Koji Yonemoto

A nonsynonymous SNP in PRKCH (protein kinase C η) increases the risk of cerebral infarction

Cerebral infarction is the most common type of stroke and often causes long-term disability. To investigate the genetic contribution to cerebral infarction, we conducted a case-control study using 52,608 gene-based tag SNPs selected from the JSNP database. Here we report that a nonsynonymous SNP in a member of protein kinase C (PKC) family, PRKCH, was significantly associated with lacunar infarction in two independent Japanese samples (P = 5.1 × 10−7, crude odds ratio of 1.40). This SNP is likely to affect PKC activity. Furthermore, a 14-year follow-up cohort study in Hisayama (Fukuoka, Japan) supported involvement of this SNP in the development of cerebral infarction (P = 0.03, age- and sex-adjusted hazard ratio of 2.83). We also found that PKCη was expressed mainly in vascular endothelial cells and foamy macrophages in human atherosclerotic lesions, and its expression increased as the lesion type progressed. Our results support a role for PRKCH in the pathogenesis of cerebral infarction.

A prospective study of dietary salt intake and gastric cancer incidence in a defined Japanese population: the Hisayama study.

The results of prospective studies of the association between dietary salt intake and gastric cancer occurrence remain controversial. To examine this issue in a cohort study of a general population, 2,476 subjects aged 40 years or older were stratified into 4 groups according to the amount of daily salt intake: namely, <10.0, 10.0–12.9, 13.0–15.9, and ≥ 16.0 per day and were followed up prospectively for 14 years. During the follow‐up period, 93 subjects developed gastric cancer. The age‐ and sex‐adjusted incidence was significantly higher in the second to fourth groups than in the first group (age‐ and sex‐adjusted hazard ratio [95% confidence interval], 2.42 [1.24–4.71] for the second group; 2.10 [1.03–4.30] for the third group; 2.98 [1.53–5.82] for the fourth group). This association remained substantially unchanged even after adjusting for other confounding factors such as age, sex, Helicobacter pylori infection, atrophic gastritis, medical history of peptic ulcer, family history of cancer, body mass index, diabetes, total cholesterol, physical activity, alcohol intake, smoking habit and other dietary factors. In the stratified analysis, a significant salt–cancer association was observed only in subjects who had both Helicobacter pylori infection and atrophic gastritis (age‐ and sex‐adjusted hazard ratio, 2.87 [1.14–7.24]). Our findings suggest that high dietary salt intake is a significant risk factor for gastric cancer; moreover, this association was found to be strong in the presence of Helicobacter pylori infection with atrophic gastritis.

Relationship of metabolic syndrome to periodontal disease in Japanese women: the Hisayama Study.

Recent studies have suggested that several systemic conditions—such as obesity, hypertension, hyperlipidemia, and diabetes—are related to periodontitis. The objective of this study was to examine the relationship between periodontitis and 5 components of metabolic syndrome—abdominal obesity, triglyceride level, high-density lipoprotein cholesterol level, blood pressure, and fasting blood sugar level—in 584 Japanese women. In multivariate analyses, persons exhibiting more components of metabolic syndrome had significantly higher odds ratios for a greater pocket depth and clinical attachment loss than did those with no components; the odds ratios for a greater pocket depth and clinical attachment loss of the persons exhibiting 4 or 5 components were 6.6 (95% confidence interval = 2.6–16.4) and 4.2 (95% confidence interval = 1.2–14.8), respectively. These results indicate that metabolic syndrome increases risk of periodontitis, and suggest that people exhibiting several components of metabolic syndrome should be encouraged to undergo a periodontal examination.

Impact of Metabolic Syndrome on the Development of Cardiovascular Disease in a General Japanese Population: The Hisayama Study

Background and Purpose— The metabolic syndrome (MetS) is associated with an increased risk of cardiovascular disease (CVD) events in general populations. However, well-designed prospective studies in Asian populations are very limited. Methods— We prospectively evaluated a total of 2452 community-dwelling Japanese individuals aged 40 years or older from 1988 to 2002 and examined the effects of MetS defined by the modified National Cholesterol Education Program Adult Treatment Panel III criteria on incident CVD. Results— The prevalence of the MetS was 21% in men and 30% in women at baseline. During the follow up, 307 CVD events occurred. Compared with those without MetS, the age-adjusted incidence of CVD (per 1000 person-years) was significantly higher in subjects with the MetS in both men (21.8 versus 11.6, P<0.01) and women (12.9 versus 6.5, P<0.01). The risk of CVD events was significantly higher even after adjusting for the following confounding factors: age, proteinuria, electrocardiographic abnormalities, serum total cholesterol, smoking habits, alcohol intake, and regular exercise (hazard ratio, 1.86; 95% CI, 1.32 to 2.62 in men and hazard ratio, 1.70; 95% CI, 1.22 to 2.36 in women). The risk of incident CVD was found to increase with the number of components of MetS and became significantly predictive when the number of components reached 3. Similar associations were also observed when CVD was divided into coronary heart disease and stroke. Conclusions— Our findings suggest that MetS is a significant risk factor for the development of CVD in the Japanese middle-aged population.

High-Sensitivity C-Reactive Protein and Coronary Heart Disease in a General Population of Japanese The Hisayama Study

Objective—The purpose of this study was to investigate the effects of high-sensitivity C-reactive protein (hs-CRP) on the risks of coronary heart disease (CHD) in a general population of Japanese. Methods and Results—The Hisayama study is a population-based prospective cohort study. A total of 2589 participants aged 40 years or older were followed up for 14 years. Outcomes are incident CHD (myocardial infarction, coronary revascularization, and sudden cardiac death). The median hs-CRP level was 0.43 mg/L at baseline. During the follow-up period, 129 coronary events were observed. Age- and sex-adjusted annual incidence rates of CHD rose progressively with higher hs-CRP levels: 1.6, 3.3, 4.5, and 7.4 per 1000 person-years for quartile groups defined by hs-CRP levels of <0.21, 0.21 to 0.43, 0.44 to 1.02, and >1.02 mg/L, respectively (P<0.0001 for trend). The risk of CHD in the highest quartile group was 2.98-fold (95% CI, 1.53 to 5.82) higher than that in the lowest group even after controlling for other cardiovascular risk factors. Conclusions—hs-CRP levels were clearly associated with future CHD events in a general population of Japanese. In Japanese populations, the hs-CRP cut-off point for high-risk of future development of CHD is likely to be >1.0 mg/L, which is much lower than that for Western populations.

LDL Cholesterol and the Development of Stroke Subtypes and Coronary Heart Disease in a General Japanese Population The Hisayama Study

Background and Purpose— Although the relation between serum LDL cholesterol level and coronary heart disease (CHD) is well established, its relation with stroke subtypes is less clear. Methods— A total of 2351 inhabitants age ≥40 years in a Japanese community were followed up for 19 years. Results— During follow-up, 271 subjects developed stroke and 144 developed CHD. Whereas the age- and sex-adjusted incidences of CHD significantly increased with increasing LDL cholesterol levels (P for trend <0.001), the associations between LDL cholesterol level and the incidences of ischemic or hemorrhagic stroke were not significant. The age- and sex-adjusted incidences of atherothrombotic infarctions (ATIs) and lacunar infarctions (LIs) significantly increased with increasing LDL cholesterol level (P for trend=0.03 for ATIs and=0.02 for LIs), but no such association was observed for cardioembolic infarction. After multivariate adjustment, the positive associations of LDL cholesterol level with the risks of ATI and CHD remained significant (P for trend=0.02 for ATIs and=0.03 for CHD), whereas the association with LIs was not significant. The risk of ATI significantly increased in the fourth quartile of LDL cholesterol compared with the first quartile (multivariate-adjusted hazard ratio=2.84; 95% CI, 1.17 to 6.93). The multivariate-adjusted risks for developing nonembolic infarction (ATIs and LIs) and CHD were significantly elevated in the groups with elevated LDL cholesterol values with and without the metabolic syndrome. Conclusions— Our findings suggest that an elevated LDL cholesterol level is a significant risk factor for developing ATI as well as CHD, and these associations are independent of the metabolic syndrome.

Secular Trends in Cardiovascular Disease and Its Risk Factors in Japanese Half-Century Data From the Hisayama Study (1961–2009)

Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors. # Clinical Perspective {#article-title-30}Background— Changes in lifestyle and advances in medical technology during the past half century are likely to have affected the incidence and mortality of cardiovascular disease and the prevalence of its risk factors in Japan. Methods and Results— We established 5 cohorts consisting of residents aged ≥40 years in a Japanese community, in 1961 (n=1618), 1974 (n=2038), 1983 (n=2459), 1993 (n=1983), and 2002 (n=3108), and followed up each cohort for 7 years. The age-adjusted incidence of stroke decreased greatly, by 51% in men and by 43% in women, from the 1960s to the 1970s, but this decreasing trend slowed from the 1970s to the 2000s. Among the stroke subtypes, ischemic stroke in both sexes and intracerebral hemorrhage in men showed a similar pattern. Stroke mortality decreased as a result of the decline in incidence and a significant improvement in survival rate. Although the incidence of acute myocardial infarction did not change in either sex, disease mortality declined slightly in women. From the 1960s to the 2000s, blood pressure control among hypertensive individuals improved significantly and the smoking rate decreased, but the prevalence of glucose intolerance, hypercholesterolemia, and obesity increased steeply. Conclusions— Our findings suggest that in Japanese, the decreasing trends in the incidence of ischemic stroke have recently slowed down, and there has been no clear change in the incidence of acute myocardial infarction, probably because the benefits of hypertension control and smoking cessation have been negated by increasing metabolic risk factors.

Impact of Glucose Tolerance Status on Development of Ischemic Stroke and Coronary Heart Disease in a General Japanese Population The Hisayama Study

Background and Purpose— Few studies have shown the association between glucose tolerance status defined by a 75-g oral glucose tolerance test and the development of different types of cardiovascular disease. Methods— A total of 2421 community-dwelling Japanese subjects aged 40 to 79 years who underwent the oral glucose tolerance test were followed up for 14 years. Results— In multivariable analysis, the risks of ischemic stroke in both sexes and coronary heart disease (CHD) in women were significantly higher in subjects with diabetes determined by the World Health Organization criteria than in those with normal glucose tolerance even after adjustment for other confounding factors, but such association was not seen for CHD in men (ischemic stroke: adjusted hazard ratio [HR]=2.54, P=0.002 in men; adjusted HR=2.02, P=0.03 in women; CHD: adjusted HR=1.26, P=0.47 in men; adjusted HR=3.46, P=0.002 in women). Similar associations were observed for fasting plasma glucose levels of ≥7.0 mmol/L (ischemic stroke: adjusted HR=2.15, P=0.03 in men; adjusted HR=2.10, P=0.045 in women; CHD: adjusted HR=1.29, P=0.47 in men; adjusted HR=3.83, P=0.003 in women) and for 2-hour postload glucose levels of ≥11.1 mmol/L (ischemic stroke: adjusted HR=2.71, P=0.003 in men; adjusted HR=2.19, P=0.03 in women; CHD: adjusted HR=1.58, P=0.16 in men; adjusted HR=4.44, P<0.001 in women). The age-adjusted incidences of ischemic stroke and CHD did not significantly increase in subjects with impaired fasting glycemia or impaired glucose tolerance in either sex. Conclusions— Our findings suggest that diabetes is an independent risk factor for ischemic stroke in both sexes and CHD in women in the Japanese population.

Liver Enzymes as a Predictor for Incident Diabetes in a Japanese Population: The Hisayama Study

Objective: We studied the relationship between liver enzymes and the development of diabetes in a general Japanese population.

Incidence and survival of dementia in a general population of Japanese elderly: the Hisayama Study

Objective: To estimate the incidence and survival rates of total and cause specific dementia in a general Japanese population. Methods: A total of 828 subjects without dementia, aged 65 years or over, were followed-up prospectively for 17 years. Dementia was subdivided into cause specific subtypes: namely, Alzheimer’s disease (AD), vascular dementia (VD), dementia with Lewy bodies (DLB), combined dementia and other types of dementia. During the follow-up, 275 subjects developed dementia; of these, 251 (91.2%) were evaluated morphologically, with 164 subjected to brain autopsy examination and the remaining 87 to neuroimaging. Results: The incidences of total dementia, AD, VD, DLB, combined dementia and other types of dementia were 32.3 (n = 275), 14.6 (124), 9.5 (81), 1.4 (12), 3.8 (33), and 3.1 (16) per 1000 person years, respectively. The incidences of AD, combined dementia and other types of dementia rose with increasing age, particularly after the age of 85 years, but this tendency was not observed for VD or DLB. The survival curve of dementia cases aged 65–89 years was significantly lower than that of age and sex matched controls (10 year survival rate, 13.6% vs 29.3%; hazard ratio 1.67; 95% confidence interval 1.31 to 2.13). The 10 year survival rates were not significantly different among dementia subtypes. Conclusions: Our findings suggest that the Japanese elderly population has a high risk for the development of dementia, specifically AD and VD, and once dementia is established, the risk of death is considerable.