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Coronary artery disease (CAD) has become a major health problem in many countries. Recent genomewide association studies have identified the association between rs1333049 on chromosome 9p21 and susceptibility to CAD in Caucasoid populations. In this study, we evaluated the associations of rs1333049 with CAD in Japanese (604 patients and 1,151 controls) and Koreans (679 patients and 706 controls). We found a significant association in both Japanese [odds ratio (OR) = 1.30, 95% confidence interval (CI); 1.13-1.49, p = 0.00027, allele count model] and Koreans (OR = 1.19, 95% CI; 1.02-1.38, p = 0.025, allele count model). These observations demonstrated that chromosome 9p21 was the susceptibility locus for CAD also in East Asians.

These observations suggest that the difference in clinical phenotype (HCM or DCM) may be correlated with the property of altered binding among the Z-disc components.

Dilated cardiomyopathy is characterized by ventricular dilation with systolic dysfunction of cardiac muscle. Recent genetic studies have revealed that mutations in genes for cytoskeleton proteins distributed in the Z-disc and/or intercalated discs of the cardiac muscle are major predictors of cardiomyopathy. However, as mutations in these genes can account for only a part of the patient population, there should be another diseasecausing gene(s) for cardiomyopathy. Cypher/ZASP appears to be an ideal candidate for the cardiomyopathy causative gene, because Cypher/ZASP encodes a Z-disc associated protein, and recent studies have demonstrated that Cypher/ZASP knock-out mice develop cardiomyopathy. In this study, we searched for sequence variations in Cypher/ZASP in 96 unrelated Japanese patients with dilated cardiomyopathy. A D626N mutation located within the third LIM domain was identified in a familial case but not found in the unrelated controls. A family study of the patient showed that all affected siblings tested had the same mutation. Clinical information of the affected family members suggested that the mutation was associated with late onset cardiomyopathy. To reveal the biochemical changes due to the mutation, we performed a yeast two-hybrid assay and a pull-down assay. It was demonstrated by both assays that the D626N mutation of Cypher/ZASP increased the affinity of the LIM domain for protein kinase C, suggesting a novel biochemical mechanism of the pathogenesis of dilated cardiomyopathy. Dilated cardiomyopathy (DCM)1 is characterized by ventricular dilation accompanied by systolic dysfunction in the absence of known causes that affect the cardiac function. Family studies of DCM patients have demonstrated that 20 -35% of DCM is caused by inherited gene mutations (familial DCM) (1). Although familial DCM can be transmitted as autosomal recessive, X-linked, or through mitochondrial traits, it is evident that autosomal dominant inheritance occurs the most (2, 3). Missense mutations in genes for cardiac ␣-actin, desmin, lamin A/C, ␦-sarcoglycan, ␤-cardiac myosin heavy chain, cardiac troponin T, ␣-tropomyosin, metavinculin, titin, muscle LIM protein (MLP), Tcap/telethonin, and phospholamban are all associated with autosomal dominant DCM (4 -15). However, mutations in the known causative genes can be found only in a part of the patient population. In addition, linkage studies in multiplex families have suggested that there are several other disease loci of which the gene responsible for causing DCM remains to be identified, including one mapped on 10q21-q23 (16).Abnormalities in Z-disc-related cytoskeletal proteins are associated with DCM also in animal models. For example, mice lacking MLP display many characteristic features of human DCM (17). Similarly, loss of ␦-sarcoglycan results in DCM in a hamster model (18), and a mouse knock-out for the actininassociated LIM protein develops DCM (19). These observations suggest that abnormalities in cytoskeletal proteins expressed in cardiac muscle cause DCM (20).Myo...