In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10
) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for ...nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with β-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.
ObjectivesCardiovascular disease (CVD) is highly preventable and optimal treatments based on absolute risk can halve risk of future events. Compared with women, men have higher risks of developing ...CVD. However, women can experience suboptimal treatment. We aimed to quantify sex differences in CVD risk, assessment and treatment in Australian adults.Design, participants, settingCross-sectional analysis of nationally representative data from interview, physical measures, medication review and blood and urine samples, from 2011 to 2012 Australian Health Survey participants aged 45–74 (n=11 518).Outcome measuresCVD risk factors, absolute 5-year risk of a primary CVD event, blood pressure and cholesterol assessment in the previous 2 and 5 years and use of recommended CVD preventive medications were compared using Poisson regression to estimate age-adjusted male versus female prevalence ratios (PRs).ResultsWomen had a generally more favourable CVD risk factor profile than men, including lower: current smoking prevalence (women=14.5%; men=18.4%, PR=0.78, 95% CI=0.70 to 0.88); body mass index (women (mean)=28.3 kg/m2; men (mean)=28.8 kg/m2, p<0.01); systolic and diastolic blood pressure (systolic: women (mean)=127.1 mm Hg; men (mean)=130.5 mm Hg, p<0.001); blood glucose (women (mean)=5.2 mmol/L; men (mean)=5.5 mmol/L); diabetes prevalence (women=6.8%; men=12.5%, PR=0.55, 95% CI=0.44 to 0.67); prior CVD (women=7.9%; men=11.3%) and absolute primary CVD risk (absolute 5-year CVD risk >15%: women=6.6%, 95% CI=5.4 to 7.8; men=15.4%, 95% CI=13.9% to 16.9%). Compared with men, women had higher low-density lipoprotein, high-density lipoprotein and total cholesterol and sedentary behaviour and lower physical activity. Blood pressure and cholesterol assessment were common in both sexes. Among those at high absolute risk, age-adjusted proportions receiving recommended CVD medications were low, without sex differences (women=21.3%; men=23.8%, PR=0.93, 95% CI=0.49 to 1.78). Fewer women than men with prior atherosclerotic CVD were receiving recommended treatment (women=21.8%, men=41.4%, PR=0.55, 95% CI=0.31 to 0.96).ConclusionWomen have a more favourable CVD risk factor profile than men. Preventive treatment is uncommon and women with prior atherosclerotic CVD are around half as likely as men to be receiving recommended treatment.
The World Health Organization's (WHO) 25X25 goal aims for a 25% relative reduction in premature death due to four non-communicable diseases (NCD4)-cancer, cardiovascular disease, chronic respiratory ...diseases and diabetes-by 2025 compared to 2010. This study aimed to quantify the premature mortality in the Australian population due to NCD4, quantify the variation in mortality rates by age and sex, predict the premature mortality due to NCD4 in 2025 and evaluate the progress towards the WHO 25X25 goal.
A population-based study using cause-specific mortality data of all deaths which occurred in Australia from 2010 to 2016 and registered up to 2017, for adults aged 30-69 years, was conducted. Age-specific and age-standardised mortality rates (ASMR) and probability of death for NCD4 were calculated for each year. ASMRs in 2016 were calculated for men and women. Deaths and the probability of death in 2025 were predicted using Poisson regression based on data from 2006 to 2016. To assess the progress against the WHO 25X25 goal, the relative reduction in the probability of death from NCD4 conditions in 2025 compared to 2010 was calculated.
ASMRs for NCD4 decreased from 2010 to 2016, except for diabetes which increased on average by 2.5% per year. Across sociodemographic factors, ASMRs were highest in males and increased with age. The projected probability of premature death in 2025 was 7.36%, equivalent to a relative reduction of 25.16% compared to 2010 levels.
Premature mortality due to cancer, cardiovascular disease, respiratory diseases and diabetes declined in Australia from 2010 to 2016. This trend is consistent across age groups and by sex, and higher mortality rates were observed in males and at older ages. Nationally, if the current trends continue, we estimate that Australia will achieve a 25.16% relative reduction in premature deaths due to NCD4 in 2025 compared to 2010, signifying substantial progress towards the WHO 25X25 goal. Concerted efforts will need to continue to meet the 25X25 goal, especially in the context of the COVID-19 pandemic.
Workforce participation is reduced among people with cardiovascular disease (CVD). However, detailed quantitative evidence on this is limited. We examined the relationship of CVD to workforce ...participation in older working-age people, by CVD subtype, within population subgroups and considering the role of physical disability.
Questionnaire data (2006-2009) for participants aged 45-64 years (n = 163,562) from the population-based 45 and Up Study (n = 267,153) were linked to hospitalisation data through the Centre for Health Record Linkage. Prior CVD was from self-report or hospitalisation. Modified Poisson regression estimated adjusted prevalence ratios (PRs) for non-participation in the workforce in people with versus without CVD, adjusting for sociodemographic factors.
There were 19,161 participants with CVD and 144,401 without. Compared to people without CVD, workforce non-participation was greater for those with CVD (40.0% vs 23.5%, PR = 1.36, 95%CI = 1.33-1.39). The outcome varied by CVD subtype: myocardial infarction (PR = 1.46, 95%CI = 1.36-1.55); cerebrovascular disease (PR = 1.92, 95%CI = 1.80-2.06); heart failure (PR = 1.83, 95%CI = 1.68-1.98) and peripheral vascular disease (PR = 1.76, 95%CI = 1.65-1.88). Workforce non-participation in those with CVD versus those without was at least 21% higher in all population subgroups examined, with PRs ranging from 1.75 (95%CI = 1.65-1.85) in people aged 50-55 years to 1.21 (95%CI = 1.19-1.24) among those aged 60-64. Compared to people with neither CVD nor physical functioning limitations, those with physical functional limitations were around three times as likely to be out of the workforce regardless of CVD diagnosis; participants with CVD but without physical functional limitations were 13% more likely to be out of the workforce (PR = 1.13, 95%CI = 1.07-1.20).
While many people with CVD participate in the workforce, participation is substantially lower, especially for people with cerebrovascular disease, than for people without CVD, highlighting priority areas for research and support, particularly for people experiencing physical functioning limitations.
Switching regular salt (sodium chloride) to salt enriched with potassium chloride (25 % potassium chloride, 75 % sodium chloride) has been shown to reduce blood pressure and the risk of ...cardiovascular diseases. We sought to define the potential for the current production of sodium chloride and potassium chloride to support a global switch to the use of potassium-enriched salt.
We summarised data from geological surveys, government reports and trade organisations describing the global production and supply of sodium chloride and potash (the primary source of potassium chloride) and compared this to potential requirements for potassium-enriched salt.
Global.
Not applicable.
Approximately 280 million tonnes of sodium chloride were produced in 2020 with China and the USA the main producers. Global production of potash from which potassium chloride is extracted was about forty-four million tonnes with Canada, Belarus, Russia and China providing 77 % of the world's supply. There were forty-eight countries in which potassium-enriched salt is currently marketed with seventy-nine different brands identified. Allowing for loss of salt between manufacture and consumption, a full global switch from regular salt to potassium-enriched salt would require about 9·7 million tonnes of sodium chloride to be replaced with 9·7 million tonnes of potassium chloride annually.
Significant upscaling of the production of potassium chloride and the capacity of companies able to manufacture potassium-enriched salt, as well as a robust business case for the switch to potassium chloride, would be required.
To provide quantitative evidence for systematically prioritising individuals for full formal cardiovascular disease (CVD) risk assessment using primary care records with a novel tool (eHEART) with ...age- and sex- specific risk thresholds.
eHEART was derived using landmark Cox models for incident CVD with repeated measures of conventional CVD risk predictors in 1,642,498 individuals from the Clinical Practice Research Datalink. Using 119,137 individuals from UK Biobank, we modelled the implications of initiating guideline-recommended statin therapy using eHEART with age- and sex-specific prioritisation thresholds corresponding to 5% false negative rates to prioritise adults aged 40-69 years in a population in England for invitation to a formal CVD risk assessment.
Formal CVD risk assessment on all adults would identify 76% and 49% of future CVD events amongst men and women respectively, and 93 (95% CI: 90, 95) men and 279 (95% CI: 259, 297) women would need to be screened (NNS) to prevent one CVD event. In contrast, if eHEART was first used to prioritise individuals for formal CVD risk assessment, we would identify 73% and 47% of future events amongst men and women respectively, and a NNS of 75 (95% CI: 72, 77) men and 162 (95% CI: 150, 172) women. Replacing the age- and sex-specific prioritisation thresholds with a 10% threshold identify around 10% less events.
The use of prioritisation tools with age- and sex-specific thresholds could lead to more efficient CVD assessment programmes with only small reductions in effectiveness at preventing new CVD events.
To inform national evidence gaps on cardiovascular disease (CVD) preventive medication use and factors relating to under‐treatment ‐ including primary healthcare engagement ‐ among CVD survivors in ...Australia.
Data from 884 participants with self‐reported CVD from the 2014–15 National Health Survey were linked to primary care and pharmaceutical dispensing data for 2016 through the Multi‐Agency Data Integration Project. Logistic regression quantified the relation of combined blood pressure‐ and lipid‐lowering medication use to participant characteristics.
Overall, 94.8% had visited a general practitioner (GP) and 40.0% were on both blood pressure‐ and lipid‐lowering medications. Medication use was least likely in: women versus men (OR=0.4995%CI:0.37‐0.65), younger participants (e.g. 45–64y versus 65–85y: OR=0.580.42–0.79)and current versus never‐smokers (OR=0.730.44–1.20). Treatment was more likely in those with ≥9 versus ≤4 conditions (OR=2.151.39–3.31), with ≥11 versus 0–2 GP visits/year (OR=2.621.53–4.48) and with individual CVD risk factors (e.g. high blood pressure OR=3.13 2.34–4.19) versus without); the latter even accounting for GP service‐use frequency.
Younger people, smokers, those with infrequent GP visits or without CVD risk factors were the least likely to be on medication.
Substantial under‐treatment, even among those using GP services, indicates opportunities to prevent further CVD events in primary care.
The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic ...obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 95% CI: 0.96, 1.07). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 1.01, 1.13). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.
To describe the attributes that have underscored the success of the 45 and Up Study (the Study) and demonstrate its value by reflecting on two case studies: our research on socioeconomic inequalities ...in cardiovascular disease; and the harms of smoking. Type of program or service: The Study is the largest study of healthy ageing in Australia, and one of the biggest in the world; it recruited 267 357 participants aged 45 years and older from NSW, Australia from 2005 to 2009. For more than 15 years, it has provided high-quality evidence on a broad range of public health related issues. We reflect on its value using two research case studies.
Four key attributes have enabled the success of the Study: its establishment as a collaborative resource, including early and ongoing engagement with researchers and policy and practice partners; its large scale, which makes it ideally suited to quantify associations between risk factors and health outcomes, including for high priority populations; high quality self-reported survey data; and linkage to routinely collected administrative data, including specialised data. Novel Australian findings on cardiovascular disease (CVD) and smoking illustrate how the Study has contributed to national and international evidence, informing policy and practice. Results on CVD demonstrated individual-level education-related inequalities in CVD incidence and mortality, and greater use of pharmacotherapy for secondary prevention of CVD, in people with low versus high socioeconomic status. In terms of smoking, Study data showed that current smokers have around three times the mortality of never-smokers; that even "light" smoking of <14 cigarettes per day doubles mortality; that quitting is beneficial at any age; that smoking increases the risk of multiple cancer types; and that smoking causes half of deaths in Aboriginal and Torres Strait Islander adults aged 45 years and over and more than one-third of all deaths in the population. This evidence has been used by more than 50 government and non-government organisations, including contributing to legislation, policy and national and international monitoring and reporting.
The Study has fulfilled a vital role in public health research and practice in Australia, providing locally relevant data to enable research on health issues of importance, including health inequity. Through ongoing partnerships, the Study's data has contributed to international scientific evidence and been used to inform public health policy and practice. It has also been used as a focus for collaboration and capacity building.
The burden of chronic disease continues to rise as populations age. There is relatively little published on the socioeconomic distribution of this burden in older people. This study quantifies ...absolute and relative income-related inequalities in prevalence of chronic diseases, severe physical functioning limitation and high psychological distress in mid-age and older people in Australia.
Cross-sectional study of 208,450 participants in the 45 and Up Study, a population-based cohort of men and women aged 45-106 years from New South Wales, Australia. Chronic conditions included self-reported heart disease, diabetes, Parkinson's disease, cancer and osteoarthritis; physical functioning limitation (severe/not) was measured using Medical Outcomes Study measures and psychological distress (high/not) using the Kessler Psychological Distress Scale. For each outcome, prevalence was estimated in relation to annual household income (6 categories). Prevalence differences (PDs) and ratios (PRs) were generated, comparing the lowest income category (< $20,000) to the highest (≥ $70,000), using Poisson regression with robust standard errors, weighted for age, sex and region of residence. Analyses were stratified by age group (45-64, 65-79 and ≥ 80 years) and sex and adjusted for age and country of birth.
With few exceptions, there were income gradients in the prevalence of chronic conditions among all age-sex groups, with prevalence decreasing with increasing income. Of the chronic diseases, PDs were highest for diabetes (ranging between 5.69% and 10.36% across age-sex groups) and in women, also for osteoarthritis (5.72% to 8.14%); PRs were highest for osteoarthritis in men aged 45-64 years (4.01), otherwise they were highest for diabetes (1.78 to 3.43). Inequalities were very high for both physical functioning limitation and psychological distress, particularly among those aged 45-64 (PDs between 18.67% and 29.23% and PRs between 4.63 and 16.51). Absolute and relative inequalities tended to decrease with age, but remained relatively high for diabetes and physical functioning in the elderly (≥ 80 years).
Significant inequalities in the prevalence of chronic conditions, physical functioning and psychological distress persist into old age. The additional health burden placed on those who are already disadvantaged is likely to become an increasingly important issue in an ageing population.
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