorfismo de Nucleótido Simple , Pronóstico , Regiones Promotoras Genéticas/genética , Estudios Retrospectivos , Coronavirus Relacionado al Síndrome Respiratorio Agudo Severo/aislamiento & purificación , Síndrome Respiratorio Agudo Grave/virología , Índice de Severidad de la EnfermedadAsunto(s)
Antígenos CD/genética , Moléculas de Adhesión Celular/genética , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Síndrome Respiratorio Agudo Grave/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Moléculas de Adhesión Celular/fisiología , Células Cultivadas , Niño , Preescolar , Femenino , Estudios de Asociación Genética , Humanos , L-Lactato Deshidrogenasa/sangre , Lectinas Tipo C/genética , Lectinas Tipo C/fisiología , Recuento de Leucocitos , Masculino , Persona de Mediana Edad , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/fisiología , Síndrome Respiratorio Agudo Grave/sangreRESUMEN
BACKGROUND: The BRCA1 gene is an important breast-cancer susceptibility gene. Promoter polymorphisms can alter the binding affinity of transcription factors, changing transcriptional activity and may affect susceptibility to disease. METHODS AND RESULTS: Using direct sequencing of the BRCA1 promoter region, we identified four polymorphisms c.-2804T-->C (rs799908:T-->C), c.-2265C-->T (rs11655505:C-->T), c.-2004A-->G (rs799906:A-->G) and c.-1896(ACA)(1)-->(ACA)(2) (rs8176071:(ACA)(1)-->(ACA)(2)) present in Hong Kong Chinese. Each polymorphism was studied independently and in combination by functional assays. Although all four variants significantly altered promoter activity, the c.-2265T allele had stronger binding than the C allele, and the most common mutant haplotype, which contains the c.-2265T allele, increased promoter activity by 70%. Risk association first tested in Hong Kong Chinese women with breast cancer and age-matched controls and replicated in a large population-based study of Shanghai Chinese, together totalling >3000 participants, showed that carriers of the c.-2265T allele had a reduced risk for breast cancer (combined odd ratio (OR) = 0.80, 95% CI 0.69 to 0.93; p = 0.003) which was more evident among women aged >or=45 years at first diagnosis of breast cancer and without a family history of breast cancer (combined OR = 0.75, 95% CI 0.61 to 0.91; p = 0.004). The most common haplotype containing the c.-2265T allele also showed significant risk association for women aged >or=45 years without a family history of breast cancer (OR = 0.64, 95% CI 0.46 to 0.89; p = 0.008). CONCLUSION: This comprehensive study of BRCA1 promoter polymorphisms found four variants that altered promoter activity and with the most significant contribution from c.-2265C-->T, which could affect susceptibility to breast cancer in the Chinese population. Its significance in other populations remains to be investigated.
Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Polimorfismo Genético/genética , Regiones Promotoras Genéticas/genética , Transcripción Genética , Pueblo Asiatico/genética , Sitios de Unión , Neoplasias de la Mama/epidemiología , Estudios de Casos y Controles , China/epidemiología , Estudios de Cohortes , Ensayo de Cambio de Movilidad Electroforética , Femenino , Predisposición Genética a la Enfermedad , Genotipo , Hong Kong/epidemiología , Humanos , Factores de Riesgo , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
1. A genetic risk-association study involving more than 1200 subjects showed individuals homozygous for L-SIGN tandem repeats are less susceptible to SARS infection. 2. This was supported by in vitro binding studies that demonstrated homozygous L-SIGN, compared to heterozygous, had higher binding capacity for SARS coronavirus (SARS-CoV), with higher proteasome-dependent viral degradation. In contrast, homozygous L-SIGN demonstrated lower binding capacity for HIV1-gp120.3. Genetic-association studies for single nucleotide polymorphisms of the inflammatory response genes, namely TNF-alpha, INF-alpha, INF-beta, INF-gamma, IL1-alpha, IL1-beta, IL-4, IL-6 and iNOS, failed to show a significant association with SARS clinical outcomes or susceptibility.
