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1.
Circ Cardiovasc Genet ; 6(6): 569-78, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24122612

ABSTRACT

BACKGROUND: Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention. METHODS AND RESULTS: We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alström syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the ALMS1 promoter region were significantly associated with early-onset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI. CONCLUSIONS: The glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.


Subject(s)
Genetic Predisposition to Disease/genetics , Glutamic Acid/genetics , Myocardial Infarction/genetics , Polymorphism, Single Nucleotide , Proteins/genetics , Repetitive Sequences, Amino Acid/genetics , Age of Onset , Asian People/genetics , Cell Cycle Proteins , Cell Line , Chromosome Mapping/methods , Chromosomes, Human, Pair 2/genetics , Coronary Artery Disease/ethnology , Coronary Artery Disease/genetics , Family Health , Gene Frequency , Genetic Linkage , Genetic Predisposition to Disease/ethnology , Genome-Wide Association Study/methods , Genotype , Humans , Japan/epidemiology , Myocardial Infarction/epidemiology , Myocardial Infarction/ethnology , Odds Ratio , Republic of Korea/epidemiology , Risk Factors
2.
Coron Artery Dis ; 22(1): 1-5, 2011 Jan.
Article in English | MEDLINE | ID: mdl-20890183

ABSTRACT

OBJECTIVE: Several studies have shown that significant coronary narrowing makes the prognosis of vasospastic angina pectoris (VAP) worse. However, the effects of various factors on the prognosis of patients without significant arterial narrowing have not yet been shown. METHODS AND RESULTS: We investigated 1248 consecutive patients with VAP who had no coronary stenosis of more than or equal to 50%. The mean follow-up was 11.7±6.8 years. Ninety-one patients (7.3%) developed unstable angina, acute myocardial infarction, or effort angina with new coronary narrowings. Thirty patients (2.4%) died suddenly. Multivariate analysis showed that the presence of coronary stenosis, even if trivial, made the prognosis worse (P=0.027; odds ratio, 1.66; 95% confidence interval, 1.06-2.61). In addition, unusually, female patients had a better prognosis than male patients (P=0.007; odds ratio, 0.35; 95% confidence interval, 0.16-0.75). Other factors, such as hyperlipemia, diabetes, and hypertension did not affect the prognosis. CONCLUSION: In patients with VAP, the presence of coronary narrowing, even if mild, was associated with worse prognosis.


Subject(s)
Angina Pectoris, Variant/complications , Angina Pectoris, Variant/physiopathology , Coronary Stenosis , Death, Sudden, Cardiac/etiology , Myocardial Infarction/etiology , Adult , Aged , Angina Pectoris, Variant/drug therapy , Calcium Channel Blockers/therapeutic use , Coronary Angiography , Coronary Stenosis/complications , Coronary Stenosis/diagnosis , Coronary Stenosis/mortality , Coronary Stenosis/physiopathology , Coronary Vessels/drug effects , Coronary Vessels/pathology , Diltiazem/therapeutic use , Disease Progression , Electrocardiography , Female , Humans , Japan , Male , Middle Aged , Prognosis , Prospective Studies , Sex Factors
3.
J Hum Genet ; 55(1): 42-9, 2010 Jan.
Article in English | MEDLINE | ID: mdl-19911011

ABSTRACT

Coronary artery spasm has an important function in the etiology of variant angina and other acute coronary syndromes. Abnormal activation of Rho-family GTPases has been observed in cardiovascular disorders, but the function of genetic variability in Rho-family GTPases remains to be evaluated in cardiovascular disorders. We examined the genetic variability of Rho-family GTPases and their regulators in coronary artery spasm. We performed a comprehensive candidate gene analysis of 67 single nucleotide polymorphisms with amino-acid substitution in Rho-family GTPases and their regulators in 103 unrelated Japanese patients with acetylcholine-induced coronary artery spasm and 102 control Japanese subjects without acetylcholine-induced coronary artery spasm. We noted an association of the single nucleotide polymorphism of ARHGAP9 (rs11544238, Ala370Ser) with coronary artery spasm (odds ratio =2.67). We found that ARHGAP9 inactivated Rac as RacGAP and that the mRNA level of ARHGAP9 was strongly detected in hematopoietic cells. ARHGAP9 negatively regulated cell migration. The Ala370Ser polymorphism counteracted ARHGAP9-reduced cell migration, spreading and adhesion. The Ala370Ser polymorphism in the ARHGAP9 gene is associated with coronary artery spasm. These data suggest that the polymorphism of ARHGAP9 has a critical function in the infiltration of hematopoietic cells into the endothelium and inflammation leading to endothelial dysfunction.


Subject(s)
Coronary Vasospasm/genetics , GTPase-Activating Proteins/genetics , Genetic Predisposition to Disease , Mutation , Acetylcholine/administration & dosage , Angina Pectoris, Variant/genetics , Angina Pectoris, Variant/physiopathology , Coronary Angiography , Coronary Vasospasm/chemically induced , Coronary Vasospasm/physiopathology , Female , GTPase-Activating Proteins/metabolism , HeLa Cells , Humans , Japan , Jurkat Cells , Male , Polymorphism, Single Nucleotide
4.
Eur Heart J ; 25(11): 970-7, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15172469

ABSTRACT

AIMS: The aim of the study was to identify genes that confer susceptibility to coronary artery spasm and clarify the interaction between genetic and environmental factors in this condition. METHODS AND RESULTS: The study population comprised 2188 Japanese individuals, including 593 subjects with coronary artery spasm (453 men, 140 women) and 1595 controls (762 men, 833 women). The genotypes for 35 polymorphisms of 29 candidate genes were determined with an allele-specific DNA primer-probe assay. Multivariable logistic regression analysis adjusted for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolaemia, and hyperuricaemia revealed a significant association with coronary artery spasm of one polymorphism (242C-->T in the NADH/NADPH oxidase p22 phox gene) in men and two polymorphisms (-1171/5A-->6A in the stromelysin-1 gene and -634C-->G in the interleukin-6 gene) in women. A stepwise forward selection procedure revealed that smoking was the most important risk factor for coronary artery spasm and that the effects of these polymorphisms on this condition were statistically independent of smoking. CONCLUSION: The NADH/NADPH oxidase p22 phox gene is a susceptibility locus for coronary artery spasm in men, and the stromelysin-1 and interleukin-6 genes are susceptibility loci in women.


Subject(s)
Coronary Vasospasm/genetics , Genetic Predisposition to Disease/genetics , Polymorphism, Genetic/genetics , Coronary Vasospasm/epidemiology , Female , Genotype , Humans , Japan/epidemiology , Male , Middle Aged , Multivariate Analysis , Regression Analysis , Risk Factors
5.
Atherosclerosis ; 174(1): 181-7, 2004 May.
Article in English | MEDLINE | ID: mdl-15135268

ABSTRACT

Plain old balloon angioplasty (POBA) is a useful therapeutic strategy especially for angioplasty of small coronary arteries. An association study was performed to identify genes that confer susceptibility to restenosis after POBA. The study population comprised 730 individuals (424 men, 306 women) who underwent successful POBA in at least one major coronary artery and were examined angiographically 6 months after the procedure. A total of 469 subjects (273 men, 196 women) exhibited no restenosis after POBA for any of the coronary lesions, whereas 261 subjects (151 men, 110 women) manifested restenosis for all lesions. The genotypes for 40 polymorphisms of 34 genes were determined with a fluorescence- or colorimetry-based allele-specific DNA primer-probe assay. Multivariate logistic regression analysis with adjustment for age, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia revealed that two polymorphisms (242C --> T in the NADH/NADPH oxidase p22 phox (p22-PHOX) gene and 2136C --> T in the thrombomodulin (THBD) gene) in men and two polymorphisms (584G --> A in the paraoxonase 1 (PON1) gene and 2445G --> A in the fatty acid-binding protein 2 (FABP2) gene) in women were significantly associated with restenosis after POBA. A stepwise forward selection procedure revealed that the effects of these polymorphisms on restenosis were statistically independent of conventional risk factors for coronary artery disease. Genotyping of these polymorphisms may prove informative for assessment of genetic risk for restenosis after POBA.


Subject(s)
Angioplasty, Balloon/methods , Coronary Restenosis/genetics , Coronary Stenosis/genetics , Coronary Stenosis/therapy , Genetic Predisposition to Disease , Polymorphism, Genetic , Age Distribution , Aged , Angioplasty, Balloon/adverse effects , Cohort Studies , Coronary Angiography , Coronary Restenosis/diagnostic imaging , Coronary Restenosis/epidemiology , Coronary Stenosis/diagnostic imaging , Female , Genotype , Humans , Logistic Models , Male , Middle Aged , Multivariate Analysis , Prevalence , Prognosis , Risk Assessment , Severity of Illness Index , Sex Distribution , Survival Analysis
6.
Circ J ; 68(1): 47-52, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14695465

ABSTRACT

BACKGROUND: Insulin resistance and hyperinsulinemia are important risk factors for coronary artery disease (CAD) and cardiovascular event (CVE). However, their independent relationship to new CVE in patients with normal glucose tolerance (NGT) and CAD is not known. METHODS AND RESULTS: Subjects of this 3-year observational study were 102 patients with CAD. Plasma glucose and insulin concentrations were determined at 2 time points (baseline and post oral glucose tolerance test [OGTT]. The fasting plasma glucose <110 mg/dl and post-OGTT <140 mg/dl was diagnosed as NGT (World Health Organization criteria). Insulin resistance was evaluated by the homeostasis model assessment of insulin resistance (HOMA-IR). Of the 102 patients, 23 had onset of new CVE, including 19 with new CAD. They had significantly higher fasting and post-OGTT insulin levels and HOMA-IR than those without new CVE (P<0.01, 0.031 and <0.01, respectively). Using the univariate Cox proportional hazards model, fasting and post-OGTT insulin values, HOMA-IR and high density lipoprotein (HDL) cholesterol differed significantly between the 2 groups. The multivariate Cox model showed that the effect of fasting plasma insulin and HOMA-IR remained significant and independent of HDL cholesterol. CONCLUSION: Fasting hyperinsulinemia and high insulin resistance increased the risk of new CVE in patients with NGT and CAD.


Subject(s)
Blood Glucose/metabolism , Cardiovascular Diseases/epidemiology , Coronary Disease/epidemiology , Hyperinsulinism/blood , Insulin Resistance/physiology , Blood Glucose/analysis , Body Mass Index , Coronary Angiography , Fasting , Female , Glucose Tolerance Test , Humans , Insulin/blood , Male , Middle Aged , Reference Values , Risk Factors
7.
N Engl J Med ; 347(24): 1916-23, 2002 Dec 12.
Article in English | MEDLINE | ID: mdl-12477941

ABSTRACT

BACKGROUND: Although epidemiologic studies have suggested that several genetic variants increase the risk of myocardial infarction, large-scale association studies that examine many polymorphisms simultaneously are required to allow reliable prediction of the genetic risk of myocardial infarction. METHODS: We used a fluorescence- or colorimetry-based allele-specific DNA-primer-probe assay system to determine the genotypes of 112 polymorphisms of 71 candidate genes in 2819 unrelated Japanese patients with myocardial infarction (2003 men and 816 women) and 2242 unrelated Japanese controls (1306 men and 936 women). RESULTS: In an initial screening of the 112 polymorphisms for an association with myocardial infarction in 909 subjects, 19 polymorphisms were selected in men and 18 in women by means of logistic-regression analysis, after adjustment for age, body-mass index, and the prevalence of smoking, hypertension, diabetes mellitus, hypercholesterolemia, and hyperuricemia. In a large-scale study involving the selected polymorphisms and the remaining 4152 subjects, similar logistic-regression analysis revealed that the risk of myocardial infarction was significantly associated with the C1019T polymorphism in the connexin 37 gene (P<0.001) in men and the 4G-668/5G polymorphism in the plasminogen-activator inhibitor type 1 gene (P<0.001) and the 5A-1171/6A polymorphism in the stromelysin-1 gene (P<0.001) in women. CONCLUSIONS: Determination of the genotypes of the connexin 37, plasminogen-activator inhibitor type 1, and stromelysin-1 genes may prove reliable in predicting the genetic risk of myocardial infarction and might thus contribute to the primary prevention of this condition.


Subject(s)
Connexins/genetics , Matrix Metalloproteinase 3/genetics , Myocardial Infarction/genetics , Plasminogen Activator Inhibitor 1/genetics , Polymorphism, Genetic , Case-Control Studies , DNA Probes , Female , Genotype , Humans , Logistic Models , Male , Middle Aged , Risk Factors , Gap Junction alpha-4 Protein
8.
Circ J ; 66(6): 534-6, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12074267

ABSTRACT

Although it is commonly believed that ischemia does not develop during coronary intervention in patients with rich collateral circulation to the target vessel, ST changes are often observed, the study group comprised 40 consecutive patients who underwent elective percutaneous coronary angioplasty and who had rich collateral vessels to the target lesions. None had side branches in the target vessel that would be occluded by the angioplasty balloon. During the intervention, the 12-lead electrocardiogram was monitored for any change in the ST-T segment and 13 (32.5%) showed significant ST changes. Of these, 3 had ST changes with every balloon inflation and the remaining 10 patients had ST changes with the second or subsequent inflations. Myocardial ischemia caused by balloon inflation is not uncommon during coronary angioplasty in patients with rich collaterals to the target vessel. The collateral circulation may stop functioning very early after improvement in the forward flow of the target vessel.


Subject(s)
Angioplasty, Balloon, Coronary/adverse effects , Collateral Circulation/physiology , Coronary Stenosis/therapy , Myocardial Ischemia/complications , Angina Pectoris/therapy , Catheterization , Chi-Square Distribution , Electrocardiography , Female , Humans , Male , Middle Aged
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