Hitoshi Matsuo

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.

Correlation between lipoprotein(a) and aortic valve sclerosis assessed by echocardiography (the JMS Cardiac Echo and Cohort Study)

An elevated serum level of lipoprotein(a) (Lp[a]) may be an independent risk factor for atherosclerotic disease, but the relation of Lp(a) to aortic valve (AV) sclerosis has not been determined. We measured serum concentrations of Lp(a) and investigated their relation to the presence of echocardiographic AV sclerosis in residents of a rural village in Japan. We measured serum Lp(a) levels in 347 men and 437 women aged 35 to 90 years (mean +/- SD: 62 +/- 11 years) who participated in mass screening examinations in Wara village, Gifu, Japan. AV sclerosis was assessed by long- and short-axis 2-dimensional echocardiographic views and continuous-wave Doppler echocardiography. AV sclerosis was graded as follows: 0 = normal AV; 1 = increased echo density; 2 = thickening or calcific deposits > or = 3 mm; and 3 = same as 2 with mildly restricted motion (pressure gradient < 16 mm Hg). Lp(a) levels ranged from < 1 mg/dl to 153 mg/dl. The 25th, 50th, and 75th percentile values were 7, 16, and 28 mg/dl, respectively. Lp(a) levels were significantly higher in women than in men (p < 0.01), and did not increase significantly with age. The prevalence of AV sclerosis (grades 2 and 3) increased significantly with age (p < 0.001). AV sclerosis was present in 65 (36.1%) of 180 subjects with Lp(a) levels > or = 30 mg/dl and in 77 (12.7%) of 604 subjects with Lp(a) levels < 30 mg/dl (p < 0.001). There were no significant differences in the prevalence of AV sclerosis in terms of sex, blood pressure, or levels of total cholesterol, high-density lipoprotein cholesterol, triglycerides, or blood sugar. We conclude that increased serum levels of Lp(a), as well as aging, are closely related to AV sclerosis.

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.

Women With Mitochondrial Haplogroup N9a Are Protected Against Metabolic Syndrome

To identify mitochondrial haplogroups that confer resistance against or susceptibility to metabolic syndrome, we performed a large-scale association study on 1,337 unrelated Japanese individuals, including 871 subjects with metabolic syndrome and 466 control subjects. Metabolic syndrome was diagnosed according to modified National Cholesterol Education Program Adult Treatment Panel III guidelines, using the cutoff point for obesity as a BMI of ≥25 kg/m2 instead of waist circumference. 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, G1, G2, D5, and D4. Multivariate logistic regression analysis revealed that the haplogroup N9a was significantly associated with resistance against metabolic syndrome in women with an odds ratio (OR) of 0.21 (95% CI 0.07–0.58, P = 0.0042). Women with haplogroups G1 and D5 tended to be resistant against metabolic syndrome with an OR of 0.22 (0.06–0.68, P = 0.0129) for G1 and with an OR of 0.32 (0.10–0.96, P = 0.0469) for D5, respectively. These results indicate that mitochondrial haplogroup N9a may be a protective factor against metabolic syndrome in Japanese women.

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 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.

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.

Reverse short-channel effect of threshold voltage in LOCOS parasitic MOSFETs

Abstract A reverse short-channel effect in LOCOS parasitic MOSFETs is investigated by simulations and experiments. Increase in threshold voltage of the MOSFETs is clearly observed as the LOCOS width decreases to 0.5 μm or less, especially for high substrate doping. Analysis using a nonplanar device simulator shows that this enhancement of the threshold voltage arises from the variation in direction of the electric field at the LOCOS isolation edge due to the two-dimensional structural effect of narrow LOCOS isolation. The reverse short-channel effect is explained by the concept of charge sharing, and the dependence of the reverse short-channel effect on substrate doping and junction depth is examined. As substrate doping increases, a shallow junction depth is found to become an influential parameter for this effect.

Automatic classification of urinary sediment images by using a hierarchical modular neural network

We have developed an automated image-classification method for the examination of urinary sediment. Urine contains many kinds of particles of various colors and sizes. To classify these particles automatically, we developed a hierarchical modular neural network (HMNN) to enable accurate classification of urinary-sediment images. Simulations results showed that a neural network with a modular structure can classify artificially generated patterns more accurately than a single neural network (SNN). By using a HMNN, any kind of particle contained in urine can be automatically classified. We compared the classification accuracy when using the HMNN to that with a SNN and found that the classification accuracy for some classes of particles when using the HMNN was 25% to 30% higher than when using the SNN. With the HMNN, the examination accuracy was sufficient to allow automation of the examination process.

Cardiac Sympathetic Imaging with Radiolabelled Metaiodobenzylguanidine (MIBG) in Patients with Parkinson’s Disease

A radiolabelled norepinephrine analogue, 123I metaiodobenzylguanidine (MIBG) has been widely used to detect cardiac sympathetic denervation or hyperactivity in cardiac diseases. Recently, cardiac 123I MIBG accumulation was reported to be significantly reduced in patients with Parkinson’s disease (PD). On the other hand, PD is known to be associated with various sympathetic disorders. Therefore, we sought to examine the relationship between severity of clinical symptoms or of autonomic dysfunction of PD and reduction of cardiac 123I MIBG accumulation.