RESUMO
Although over 30 common genetic susceptibility loci have been identified to be independently associated with coronary artery disease (CAD) risk through genome-wide association studies (GWAS), genetic risk variants reported to date explain only a small fraction of heritability. To identify novel susceptibility variants for CAD and confirm those previously identified in European population, GWAS and a replication study were performed in the Koreans and Japanese. In the discovery stage, we genotyped 2123 cases and 3591 controls with 521 786 SNPs using the Affymetrix SNP Array 6.0 chips in Korean. In the replication, direct genotyping was performed using 3052 cases and 4976 controls from the KItaNagoya Genome study of Japan with 14 selected SNPs. To maximize the coverage of the genome, imputation was performed based on 1000 Genome JPT+CHB and 5.1 million SNPs were retained. CAD association was replicated for three GWAS-identified loci (1p13.3/SORT1 (rs599839), 9p21.3/CDKN2A/2B (rs4977574), and 11q22.3/ PDGFD (rs974819)) in Koreans. From GWAS and a replication, SNP rs3782889 showed a strong association (combined P=3.95 × 10(-14)), although the association of SNP rs3782889 doesn't remain statistically significant after adjusting for SNP rs11066015 (proxy SNP with BRAP (r(2)=1)). But new possible CAD-associated variant was observed for rs9508025 (FLT1), even though its statistical significance did marginally reach at the genome-wide a significance level (combined P=6.07 × 10(-7)). This study shows that three CAD susceptibility loci, which were previously identified in European can be directly replicated in Koreans and also provides additional evidences implicating suggestive loci as risk variants for CAD in East Asian.
Assuntos
Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Povo Asiático/genética , Estudos de Casos e Controles , Feminino , Loci Gênicos , Predisposição Genética para Doença , Genoma Humano , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: We sought to describe the long-term outcome of individuals in 4 Korean families with hypertrophic cardiomyopathy (HCM) with known mutations. HYPOTHESIS: Long-term clinical features of familial HCM might be characterized according to the mutation causing HCM. METHODS: We performed long-term (mean, 13.1 y) clinical evaluations on 46 subjects from 4 Korean families with different mutations. RESULTS: Myosin light chain 3 gene (MYL3) mutation was associated with late-onset HCM with relatively poor prognosis; 1 sudden cardiac death and 2 cases of heart failure with atrial fibrillation occurred among 12 subjects with this mutation. Myosin binding protein C gene (MYBPC3) mutation was associated with 2 cases of sudden cardiac death and 3 cases of heart failure among 7 affected members. Cardiac troponin I type 3 gene (TNNI3) mutation was associated with 5 deaths related to atrial fibrillation and stroke among 12 mutation-positive members. Myosin heavy chain 7 gene (MYH7) mutation was associated with 11 deaths in 15 affected members. CONCLUSIONS: The clinical course was quite different for different HCM mutations. Even within the same family, individuals carrying the same mutation differed in disease expression and prognosis.
