Kiyoshi Yokoi

Mitochondrial haplogroup N9a confers resistance against type 2 diabetes in Asians.

Because mitochondria play pivotal roles in both insulin secretion from the pancreatic beta cells and insulin resistance of skeletal muscles, we performed a large-scale association study to identify mitochondrial haplogroups that may confer resistance against or susceptibility to type 2 diabetes mellitus (T2DM). The study population comprised 2,906 unrelated Japanese individuals, including 1,289 patients with T2DM and 1,617 controls, and 1,365 unrelated Korean individuals, including 732 patients with T2DM and 633 controls. The genotypes for 25 polymorphisms in the coding region of the mitochondrial genome were determined, and the haplotypes were classified into 10 major haplogroups (i.e., F, B, A, N9a, M7a, M7b, G, D4a, D4b, and D5). Multivariate logistic-regression analysis with adjustment for age and sex revealed that the mitochondrial haplogroup N9a was significantly associated with resistance against T2DM (P=.0002) with an odds ratio of 0.55 (95% confidence interval 0.40-0.75). Even in the modern environment, which is often characterized by satiety and physical inactivity, this haplogroup might confer resistance against T2DM.

Genetic Risk for Ischemic and Hemorrhagic Stroke

Objective—We performed an association study to identify gene polymorphisms for assessing the genetic risk of ischemic or hemorrhagic stroke. Methods and Results—The study population comprised 3151 unrelated Japanese individuals: 1141 stroke patients (636 with atherothrombotic cerebral infarction, 282 with intracerebral hemorrhage, and 223 with subarachnoid hemorrhage) and 2010 controls. The genotypes for 202 polymorphisms of 152 genes were determined by suspension array technology. Multivariable logistic regression analysis with adjustment for conventional risk factors revealed that the –572G→C polymorphism of the interleukin-6 (IL-6) gene (IL6) was significantly (P<0.001) associated with both atherothrombotic cerebral infarction and intracerebral hemorrhage and that the –55C→T polymorphism of the uncoupling protein 3 gene (UCP3), the –863C→A polymorphism of the tumor necrosis factor (TNF) gene (TNF), and the G→A (Gly243Asp) polymorphism of the polycystic kidney disease 1–like gene (PKD1-like) were significantly associated with subarachnoid hemorrhage. Conclusions—IL6 genotype may be useful in assessing the genetic risk for atherothrombotic cerebral infarction and intracerebral hemorrhage, and genotypes for UCP3, TNF, and PKD1-like may be similarly beneficial in assessment of the risk for subarachnoid hemorrhage. Validation of our findings will require additional studies with independent subject panels.

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 &khgr;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.

Genetic risk for metabolic syndrome: examination of candidate gene polymorphisms related to lipid metabolism in Japanese people

Background: The aetiology of metabolic syndrome is complex, being determined by the interplay of both genetic and environmental factors. The aim of this study was to identify genetic polymorphisms that confer susceptibility to metabolic syndrome, to allow prediction of genetic risk for this condition. Methods: The study population comprised 2417 unrelated Japanese subjects (1522 with metabolic syndrome and 895 controls). The genotypes for 44 polymorphisms of 31 candidate genes related to lipid metabolism were determined using a combination of PCR and sequence-specific oligonucleotide probes with suspension array technology. Results: The χ2 test and subsequent multivariate logistic regression analysis with adjustment for age, sex and smoking status found that the–3A→G and 553G→T (Gly185Cys) polymorphisms of APOA5, the 2052T→C (Val653Val) and 1866C→T (Asn591Asn) polymorphisms of LDLR, the 13989A→G (Ile118Val) polymorphism of CYP3A4 and the 1014T→A polymorphism of C1QTNF5 were significantly (false discovery rate <0.05) associated with the prevalence of metabolic syndrome, with the variant alleles of APOA5 and C1QTNF5 representing risk factors for and those of LDLR and CYP3A4 being protective against this condition. Serum levels of triglycerides and high-density lipoprotein (HDL) cholesterol differed significantly (p<0.05) among APOA5 genotypes; the serum level of HDL cholesterol differed among LDLR genotypes; and the fasting plasma glucose level and body mass index differed between CYP3A4 and C1QTNF5 genotypes, respectively. Conclusions: APOA5, LDLR, CYP3A4 and C1QTNF5 are susceptibility loci for metabolic syndrome in Japanese people. Genotypes for these polymorphisms may prove informative for prediction of genetic risk for metabolic syndrome.

Assessment of genetic risk for myocardial infarction

Although lifestyle and environmental factors influence the prevalence of myocardial infarction, genetic epidemiological studies have suggested that several genetic variants increase the risk for this condition. We have performed a large-scale association study to identify gene polymorphisms for reliable assessment of the genetic risk of myocardial infarction. The study population comprised 3,483 unrelated Japanese individuals (1,913 men; 1,570 women), including 1,192 subjects with myocardial infarction and 2,291 controls. The genotypes for 164 polymorphisms of 137 candidate genes were determined with an oligonucleotide ligation assay based on analysis of fluorescent microspheres 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 hypercholesterolemia revealed that the 677C-->T (Ala222Val) polymorphism of MTHFR, the 1595C-->G (Ser447Stop) polymorphism of LPL, and the -108/3G-->4G polymorphism of IPF1 were significantly associated with the prevalence of myocardial infarction. A stepwise forward selection procedure demonstrated that IPF1, MTHFR, and LPL genotypes significantly affected the prevalence of myocardial infarction. Combined genotype analysis of these polymorphisms yielded a maximum odds ratio of 2.54 for the combined genotype of TT for MTHFR, CC for LPL, and 3G3G for IPF1. The genotypes for MTHFR, LPL, and IPF1 may prove reliable for assessment of genetic risk for myocardial infarction. Determination of the combined genotype for these genes may contribute to primary, personalized prevention of this condition.

Association of genetic variants with myocardial infarction in Japanese individuals with metabolic syndrome

OBJECTIVE The purpose of the present study was to identify genetic variants that confer susceptibility to myocardial infarction (MI) in individuals with metabolic syndrome (MetS). METHODS The study population comprised 1887 Japanese individuals with MetS, including 773 subjects with MI and 1114 controls. The genotypes for 136 polymorphisms of 97 candidate genes were determined. RESULTS An initial screen by the chi-square test revealed that seven polymorphisms were significantly (false discovery rate<0.05) associated with the prevalence of MI in individuals with MetS. Subsequent multivariable logistic regression analysis with adjustment for covariates revealed that the G-->A (Ser89Asn) polymorphism of UTS2 [odds ratio (OR), 1.90; 95% confidence interval (CI), 1.18-3.08], the 2445G-->A (Ala54Thr) polymorphism of FABP2 (OR, 1.72; 95% CI, 1.23-2.40), the -11377C-->G polymorphism of ADIPOQ (OR, 1.43; 95% CI, 1.15-1.79), the -231A-->G polymorphism of EDNRA (OR, 0.65; 95% CI, 0.48-0.89), and the -108/3G-->4G polymorphism of PDX1 (OR, 0.64; 95% CI, 0.48-0.87) were significantly (P<0.05) associated with MI. The variant alleles of UTS2, FABP2, and ADIPOQ were risk factors for MI, whereas the variant alleles of EDNRA and PDX1 were protective against this condition. A stepwise forward selection procedure demonstrated that UTS2, FABP2, ADIPOQ, EDNRA, and PDX1 genotypes were significant (P<0.05) and independent determinants of MI. CONCLUSIONS Determination of genotypes for these polymorphisms of UTS2, FABP2, ADIPOQ, EDNRA, and PDX1 may prove informative for assessment of the genetic risk for MI in Japanese individuals with MetS.

Association of a polymorphism of BTN2A1 with myocardial infarction in East Asian populations

OBJECTIVE We have performed a genome-wide association study (GWAS) to identify genetic variants that confer susceptibility to myocardial infarction (MI) in Japanese and Korean populations. METHODS A total of 17,447 Japanese or Korean individuals from four independent subject panels was examined. Japanese subject panels A, B, and C comprised 134 individuals with MI and 137 controls, 1431 individuals with MI and 3161 controls, and 643 individuals with MI and 1347 controls, respectively, whereas the Korean population comprised 1880 individuals with MI and 8714 controls. A GWAS for MI was performed in Japanese subject panel A with the use of the Affymetrix GeneChip Human Mapping 500K Array Set. RESULTS Seventy single nucleotide polymorphisms (SNPs) significantly (P<1.0×10(-7)) associated with MI by the GWAS were examined further in Japanese subject panel B, revealing two SNPs (rs6929846 of BTN2A1, rs2569512 of ILF3) to be significantly (P<0.0007) associated with MI. The rs6929846 SNP of BTN2A1, but not rs2569512 of ILF3, was also significantly associated with MI in Japanese subject panel C. However, the association of neither rs6929846 nor rs2569512 with MI was replicated in the Korean population. CONCLUSION BTN2A1 may be a susceptibility gene for MI in Japanese individuals.

Association of Genetic Variants with Chronic Kidney Disease in Japanese Individuals

BACKGROUND AND OBJECTIVES Although genetic linkage analyses and association studies have implicated several loci and candidate genes in predisposition to chronic kidney disease (CKD), the genes that underlie genetic susceptibility to this condition have remained uncharacterized. The purpose of the present study was to identify genetic variants that confer susceptibility to CKD in Japanese individuals. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS The study population comprised 5217 Japanese individuals (2955 men, 2262 women), including 778 subjects (480 men, 298 women) with CKD [estimated GFR (eGFR), <50 ml min(-1) 1.73 m(-2)] and 4439 controls (2475 men, 1964 women; eGFR, > or =60 ml min(-1) 1.73 m(-2)). The genotypes for 40 polymorphisms of 32 candidate genes were determined. RESULTS The chi-square test and multivariable logistic regression analysis with adjustment for covariates revealed that the -219G-->T polymorphism of APOE, the -519A-->G of MMP1, the -866G-->A of UCP2, the -1607/1G-->2G of MMP1, the A-->G (Lys45Glu) of MMP3, the G-->A (Ala163Thr) of AGTR1, the G-->A (Gly670Arg) of PECAM1, and the -55C-->T of UCP3 were significantly (false discovery rate <0.05) associated with CKD. Comparison of allele frequencies of these polymorphisms by the chi-square test between subgroups of CKD and control subjects individually matched for covariates revealed that the -519A-->G of MMP1 and the -866G-->A of UCP2 were significantly (P < 0.05) associated with CKD. CONCLUSIONS MMP1 and UCP2 may be susceptibility loci for CKD in Japanese individuals. Determination of genotypes for these polymorphisms may prove informative for prediction of genetic risk for CKD.

Diagnostic accuracy of cardiac markers for myocardial damage after radiofrequency catheter ablation

AimsThis study compares serum markers of myocardial damage incurred during radiofrequency catheter ablation (RFCA).Methods and resultsBlood was sampled from 34 patients with atrial flutter (n = 16), atrioventricular nodal reentrant tachycardia (AVNRT; n = 13), and Wolff–Parkinson–White syndrome (WPW; n = 5) to measure creatine kinase MB subfraction (CK-MB), human heart-type fatty acid protein (h-FABP), and cardiac troponin T (cTnT) values at baseline and after RFCA. The controls comprised 12 patients without significant elevation of all myocardial markers during electrophysiological study (EPS) without RFCA. h-FABP values did not elevate significantly, whereas CK-MB and cTnT demonstrated significant change after RFCA (P < 0.001). Neither peak h-FABP nor CK-MB correlated with following RFCA parameters: delivery duration, number of RFCA discharges, and cumulative RFCA energy. In contrast, correlations were significant between mean peak values of cTnT and these RFCA parameters (all P < 0.05). The sensitivity (71.6%) and specificity (35.6%) of h-FABP were inferior to those of cTnT (93.3% and 89.8%, respectively).Conclusionh-FABP is an insensitive and less specific marker of myocardial damage in RFCA much along the lines of CK-MB and when compared with the proven accuracy of cTnT.

Association of a polymorphism of ABCB1 with obesity in Japanese individuals.

The aim of the present study was to identify gene polymorphisms that confer susceptibility to obesity. A total of 5448 unrelated Japanese individuals from two independent populations were examined: subject panel A comprised 4252 individuals who visited participating hospitals; subject panel B comprised 1196 community-dwelling elderly individuals. The genotypes for 95 polymorphisms of 67 candidate genes were determined. The chi(2) test revealed that six polymorphisms were related (p<0.05) to the prevalence of obesity in subject panel A; after application of Bonferronis correction, however, only the 2677G --> A/T polymorphism (rs2032582) of the ATP-binding cassette, subfamily B, member 1 gene (ABCB1) was significantly associated (p=0.0003) with obesity. Subsequent multivariable logistic regression analysis also revealed that the 2677G --> A/T polymorphism of ABCB1 was significantly associated with obesity. For validation of this association, the 2677G --> A/T polymorphism of ABCB1 was examined in subject panel B and again found to be significantly associated with obesity. Body mass index was significantly (p=0.01) greater for individuals with the variant T allele of this polymorphism than for those with the GG genotype in the combined subject panels A and B. Our results suggest that the ABCB1 genotype may prove informative for assessment of genetic risk for obesity in Japanese individuals.