Roseanne Peel

Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR) = 1.62, P = 3.9 × 10−8) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR = 1.15, P = 3.9 × 10−4; discovery and replication combined OR = 1.21, P = 4.7 × 10−8). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Cohort Profile: The Hunter Community Study

In almost every country, the proportion of people aged 460 years is growing faster than any other age group and is expected to reach 2 billion worldwide by 2050. Internationally and nationally, considerable efforts are being made to promote active ageing. However, Australia lacks the kind of comprehensive longitudinal research underway in Europe and North America. Although Australia does have a number of longitudinal studies designed to address various issues of health and ageing among older adults, only a few of these studies include a broad and comprehensive range of physical and biological measures. The Hunter Community Study (HCS) is a collaborative study between the University of Newcastle’s School of Medicine and Public Health and the Hunter New England Area Health Service. It is a multi disciplinary initiative that was established to fill some existing gaps in ageing research in Australia and is unique in that it has collected detailed information across all six key policy themes as identified in the Framework for an Australian Ageing Research Agenda. What does the study cover?

Association between type 2 diabetes and chronic arsenic exposure in drinking water: A cross sectional study in Bangladesh

BackgroundChronic exposure to high level of inorganic arsenic in drinking water has been associated with Type 2 Diabetes (T2D). Most research has been ecological in nature and has focused on high levels of arsenic exposure with few studies directly measuring arsenic levels in drinking water as an index of arsenic exposure. The effect of low to moderate levels of arsenic exposure on diabetes risk is largely unknown thus our study is adding further knowledge over previous works.MethodsThis cross sectional study was conducted in 1004 consenting women and men from 1682 eligible participants yielding a participation rate of 60%. These participants are aged > 30 years and were living in Bangladesh and had continuously consumed arsenic-contaminated drinking water for at least 6 months. T2D cases were diagnosed using glucometer following the new diagnostic criteria (Fasting Blood Glucose > 126 mg/dl) from the WHO guideline (WHO 2006), or a self-reported physician diagnosis of type 2 diabetes. Association between T2D and chronic arsenic exposure was estimated by multiple logistic regression with adjustment for age, sex, education, Body Mass Index (BMI) and family history of T2D.ResultsA total of 1004 individuals participated in the study. The prevalence of T2D was 9% (95% CI 7-11%). After adjustment for diabetes risk factors, an increased risk of type 2 diabetes was observed for arsenic exposure over 50 μg/L with those in the highest category having almost double the risk of type 2 diabetes (OR=1.9 ; 95% CI 1.1-3.5). For most levels of arsenic exposure, the risk estimates are higher with longer exposure; a dose–response pattern was also observed.ConclusionsThese findings suggest an association between chronic arsenic exposure through drinking water and T2D. Risks are generally higher with longer duration of arsenic exposure. The risk of T2D is highest among those who were exposed to the highest concentration of arsenic for more than 10 years.

Prevalence of and Associations With Excessive Daytime Sleepiness in an Australian Older Population

The aim of this research is to estimate the prevalence of excessive daytime sleepiness in an older population and associations with sociodemographic, health, and lifestyle factors using a cross-sectional, population-based study. Participants were men (1560) and women (1759), aged 55 to 85 years, enrolled in the Hunter Community Study, a longitudinal study of aging. Measurements were self-reported questionnaires, biochemical measures, and clinical measures. Of the 3319 participants, 3053 participants completed the Epworth Sleepiness Scale questionnaire. The prevalence of excessive daytime sleepiness was 15.3% overall and this was higher in males. In adjusted multivariate analysis, gender, working full time, body mass index, high-density and low-density lipoprotein cholesterol, Center for Epidemiologic Studies–Depression scale score, and Kessler psychological distress score were associated with excessive daytime sleepiness. Given the high prevalence of excessive daytime sleepiness observed in this study, further investigation and/or interventions to reduce adverse health outcomes, especially in males is warranted.

Is serum zinc level associated with prediabetes and diabetes?: A cross-sectional study from Bangladesh

Aims To determine serum zinc level and other relevant biological markers in normal, prediabetic and diabetic individuals and their association with Homeostasis Model Assessment (HOMA) parameters. Methods This cross-sectional study was conducted between March and December 2009. Any patient aged ≥30 years attending the medicine outpatient department of a medical university hospital in Dhaka, Bangladesh and who had a blood glucose level ordered by a physician was eligible to participate. Results A total of 280 participants were analysed. On fasting blood sugar results, 51% were normal, 13% had prediabetes and 36% had diabetes. Mean serum zinc level was lowest in prediabetic compared to normal and diabetic participants (mean differences were approximately 65 ppb/L and 33 ppb/L, respectively). In multiple linear regression, serum zinc level was found to be significantly lower in prediabetes than in those with normoglycemia. Beta cell function was significantly lower in prediabetes than normal participants. Adjusted linear regression for HOMA parameters did not show a statistically significant association between serum zinc level, beta cell function (P = 0.07) and insulin resistance (P = 0.08). Low serum zinc accentuated the increase in insulin resistance seen with increasing BMI. Conclusion Participants with prediabetes have lower zinc levels than controls and zinc is significantly associated with beta cell function and insulin resistance. Further longitudinal population based studies are warranted and controlled trials would be valuable for establishing whether zinc supplementation in prediabetes could be a useful strategy in preventing progression to Type 2 diabetes.

Serum methylarginines and incident depression in a cohort of older adults

BACKGROUND Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in depression. This study measured serum concentrations of l-arginine, asymmetric (ADMA) and symmetric (SDMA) dimethylarginine in a representative sample of older community-dwelling adults and determined their association with incident depression over 6-years of follow-up. METHODS Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and l-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults (Median age=64 years; IQR=60-70) from the Hunter Community Study. Clinical depression was defined as a Centre for Epidemiological Studies Depression Scale (CES-D) score ≥16 or use of antidepressant medications. RESULTS In adjusted analyses ADMA (Q3), SDMA (Q2), l-arginine (Q2), gender, and asthma remained statistically significant predictors of incident depression at follow-up. Quartile 3 of ADMA concentration was associated with 3.5 times the odds of developing depression compared with Q1 (OR=3.54; 95% CI: 1.25-9.99). LIMITATIONS Limitations of our study include the use of a subjective self-reported questionnaire tool using a dichotomous cut-off, together with use of antidepressant medications, as proxies for clinical depression. Moreover, similarly to most population studies on methylated arginines, the measurement of ADMA and SDMA from blood does not necessarily reflect intracellular concentrations of these compounds. Finally, there were no measures of nitric oxide metabolites to determine if these levels were altered in the presence of elevated methylarginines and depression. CONCLUSIONS After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum ADMA was independently associated with incident depression at 6-years follow-up.

Pneumococcal vaccination may induce anti-oxidized low-density lipoprotein antibodies that have potentially protective effects against cardiovascular disease

Many animal and human studies have found an inverse association between anti-oxidized low-density lipoprotein (oxLDL) antibodies (anti-oxLDL) and atherosclerotic burden. Furthermore, anti-oxLDL antibodies have been shown to cause regression of atherosclerotic plaque in mice. Animal studies indicate that the 23-valent pneumococcal vaccine may induce the production of these potentially protective anti-oxLDL antibodies, and human epidemiological studies support their potentially beneficial effect in reducing cardiovascular events. Here we describe the association between self-reported pneumococcal vaccination, vaccination verified by linkage to health records, and anti-pneumococcal antibody titers, and anti-ox-LDL titers in a group of 116 older people. We found a bimodal distribution of anti-oxLDL antibodies, and a significant association between pneumococcal IgG and anti-oxLDL antibody titers that remained after multivariate adjustment for potential confounders (p=0.04). There was no significant association between self-reported vaccination or vaccination verified by health record linkage and ox-LDL titers, which may be due to reporting error or variability in response to the vaccine. These results support a mechanistic link between pneumococcal vaccination and a potential protective effect on cardiovascular disease, and indicate that self-reported or verified vaccine status may not be sufficient to detect this association.

Rationale and design of a randomized controlled trial of pneumococcal polysaccharide vaccine for prevention of cardiovascular events: The Australian Study for the Prevention through Immunization of Cardiovascular Events (AUSPICE)

BACKGROUND Research has shown that vaccination with Streptococcus pneumoniae reduced the extent of atherosclerosis in experimental animal models. It is thought that phosphorylcholine lipid antigens in the S. pneumoniae cell wall induce the production of antibodies that cross-react with oxidized low-density lipoprotein, a component of atherosclerotic plaques. These antibodies may bind to and facilitate the regression of the plaques. Available data provide evidence that similar mechanisms also occur in humans, leading to the possibility that pneumococcal vaccination protects against atherosclerosis. A systematic review and meta-analysis, including 8 observational human studies, of adult pneumococcal polysaccharide vaccination for preventing cardiovascular disease in people older than 65 years, showed a 17% reduction in the odds (odds ratio 0.83, 95% CI 0.71-0.97) of having an acute coronary syndrome event. METHODS/DESIGN The AUSPICE is a multicenter, randomized, placebo-controlled, double-blind, clinical trial to formally test whether vaccination with the pneumococcal polysaccharide vaccine protects against cardiovascular events (fatal and nonfatal acute coronary syndromes and ischemic strokes). Cardiovascular outcomes will be obtained during 4 to 5 years of follow-up, through health record linkage with state and national administrative data sets. CONCLUSION This is the first registered randomized controlled trial (on US, World Health Organization, Australia and New Zealand trial registries) to be conducted to test whether vaccination with the pneumococcal polysaccharide vaccine will reduce cardiovascular events. If successful, vaccination can be readily extended to at-risk groups to reduce the risk of cardiovascular diseases.

Genome-wide association study identifies two novel genomic regions in irritable bowel syndrome

Genome-Wide Association Study Identifies Two Novel Genomic Regions in Irritable Bowel Syndrome

Serum methylarginines and spirometry-measured lung function in older adults.

Rationale Methylarginines are endogenous nitric oxide synthase inhibitors that have been implicated in animal models of lung disease but have not previously been examined for their association with spirometric measures of lung function in humans. Objectives This study measured serum concentrations of asymmetric and symmetric dimethylarginine in a representative sample of older community-dwelling adults and determined their association with spirometric lung function measures. Methods Data on clinical, lifestyle, and demographic characteristics, methylated arginines, and L-arginine (measured using LC-MS/MS) were collected from a population-based sample of older Australian adults from the Hunter Community Study. The five key lung function measures included as outcomes were Forced Expiratory Volume in 1 second, Forced Vital Capacity, Forced Expiratory Volume in 1 second to Forced Vital Capacity ratio, Percent Predicted Forced Expiratory Volume in 1 second, and Percent Predicted Forced Vital Capacity. Measurements and Main Results In adjusted analyses there were statistically significant independent associations between a) higher asymmetric dimethylarginine, lower Forced Expiratory Volume in 1 second and lower Forced Vital Capacity; and b) lower L-arginine/asymmetric dimethylarginine ratio, lower Forced Expiratory Volume in 1 second, lower Percent Predicted Forced Expiratory Volume in 1 second and lower Percent Predicted Forced Vital Capacity. By contrast, no significant associations were observed between symmetric dimethylarginine and lung function. Conclusions After adjusting for clinical, demographic, biochemical, and pharmacological confounders, higher serum asymmetric dimethylarginine was independently associated with a reduction in key measures of lung function. Further research is needed to determine if methylarginines predict the decline in lung function.