Subject(s)
Cell Adhesion Molecules/genetics , Lectins, C-Type/genetics , Receptors, Cell Surface/genetics , Severe Acute Respiratory Syndrome/physiopathology , Severe acute respiratory syndrome-related coronavirus/pathogenicity , Case-Control Studies , Genetic Predisposition to Disease , Humans , L-Lactate Dehydrogenase/metabolism , Polymorphism, Single Nucleotide , Prognosis , Promoter Regions, Genetic/genetics , Retrospective Studies , Severe acute respiratory syndrome-related coronavirus/isolation & purification , Severe Acute Respiratory Syndrome/virology , Severity of Illness IndexSubject(s)
Antigens, CD/genetics , Cell Adhesion Molecules/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Severe Acute Respiratory Syndrome/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Cell Adhesion Molecules/physiology , Cells, Cultured , Child , Child, Preschool , Female , Genetic Association Studies , Humans , L-Lactate Dehydrogenase/blood , Lectins, C-Type/genetics , Lectins, C-Type/physiology , Leukocyte Count , Male , Middle Aged , Receptors, Cell Surface/genetics , Receptors, Cell Surface/physiology , Severe Acute Respiratory Syndrome/bloodABSTRACT
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.
Subject(s)
BRCA1 Protein/genetics , Breast Neoplasms/genetics , Polymorphism, Genetic/genetics , Promoter Regions, Genetic/genetics , Transcription, Genetic , Asian People/genetics , Binding Sites , Breast Neoplasms/epidemiology , Case-Control Studies , China/epidemiology , Cohort Studies , Electrophoretic Mobility Shift Assay , Female , Genetic Predisposition to Disease , Genotype , Hong Kong/epidemiology , Humans , Risk Factors , Transcription Factors/genetics , Transcription Factors/metabolismABSTRACT
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.
