Norifumi Metoki

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.

Identification of CELSR1 as a susceptibility gene for ischemic stroke in Japanese individuals by a genome-wide association study

OBJECTIVE We have performed a genome-wide association study (GWAS) to identify genetic variants that confer susceptibility to ischemic stroke. METHODS A total of 6341 individuals from three independent populations was examined. Subject panel A comprised 131 individuals with ischemic stroke and 135 controls; subject panel B comprised 790 individuals with ischemic stroke and 3435 controls; and subject panel C comprised 71 individuals with ischemic stroke and 1779 controls. A GWAS for ischemic stroke was performed in subject panel A with the use of the GeneChip Human Mapping 500K Array Set (Affymetrix). RESULTS The relation of 100 single nucleotide polymorphisms (SNPs) selected by the GWAS to ischemic stroke was examined in 705 subjects with ischemic stroke and 3426 controls selected from subject panel B. Three SNPs (rs1671021 of LLGL2, rs9615362 of CELSR1, and rs753307 of RUVBL2) were significantly (P<0.05) associated with ischemic stroke. After DNA sequencing of linkage disequilibrium blocks containing these SNPs, three tag SNPs (rs6007897 of CELSR1, rs1671021 of LLGL2, and rs1062708 of RUVBL2) and a nonsynonymous SNP (rs4044210 of CELSR1) were examined for their relation to ischemic stroke in subject panels B and C. Both rs6007897 (A-->G, Thr2268Ala) and rs4044210 (A-->G, Ile2107Val) of CELSR1 as well as rs1671021 (T-->C, Phe479Leu) of LLGL2 were significantly associated with ischemic stroke in subject panel B. The rs6007897 and rs4044210 polymorphisms of CELSR1 were also significantly associated with ischemic stroke in subject panel C. CONCLUSION CELSR1 is a susceptibility gene for ischemic stroke in Japanese individuals, although the functional relevance of the identified SNPs was not determined.

Characteristics of Intracerebral Hemorrhage During Rivaroxaban Treatment Comparison With Those During Warfarin

Background and Purpose— Neuroradiological characteristics and functional outcomes of patients with intracerebral hemorrhage (ICH) during novel oral anticoagulant treatment were not well defined. We examined these in comparison with those during warfarin treatment. Methods— The consecutive 585 patients with ICH admitted from April 2011 through October 2013 were retrospectively studied. Of all, 5 patients (1%) had ICH during rivaroxaban treatment, 56 (10%) during warfarin, and the other 524 (89%) during no anticoagulants. We focused on ICH during rivaroxaban and warfarin treatments and compared the clinical characteristics, neuroradiological findings, and functional outcomes. Results— Patients in the rivaroxaban group were all at high risk for major bleeding with hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly (HAS-BLED) score of 3 and higher rate of past history of ICH. Moreover, multiple cerebral microbleeds (≥4) were detected more frequently in rivaroxaban group than in warfarin (80% versus 29%; P=0.04). Hematoma volume in rivaroxaban group was markedly smaller than that in warfarin (median: 4 versus 11 mL; P=0.03). No patient in the rivaroxaban group had expansion of hematoma and surgical treatment. Rivaroxaban group showed lower modified Rankin Scale at discharge relative to warfarin, and the difference between modified Rankin Scale before admission and at discharge was smaller in rivaroxaban than in warfarin (median: 1 versus 3; P=0.047). No patient in the rivaroxaban group died during hospitalization, whereas 10 (18%) warfarin patients died. Conclusions— Rivaroxaban-associated ICH occurs in patients at high risk for major bleeding. However, they had a relatively small hematoma, no expansion of hematoma, and favorable functional and vital outcomes compared with warfarin-associated ICH.

Muscular Atrophy in the Hemiplegic Thigh in Patients After Stroke

Metoki N, Sato Y, Satoh K, Okumura K, Iwamoto J: Muscular atrophy in the hemiplegic thigh in patients after stroke. Am J Phys Med Rehabil 2003;82:862–865. Objectives This study evaluated muscular atrophy in the hemiplegic limbs by assessing the muscle volume of the thighs in stroke patients. Design Muscle volume of the bilateral thighs was determined by computed tomographic scanning in 50 hemiplegic patients after stroke. Results The average muscle volume in the hemiplegic side was significantly lower than that in the nonhemiplegic side. When the patients were divided into the two groups aged <65 yr old and ≥65 yr, age-dependent reduction in the muscle volume was significant only in the nonhemiplegic side. In addition, the ratio of the muscle volume in the hemiplegic side to that in the nonhemiplegic side was significantly lower in the older group than in the younger group. Muscle volume in both hemiplegic and nonhemiplegic sides correlated positively with Barthel index and negatively with patient age. Conclusion Muscle volume decreases in the hemiplegic side in stroke patients.

Efficacy of methylprednisolone pulse therapy on neuroleptic malignant syndrome in Parkinson’s disease

Background: Neuroleptic malignant syndrome (NMS) is a dangerous complication in patients with Parkinson’s disease (PD). Aims: To evaluate the efficacy of methylprednisolone pulse therapy compared to placebo in PD patients with NMS. Methods: In a double blind, placebo controlled study, 20 PD patients with NMS received steroid pulse therapy for three days, and 20 PD patients received placebo. Both groups received levodopa, bromocriptine, and dantrolene. Results: NMS in the steroid group healed within 10 days in 17 patients; median value of duration of illness of NMS in this group was 7 days (range 4–20). NMS in the placebo group healed within 10 days in five patients; in the remaining 15, it persisted for 12–27 days after the onset of NMS; median value of duration illness of NMS in this group was 18 days. Hyperthermia, rigidity, and consciousness improved within 10 days in many patients in the steroid group; these signs persisted more than 10 days in many patients in the placebo group. Conclusions: Steroid pulse therapy is useful in NMS for reducing the illness duration and improving symptoms.

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 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.