International audience ; Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 μg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 μg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 μg/m 3 an increase of 5 μg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.
International audience ; Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 μg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 μg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 μg/m 3 an increase of 5 μg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.
International audience ; Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 μg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 μg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 μg/m 3 an increase of 5 μg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.
International audience ; Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 μg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 μg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 μg/m 3 an increase of 5 μg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.
International audience ; Objective To investigate the associations between air pollution and mortality, focusing on associations below current European Union, United States, and World Health Organization standards and guidelines. Design Pooled analysis of eight cohorts. Setting Multicentre project Effects of Low-Level Air Pollution: A Study in Europe (ELAPSE) in six European countries. Participants 325 367 adults from the general population recruited mostly in the 1990s or 2000s with detailed lifestyle data. Stratified Cox proportional hazard models were used to analyse the associations between air pollution and mortality. Western Europe-wide land use regression models were used to characterise residential air pollution concentrations of ambient fine particulate matter (PM 2.5), nitrogen dioxide, ozone, and black carbon. Main outcome measures Deaths due to natural causes and cause specific mortality. Results Of 325 367 adults followed-up for an average of 19.5 years, 47 131 deaths were observed. Higher exposure to PM 2.5, nitrogen dioxide, and black carbon was associated with significantly increased risk of almost all outcomes. An increase of 5 μg/m 3 in PM 2.5 was associated with 13% (95% confidence interval 10.6% to 15.5%) increase in natural deaths; the corresponding figure for a 10 μg/m 3 increase in nitrogen dioxide was 8.6% (7% to 10.2%). Associations with PM 2.5, nitrogen dioxide, and black carbon remained significant at low concentrations. For participants with exposures below the US standard of 12 μg/m 3 an increase of 5 μg/m 3 in PM 2.5 was associated with 29.6% (14% to 47.4%) increase in natural deaths. Conclusions Our study contributes to the evidence that outdoor air pollution is associated with mortality even at low pollution levels below the current European and North American standards and WHO guideline values. These findings are therefore an important contribution to the debate about revision of air quality limits, guidelines, and standards, and future assessments by the Global Burden of Disease.
BACKGROUND: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD. ; The individual study sponsor(s) had no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Dr. Isgum is supported by research grants from Pie Medical Imaging, 3Mensio Medical Imaging B.V., the NWO and Foundation for Technological Sciences under Project 12726, The Netherlands Organization for Health Research and Development, and the Dutch Cancer Society. Dr. Arpegård has received funding through the Stockholm County Council (combined clinical residency and PhD training program). Dr. Amouyel has received personal fees from Servier, Hoffman Laroche, Total, Genoscreen, Alzprotect, Fondation Plan Alzheimer, and Takeda outside of the submitted work; and has shares in Genoscreen. Dr. Morris is a Wellcome Trust Senior Fellow in Basic Biomedical Science under grant number WT098017. Dr. Worrall has received compensation for his role as deputy editor of the Journal of Neurology; and has received National Institutes of Health funding through the National Institute of Neurological Disorders and Stroke (U-01 NS069208) and National Human Genome Research Institute (U-01 HG005160). Dr. Samani is supported by the British Heart Foundation (BHF); and is a National Institute for Health Research Senior Investigator. Dr. Nelson is supported by the BHF. Dr. Franco works in ErasmusAGE, a center for aging research across the life course funded by Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA; Nestlé Nutrition (Nestec Ltd.), Metagenics Inc., and AXA had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Patel is supported by a BHF Intermediate Fellowship. Dr. Koenig has received funds through NGFNplus, project number 01GS0834; has received research grants from Abbott, Roche Diagnostics, Beckmann, and Singulex; has received honorarium for lectures from AstraZeneca, Novartis, Merck Sharp & Dohme, Amgen, and Actavis; and has served as a consultant for Novartis, Pfizer, The Medicines Company, Amgen, AstraZeneca, Merck Sharp & Dohme, and GlaxoSmithKline. Dr. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Dr. Svensson has received a grant from the Swedish Society of Medicine (SLS-412071). Dr. Kivimaki has received funding through the Medical Research Council (K013351), Economic and Social Research Council, and National Institutes of Health (HL36310). Dr. Dehghan is supported by a Netherlands Organization for Scientific Research (NWO) grant (VENI, 916.12.154) and the EUR Fellowship; and has received consultancy and research support from Metagenics Inc. (outside the scope of this work). Dr. Ingelsson is supported by grants from Göran Gustafsson Foundation, Swedish Heart-Lung Foundation (20140422), Knut and Alice Wallenberg Foundation (Knut och Alice Wallenbergs Stiftelse), European Research Council (ERC-StG-335395), Swedish Diabetes Foundation (Diabetesfonden; grant no. 2013-024), and the Swedish Research Council (VR; grant no. 2012-1397). Dr. de Bakker is an employee of Vertex Pharmaceuticals. Dr. Ärnlöv was funded by the Swedish Research Council (2012-1727, 2012-2215), Swedish Heart-Lung Foundation, Thuréus Foundation, the Marianne and Marcus Wallenberg Foundation, Dalarna University, and Uppsala University. Dr. Asselbergs is supported by a Dekker scholarship-Junior Staff Member 2014T001–Netherlands Heart Foundation and UCL Hospitals National Institute for Health Research Biomedical Research Centre. The research leading to these results has received funding from the European Union Seventh Framework Programme FP7/2007-2013 under grant agreement n° HEALTH-F2-2013-601456 (CVgenes-at-target). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. ; Peer-reviewed ; Publisher Version
Background High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodifi ed by disease processes, mendelian random isation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal. Methods We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol. Findings Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10– ¹³) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This diff erence in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10– ¹⁰). Interpretation Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction. Funding US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research. ; 115770
