Association of genetic variants with atrial fibrillation.

Recent genome-wide association studies (GWASs) identified various genes and loci that confer susceptibility to coronary artery disease or myocardial infarction among Caucasian populations. As myocardial ischemia is an important risk factor for atrial fibrillation, we hypothesized that certain polymorphisms may contribute to the genetic susceptibility to atrial fibrillation through affecting the susceptibility to coronary artery disease. The aim of the present study was to examine the possible association of atrial fibrillation in Japanese individuals with 29 polymorphisms identified as susceptibility loci for coronary artery disease or myocardial infarction in the meta-analyses of GWASs in Caucasian populations. The study subjects comprised 5,470 Japanese individuals (305 subjects with atrial fibrillation and 5,165 controls). Genotypes for 29 polymorphisms were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test revealed that rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (PSRC1, P=0.0084) and rs11556924 (C→T, Arg363His) of the zinc finger, C3HC-type containing 1 gene (ZC3HC1, P=0.0076) were significantly (P<0.01) associated with atrial fibrillation. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, estimated glomerular filtration rate, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidemia revealed that rs599839 (P=0.0043; odds ratio, 1.56; dominant model) and rs11556924 (P=0.0043; odds ratio, 1.93; dominant model) were significantly associated with atrial fibrillation, with the minor G and T alleles, respectively, representing risk factors for this condition. PSRC1 and ZC3HC1 may thus be susceptibility loci for atrial fibrillation in Japanese individuals.

Association of FURIN and ZPR1 polymorphisms with metabolic syndrome.

Although genome-wide association studies (GWASs) have identified various genes and loci in predisposition to metabolic syndrome (MetS) or each component of this condition, the genetic basis of MetS in individuals remains to be identified definitively. The aim of the present study was to examine the possible association of MetS in individuals with 29 polymorphisms that were previously identified as susceptibility loci for coronary artery disease or myocardial infarction by meta-analyses of GWASs. The study population comprised 1,822 subjects with MetS and 1,096 controls. Subjects with MetS had ≥3 of the 5 components of the diagnostic criteria for MetS, whereas control individuals had 0-1 of the 5 components. The genotypes for the 29 polymorphisms were determined by the multiplex bead-based Luminex assay. Comparisons of allele frequencies by the χ2 test revealed that rs17514846 (A→C) of the furin (paired basic amino acid-cleaving enzyme) gene (FURIN; P=0.0006), rs964184 (C→G) of the ZPR1 zinc finger gene (ZPR1; P=0.0078) and rs599839 (G→A) of the proline/serine-rich coiled-coil 1 gene (P=0.0486) were significantly (P<0.05) associated with the prevalence of MetS. Multivariable logistic regression analysis with adjustment for age, gender and smoking status revealed that rs17514846 of FURIN (P=0.0016; odds ratio, 0.76; dominant model) and rs964184 of ZPR1 (P=0.0164; odds ratio, 1.21; dominant model) were significantly associated with MetS. The minor A allele of rs17514846 of FURIN was significantly associated with a decrease in the serum concentration of triglycerides (P=0.0293) and to an increase in the serum concentration of high-density lipoprotein (HDL) cholesterol (P=0.0460). The minor G allele of rs964184 of ZPR1 was significantly associated with increases in the serum concentration of triglycerides (P=6.2×10-9) and fasting plasma glucose level (P=0.0028) and to a decrease in the serum concentration of HDL cholesterol (P=0.0105). FURIN and ZPR1 may thus be susceptibility loci for MetS.

Association of TOMM40 and SLC22A4 polymorphisms with ischemic stroke.

Recent genome-wide association studies (GWASs) and their meta-analyses have identified various genes and loci underlying the predisposition to ischemic stroke or coronary artery disease in Caucasian populations. Given that ischemic stroke and coronary artery disease may have a shared genetic architecture, certain polymorphisms may confer genetic susceptibility to these two diseases. The aim of the present study was to examine the possible association of ischemic stroke with 29 single-nucleotide polymorphisms (SNPs) previously identified by the meta-analyses of GWASs as susceptibility loci for coronary artery disease. The study population comprised 3,187 Japanese individuals, including 894 subjects with ischemic stroke and 2,293 controls. The genotypes for the 29 SNPs of the 28 genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Comparisons of the allele frequencies by the χ2 test between subjects with ischemic stroke and controls revealed that rs9319428 (G→A) of the fms-related tyrosine kinase 1 gene (P=0.0471), rs2075650 (G→A) of the translocase of outer mitochondrial membrane 40 homolog gene (TOMM40, P=0.0102) and rs273909 (T→C) of the solute carrier family 22, member 4 gene (SLC22A4, P=0.0097) were significantly (P<0.05) associated with the prevalence of ischemic stroke. Multivariable logistic regression analysis with adjustment for age, gender, body mass index, smoking status and the prevalence of hypertension, diabetes mellitus and dyslipidemia revealed that rs2075650 of TOMM40 (P=0.0443; recessive model; odds ratio=0.50) and rs273909 of SLC22A4 (P=0.0123; dominant model; odds ratio=0.45) were significantly associated with ischemic stroke with the minor G and C allele, respectively, being protective against this condition. TOMM40 and SLC22A4 may thus be susceptibility loci for ischemic stroke in Japanese individuals.

Association of a transcription factor 21 gene polymorphism with hypertension.

Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P<0.05) associated with hypertension. Allele frequencies for rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1) and genotype distributions for rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1) were also significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs12190287 of TCF21 (P=0.0014; recessive model; odds ratio, 1.21) was significantly associated with hypertension, and the C allele represented a risk factor for this condition. Similar analyses revealed that rs1122608 of SMARCA4 (P=0.0305; dominant model; odds ratio, 0.86), rs9369640 of PHACTR1 (P=0.0119; dominant model; odds ratio, 0.82) and rs599839 of PSRC1 (P=0.0248; dominant model; odds ratio, 0.84) were also related to hypertension, with the minor T, C and G alleles, respectively, being protective against this condition. Thus, the present results indicate that rs12190287 (G→C) of TCF21 is a susceptibility locus for hypertension.

Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals.

AIM: Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. METHODS: The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of <60 mL min(-1) 1.73 m(-2) ] and 659 controls (eGFR of ≥90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined. RESULTS: The χ(2) test revealed that rs4845625 (T→C) of IL6R, rs4773144 (A→G) of COL4A1, rs9319428 (G→A) of FLT1, and rs46522 (T→C) of UBE2Z were significantly (P < 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype. CONCLUSION: The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals.

Assessment of a polymorphism of SDK1 with hypertension in Japanese Individuals.

BACKGROUND: Hypertension is a major risk factor for cardiovascular disease. Although genetic studies have suggested that several genetic variants increase the risk for hypertension, the genes that underlie genetic susceptibility to this condition remain to be identified definitively. The purpose of the present study was to identify genetic variants that confer susceptibility to hypertension in Japanese individuals. METHODS: A total of 5,734 Japanese individuals from two independent populations were examined: subject panel A comprised 2,066 hypertensive individuals and 824 controls; and subject panel B comprised 834 hypertensive individuals and 2,010 controls. The 150 polymorphisms examined in the present study were selected by genome-wide association studies of myocardial infarction and ischemic stroke with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS: The chi(2)-test revealed that 10 polymorphisms were significantly (P < 0.05) related to the prevalence of hypertension in subject panel A. To validate the relations, these polymorphisms were examined in subject panel B. The A-->G polymorphism (rs645106) of SDK1 and the C-->G polymorphism (rs12078839) of RABGAP1L were significantly associated with hypertension in subject panel B. Multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that the A-->G polymorphism of SDK1 was significantly associated with hypertension in both subject panels A and B, with the G allele protecting against this condition. CONCLUSIONS: SDK1 may be a susceptibility gene for hypertension in Japanese individuals, although the functional relevance of the identified polymorphism was not determined.

Association of gene polymorphisms with chronic kidney disease in Japanese individuals.

Chronic kidney disease (CKD) is recognized as a risk factor not only for end-stage renal disease but also for cardiovascular disease. Early detection and treatment of CKD is a likely key factor for prevention of its complications. Although genetic linkage analyses and association studies have implicated several loci and candidate genes in predisposition to CKD, the genes that underlie genetic susceptibility to this condition have remained largely unknown. The purpose of the present study was to identify genetic variants that confer susceptibility to CKD in Japanese individuals. The study population comprised 4,829 Japanese individuals (2,697 men, 2,132 women), including 757 subjects with CKD [464 men, 293 women; estimated glomerular filtration rate (eGFR) <50 ml min 1.73 m(-2)] and 4,072 controls (2,233 men, 1,839 women; eGFR >or=60 ml min 1.73 m(-2)). The genotypes for 40 polymorphisms of 39 candidate genes were determined. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that six polymorphisms of F10, PITRM1, PCSK2, JPH3, MYO7B, and AKAP12 were related (P<0.05) to the prevalence of CKD. Among these polymorphisms, the Cright curved arrow T polymorphism of F10 (rs5962) was most significantly associated with this condition. Determination of genotypes for the Cright curved arrow T polymorphism of F10 may prove informative for assessment of genetic risk for CKD in Japanese individuals.

Integrated backscatter and intima-media thickness of the thoracic aorta evaluated by transesophageal echocardiography in hypercholesterolemic patients: effect of pitavastatin therapy.

The effect of a strong, lipophilic statin (pitavastatin) on the thoracic aorta has not yet been elucidated. The purpose of the present study was to evaluate the effects of pitavastatin (P) therapy on plaque components and morphology in the thoracic aorta by transesophageal echocardiography (TEE) and clarify the impact of the therapy on media and intima in patients with hypercholesterolemia. Sixty-four media and 64 intima of the thoracic aorta were investigated in 32 patients with hypercholesterolemia. The corrected integrated backscatter (c-IBS) values in the thoracic aortic wall and intima-media thickness (IMT) at the same site were measured before and after P therapy or diet (D) for 7 mo. Moreover, c-IBS values in media were measured in 168 patients without hypercholesterolemia to estimate age-dependent changes. C-IBS values in media were correlated with age (r = 0.84, p < 0.001). C-IBS and IMT of media in the P group significantly decreased from -17.8 +/- 2.4 to -20.1 +/- 3.7 dB and from 1.7 +/- 0.3 to 1.5 +/- 0.3 mm, respectively (p < 0.001), whereas those in the D group significantly increased from -18.3 +/- 2.0 to -16.7 +/- 2.1 dB and from 1.6 +/- 0.3 to 1.7 +/- 0.2 mm, respectively (p < 0.001). IMT in intima in the P group significantly decreased from 3.7 +/- 0.4 to 3.3 +/- 0.4 mm (p < 0.001). C-IBS in intima in the P group significantly increased from -10.2 +/- 2.2 to -6.9 +/- 1.7 dB, which indicated plaque stabilization. Pitavastatin improved the atherosis measured by IMT and sclerosis measured by c-IBS values in the media and induced stabilization and regression of plaques in the intima of the thoracic aorta.

Assessment of genetic risk factors for thoracic aortic aneurysm in hypertensive patients.

BACKGROUND: Conventional risk factors for thoracic aortic aneurysm including dissection (TAA) are thought to include age, arteriosclerosis, and hypertension. In addition, evidence suggests that genetic factors play a role in the development of this condition. The purpose of the present study was to identify genetic variants that confer susceptibility to TAA in hypertensive subjects. METHODS: Study subjects comprised 1,351 hypertensive individuals: 88 patients with TAA and 1,263 subjects without this condition. The genotypes for 142 polymorphisms of 119 candidate genes were determined by a method that combines the PCR and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: Evaluation of genotype distributions by the chi2-test and subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the 3949T-->G (3' untranslated region) polymorphism of the thrombospondin-2 gene (THBS2; odds ratio, 4.6), the -110A-->C polymorphism of the heat shock 70-kDa protein 8 gene (HSPA8; odds ratio, 0.4), the C-->T (Pro198Leu) polymorphism of the glutathione peroxidase 1 gene (GPX1; odds ratio, 0.3), the -6G-->A polymorphism of the angiotensinogen gene (AGT; odds ratio, 0.3), and the -850C-->T polymorphism of the tumor necrosis factor gene (TNF; odds ratio, 0.5) were significantly (P < 0.05) associated with TAA. CONCLUSIONS: The variant allele of THBS2 is a risk factor for TAA in hypertensive patients, whereas the variant alleles of HSPA8, GPX1, AGT, and TNF are protective against this condition. Determination of genotypes for these polymorphisms may prove informative for assessment of the genetic risk for TAA.

Genetic factors for ischemic and hemorrhagic stroke in Japanese individuals.

BACKGROUND AND PURPOSE: Although genetic epidemiologic studies have implicated several genetic variants as risk factors for ischemic or hemorrhagic stroke, the genetic determinants of these conditions remain largely unknown. We performed an association study to identify gene polymorphisms that confer susceptibility to atherothrombotic cerebral infarction, intracerebral hemorrhage, or subarachnoid hemorrhage. METHODS: The study population comprised 3432 unrelated Japanese individuals: 1362 stroke patients (822 with atherothrombotic cerebral infarction, 333 with intracerebral hemorrhage, and 207 with subarachnoid hemorrhage) and 2070 controls. The genotypes for 50 polymorphisms of 38 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. RESULTS: An initial chi(2) test (false discovery rate <0.05) and subsequent multivariable logistic-regression analysis with adjustment for conventional risk factors (P<0.05) revealed that the -14C-->T polymorphism (rs1800977) of ABCA1, the A-->C (rs3027898) and C-->T (Ser532Leu, rs1059703) polymorphisms of IRAK1, and the G-->C (Cys2229Ser) polymorphism (rs619203) of ROS1 were significantly associated with atherothrombotic cerebral infarction; that the -428G-->A polymorphism (rs710968) of LIMK1 was significantly associated with intracerebral hemorrhage; and that the 13989A-->G (Ile118Val) polymorphism (NC_000007.12) of CYP3A4 was significantly associated with subarachnoid hemorrhage. CONCLUSIONS: Genotypes for ABCA1, IRAK1, and ROS1 may prove useful for assessment of the genetic risk for atherothrombotic cerebral infarction, whereas those for LIMK1 and CYP3A4 may be similarly beneficial in assessment of the genetic risk for intracerebral hemorrhage and subarachnoid hemorrhage, respectively. Validation of these findings will require additional studies with independent subject panels.

Over 10 years clinical outcomes in patients with mitral stenosis with unilateral commissural calcification treated with catheter balloon commissurotomy: single-center experience.

OBJECTIVES: Treatment of mitral valve stenosis with catheter balloon commissurotomy (CBC) yields acceptable immediate results even when one commissure shows calcification. However, the long-term outcomes in such cases remain unclear. METHODS: We examined the immediate and long-term (mean: 11+/-5 years) outcomes of 57 patients who underwent 58 CBC procedures. Patients were classified into group A (no commissural calcification, n=44) or group B (unilateral commissural calcification, n=13). From the appearance of the mitral valve just after CBC, commissurotomy was judged to be bilateral, incomplete, or excessive. End points were death, recurrence of congestive heart failure necessitating hospitalization, embolism, repeat CBC, or mitral valve replacement. RESULTS: There were significant numbers of unfavorable mitral valve morphologies evaluated according to Sellors classification, estimated by echocardiograms; Sellors class I: 20 patients in group A vs. none in group B (p<0.05). Class II: 24 in group A vs. 10 in group B. and class III: none in group A vs. 3 in group B (p<0.05). CBC increased the mitral valve area (Gorin formula) from 1.3+/-0.3 to 2.1+/-0.5 cm2 in patients in group A and from 1.1+/-0.2 to 1.8+/-0.4 cm2 in those in group B (p=n.s.). Among the latter, there were significantly more excessive commissurotomies than in group A and no bilateral commissurotomy. The overall or event-free survival rate during the follow-up of group B showed a lower tendency than in group A (overall: group A: 86.2% vs. group B: 84.6%, p, n.s. event-free: 56.8% vs. 46.2%, respectively, p=n.s.). Univariate predictors of all events in group B included post-CBC pulmonary arterial pressure, and the pattern of commissurotomy after CBC (p<0.05). Excessive commissurotomy increased clinical events some years later, after the procedure. CONCLUSIONS: In this study, involving a small number of subjects, long-term outcomes of patients with unilateral commissural calcification receiving CBC showed no significant difference as compared to those with commissural calcification absence. However, it is necessary to perform careful follow-up of CBC patients with unilateral commissural calcium.

Association of genetic variants with atherothrombotic cerebral infarction in Japanese individuals with metabolic syndrome.

Metabolic syndrome is a risk factor for cardiovascular disease. The aim of the present study was to identify genetic variants that confer susceptibility to atherothrombotic cerebral infarction among individuals with metabolic syndrome in order to allow prediction of genetic risk for this condition. The study population comprised 1284 unrelated Japanese individuals with metabolic syndrome, including 313 subjects with atherothrombotic cerebral infarction and 971 controls. The genotypes for 296 polymorphisms of 202 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. The Chi-square test, multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of hypertension, hypercholesterolemia, and diabetes mellitus, as well as a stepwise forward selection procedure revealed that the 2445G-->A (Ala54Thr) polymorphism (rs1799883) of FABP2, the -108/3G-->4G polymorphism of IPF1 (S82168), the A-->G (Thr94Ala) polymorphism (rs2241883) of FABP1, the G-->A (Asp2213Asn) polymorphism (rs529038) of ROS1, the -11377C-->G polymorphism (rs266729) of ADIPOQ, the 162A-->C polymorphism (rs4769055) of ALOX5AP, the -786T-->C polymorphism (rs2070744) of NOS3, and the 3279C-->T polymorphism (rs7291467) of LGALS2 were associated (P<0.05) with the prevalence of atherothrombotic cerebral infarction. Among these polymorphisms, the 2445G-->A (Ala54Thr) polymorphism of FABP2 was most significantly associated with this condition. Our results suggest that FABP2, IPF1, FABP1, ROS1, ADIPOQ, ALOX5AP, NOS3, and LGALS2 are susceptibility loci for atherothrombotic cerebral infarction among Japanese individuals with metabolic syndrome. Genotypes for these polymorphisms, especially for the 2445G-->A (Ala54Thr) polymorphism of FABP2, may prove informative for the prediction of genetic risk for atherothrombotic cerebral infarction among such individuals.

Prospective randomized trial comparing a nitinol self-expanding coronary stent with low-pressure dilatation and a high-pressure balloon expandable bare metal stent.

The recent SCORES trial demonstrated that lower dilatation pressures seen with self-expanding (SE) stents may be associated with lower rates of target lesion revascularization (TLR). To determine whether SE stents with low-pressure dilatation are as safe and effective as balloon expandable (BE) stents. We randomly assigned 254 patients with 279 coronary lesions to groups receiving either SE with low-pressure dilatation <12 atm (n = 143) or conventional BE stents (n = 136). Thereafter, acute results and long-term outcomes were compared. Baseline patient and angiographic characteristics were similar in two groups. The incidence of procedural complications, such as slow flow, side branch occlusion, and edge dissection were significantly lower in the SE group than in the BE group (overall: SE, 17; BE, 35; P < 0.01), and the occurrence of myocardial infarction tended to be lower in SE than in BE (SE, 1; BE, 4; not significant). Although acute gain was significantly smaller with SE than BE (SE, 2.21 +/- 0.65 mm; BE, 2.42 +/- 0.62; P < 0.01), probably due to gradual expansion of the SE stent, nearly identical minimum luminal diameters on follow-up angiography (SE, 2.14 +/- 0.92 mm vs. BE, 2.22 +/- 0.93; not significant) and similar angiographic restenosis (SE, 18.1% vs. BE, 20.5%). and TLR rates (SE, 16.1% vs. BE, 14.0%) were apparent. This prospective randomized trial demonstrates that SE stents with low-pressure dilatation is safe and effective strategy for treating coronary arterial stenosis.

Association of polymorphisms of ABCA1 and ROS1 with hypertension in Japanese individuals.

Although various environmental factors, such as a high-salt diet, a smoking habit, excessive alcohol intake, and physical inactivity, influence the development of hypertension, genetic variation also contributes to an individual's susceptibility to this condition. The purpose of the present study was to identify gene polymorphisms that confer susceptibility or resistance to hypertension, and thereby contribute to the prediction of the genetic risk for this condition. The study population comprised 2752 unrelated Japanese individuals (1370 men, 1382 women), including 1276 subjects with hypertension (774 men, 502 women) and 1476 controls (596 men, 880 women). The genotypes for 50 polymorphisms of 35 candidate genes were determined by a method that combines polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the Chi-square test and subsequent multivariable logistic regression analysis with adjustment for age, sex, body mass index, smoking status, and the prevalence of diabetes mellitus and hypercholesterolemia revealed that the -14C-->T polymorphism of ABCA1, the C-->G (Ser2229Cys) polymorphism of ROS1, the C-->T (Asn591Asn) polymorphism of LDLR, the 13989A-->G (Ile118Val) polymorphism of CYP3A4, the C-->G and A-->C polymorphisms of ADIPOR1, and the -519A-->G polymorphism of MMP1 were significantly (P<0.05) associated with the prevalence of hypertension. Systolic and diastolic blood pressure differed significantly among genotypes for the -14C-->T polymorphism of ABCA1 and the C-->G (Ser2229Cys) polymorphism of ROS1, with the variant T and G alleles, respectively, being related to increased blood pressure. These results suggest that polymorphisms of ABCA1 and ROS1 are determinants of blood pressure and the development of hypertension in Japanese individuals. Determination of genotypes for ABCA1 and ROS1 may thus prove informative for the prediction of the genetic risk for hypertension.

Association of a polymorphism of CYP3A4 with type 2 diabetes mellitus.

Although several environmental factors, including a high-calorie diet and physical inactivity, influence the development of type 2 diabetes mellitus, genetic factors have been shown to contribute to individual susceptibility to this condition. The purpose of the present study was to identify gene polymorphisms that confer susceptibility or resistance to type 2 diabetes mellitus, and thereby to contribute to assessment of the genetic risk for this condition. The study population comprised 5259 unrelated Japanese individuals (2980 men, 2279 women), including 1640 subjects with type 2 diabetes mellitus (1071 men, 569 women) and 3619 controls (1909 men, 1710 women). The genotypes for 94 polymorphisms of 67 genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Evaluation of genotype distributions by the chi-square test revealed that the 13989-->G (Ile118Val) polymorphism of the cytochrome P450, subfamily IIIA, polypeptide 4 gene (CYP3A4) was significantly (false discovery rate, 0.000009) associated with the prevalence of type 2 diabetes mellitus. Multivariable logistic regression analysis with adjustment for age and sex also revealed that the 13989-->G (Ile118Val) polymorphism of CYP3A4 was significantly (P=0.00002) associated with the prevalence of type 2 diabetes mellitus, with the AG genotype being protective against this condition. Genotyping for CYP3A4 may thus prove informative for assessment of the genetic risk for type 2 diabetes mellitus.

Identification of a polymorphism of UCP3 associated with recurrent in-stent restenosis of coronary arteries.

The purpose of the present study was to identify gene polymorphisms that confer susceptibility to recurrent restenosis after bare-metal stenting of coronary arteries, and thereby to assess the genetic risk for this condition. The study population comprised 527 unrelated Japanese individuals, including 28 subjects who developed in-stent restenosis two or more times and 499 subjects without restenosis. The genotypes for 142 polymorphisms of 121 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Eleven polymorphisms were related (P<0.05) to the prevalence of recurrent in-stent restenosis as determined by the Chi-square test. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hypercholesterolemia revealed that the -55Cright curved arrow T polymorphism of the uncoupling protein 3 gene (UCP3) was significantly (P=0.0006 in a recessive model) associated with the prevalence of recurrent in-stent restenosis, with the T allele representing a risk factor for this condition. A stepwise forward selection procedure showed that the UCP3 genotype significantly (P=0.0014, recessive model) affected the prevalence of recurrent in-stent restenosis. Determination of the genotype for UCP3 may thus contribute to assessment of the genetic risk for recurrent in-stent restenosis.

Genetic factors for lone atrial fibrillation.

Atrial fibrillation (AF) may result from an electric conduction disturbance, increased hemodynamic stress, ischemia, inflammation, or remodeling in atria. Although genetic epidemiological studies have identified several genetic variants as risk factors for AF, the genetic determinants of this condition remain largely unknown. The purpose of the present study was to identify gene polymorphisms that confer susceptibility to lone AF. The study population comprised 1069 unrelated Japanese individuals, including 196 subjects with chronic lone AF and 873 controls. The genotypes for 40 polymorphisms of 32 candidate genes were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and hyperchole-sterolemia as well as a stepwise forward selection procedure revealed that the -1306C-->T polymorphism of the matrix metalloproteinase 2 gene (MMP2) and the -592A-->C polymorphism of the interleukin 10 gene (IL10) were significantly (false discovery rate of <0.05) associated with the prevalence of AF. The T allele of the MMP2 polymorphism and the C allele of the IL10 polymorphism were a risk factor for and protective factor against AF, respectively. Determination of the genotypes for these polymorphisms may thus prove informative for assessment of the genetic component of AF.

Gender differences in the association of gene polymorphisms with type 2 diabetes mellitus.

Type 2 diabetes mellitus is a complex metabolic disorder in which endogenous sex hormones may contribute to sex-dependent etiologies. We hypothesized that genetic variants related to type 2 diabetes mellitus might differ between men and women. We thus performed a large-scale association study to identify gene polymorphisms associated with type 2 diabetes mellitus in men and women separately. The study population comprised 4854 unrelated Japanese individuals (2688 men, 2166 women), including 1490 subjects with type 2 diabetes mellitus (969 men, 521 women). The genotypes for 16 gene polymorphisms were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, body mass index, and smoking status revealed that the T-->G (3' UTR) polymorphism of the thrombospondin 2 gene (THBS2), the -603A-->G polymorphism of the coagulation factor III gene (F3), and the G-->T (intron 2) polymorphism of the adipocyte, C1Q, and collagen domain containing (adiponectin) gene (ADIPOQ) were significantly associated with the prevalence of type 2 diabetes mellitus in men, and that the A-->G (Arg160Gly) polymorphism of the paraoxonase 1 gene (PON1) was significantly associated with this condition in women. A stepwise forward selection procedure demonstrated that genotypes of THBS2, F3, and ADIPOQ were significant determinants of type 2 diabetes mellitus in men, and that genotype of PON1 significantly affected this condition in women. Genotyping of these polymorphisms may prove informative for assessment of the genetic component of type 2 diabetes mellitus for men and women separately.

Genetic risk for restenosis after coronary stenting.

OBJECTIVES: The purpose of the present study was to identify gene polymorphisms that confer susceptibility to restenosis after bare-metal stenting of coronary arteries, and thereby to predict the genetic risk for this condition. METHODS AND RESULTS: The study population comprised 461 unrelated Japanese individuals (350 men, 111 women) who underwent stent implantation, including 107 subjects who developed in-stent restenosis and 354 subjects without this condition. The genotypes for 142 polymorphisms of 121 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariate logistic regression analysis with adjustment for the prevalence of diabetes mellitus revealed that the 1615G-->A polymorphism of BCHE, the 7,067,365C-->A polymorphism of INSR, the C-->T polymorphism of GPX1, the G-->A polymorphism of ROS1, and the G-->A polymorphism of MMP9 were associated (P<0.05) with in-stent restenosis. Further analysis with adjustment both for the prevalence of diabetes mellitus and for quantitative coronary angiographic measurements revealed that the BCHE, GPX1, and ROS1 genotypes were independently associated (P<0.05) with in-stent restenosis. CONCLUSIONS: Determination of the genotypes for BCHE, GPX1, and ROS1 may prove informative for assessment of the genetic risk for in-stent restenosis.

Prediction of genetic risk for metabolic syndrome.

OBJECTIVES: The aim of the study was to identify gene polymorphisms that confer susceptibility to metabolic syndrome in order to allow reliable assessment of genetic risk for this condition. METHODS AND RESULTS: The study population comprised 1788 unrelated Japanese individuals (1033 men, 755 women), including 1017 subjects with metabolic syndrome (634 men, 383 women) and 771 controls (399 men, 372 women). The genotypes for 158 polymorphisms of 133 candidate genes were determined with a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. Multivariable logistic regression analysis with adjustment for age, sex, and the prevalence of smoking revealed that the -1131T-->C polymorphism of the apolipoprotein A-V gene (APOA5) was significantly associated with the prevalence of metabolic syndrome, with the C allele representing a risk factor for this condition. A stepwise forward selection procedure demonstrated that APOA5 genotype (CC+TC versus TT) significantly affected the prevalence of metabolic syndrome. The C allele of this polymorphism was associated with an increased serum concentration of triglycerides and a decreased concentration of HDL-cholesterol. CONCLUSIONS: Genotype for APOA5 may prove reliable for assessment of genetic risk for metabolic syndrome.