Whether high blood eosinophils are associated with chronic obstructive pulmonary disease (COPD) exacerbations among individuals with COPD in the general population is largely unknown.
To test the ...hypothesis that high blood eosinophils predict COPD exacerbations.
Among 81,668 individuals in the Copenhagen General Population Study, we examined 7,225 with COPD based on spirometry. We recorded blood eosinophils at baseline and future COPD exacerbations longitudinally, defined as moderate (short-course treatment with systemic corticosteroids) or severe (hospitalization). We also assessed exacerbation risk in a subgroup of 203 individuals with clinical COPD, defined as participants with a smoking history of at least 10 pack-years, FEV1 less than 70% of predicted value, and at least one moderate or severe exacerbation in the year before baseline.
During a median of 3.3 years of follow-up (range, 0.03-8.1), 1,439 severe and 2,864 moderate COPD exacerbations were recorded. Among all participants with COPD, blood eosinophils above versus below 0.34 × 10(9) cells per liter had multivariable-adjusted incidence rate ratios of 1.76 (95% confidence interval, 1.56-1.99) for severe exacerbations and 1.15 (1.05-1.27) for moderate exacerbations. Corresponding values in those with clinical COPD were 3.21 (2.49-4.14) and 1.69 (1.40-2.04). In contrast, using a cutpoint of 2% for blood eosinophils, the risk of exacerbations was increased for severe exacerbations only among individuals with clinical COPD and not in individuals in the broader population.
Among individuals with COPD in the general population, increased blood eosinophil levels above 0.34 × 10(9) cells per liter were associated with a 1.76-fold increased risk of severe exacerbations.
Statin use and reduced cancer-related mortality Nielsen, Sune F; Nordestgaard, Børge G; Bojesen, Stig E
The New England journal of medicine,
11/2012, Letnik:
367, Številka:
19
Journal Article
Recenzirano
Odprti dostop
A reduction in the availability of cholesterol may limit the cellular proliferation required for cancer growth and metastasis. We tested the hypothesis that statin use begun before a cancer diagnosis ...is associated with reduced cancer-related mortality.
We assessed mortality among patients from the entire Danish population who had received a diagnosis of cancer between 1995 and 2007, with follow-up until December 31, 2009. Among patients 40 years of age or older, 18,721 had used statins regularly before the cancer diagnosis and 277,204 had never used statins.
Multivariable-adjusted hazard ratios for statin users, as compared with patients who had never used statins, were 0.85 (95% confidence interval CI, 0.83 to 0.87) for death from any cause and 0.85 (95% CI, 0.82 to 0.87) for death from cancer. Adjusted hazard ratios for death from any cause according to the defined daily statin dose (the assumed average maintenance dose per day) were 0.82 (95% CI, 0.81 to 0.85) for a dose of 0.01 to 0.75 defined daily dose per day, 0.87 (95% CI, 0.83 to 0.89) for 0.76 to 1.50 defined daily dose per day, and 0.87 (95% CI, 0.81 to 0.91) for higher than 1.50 defined daily dose per day; the corresponding hazard ratios for death from cancer were 0.83 (95% CI, 0.81 to 0.86), 0.87 (95% CI, 0.83 to 0.91), and 0.87 (95% CI, 0.81 to 0.92). The reduced cancer-related mortality among statin users as compared with those who had never used statins was observed for each of 13 cancer types.
Statin use in patients with cancer is associated with reduced cancer-related mortality. This suggests a need for trials of statins in patients with cancer.
Ideally, familial hypercholesterolaemia (FH) is diagnosed by testing for mutations that decrease the catabolism of low-density lipoprotein (LDL) cholesterol; however, genetic testing is not ...universally available. The aim of the present study was to assess the frequency and predictors of FH causing mutations in 98 098 participants from the general population, the Copenhagen General Population Study.
We genotyped for LDLRW23X;W66G;W556S and APOBR3500Q accounting for 38.7% of pathogenic FH mutations in Copenhagen. Clinical FH assessment excluded mutation information. The prevalence of the four FH mutations was 0.18% (1:565), suggesting a total prevalence of FH mutations of 0.46% (1:217). Using the Dutch Lipid Clinic Network (DLCN) criteria, odds ratios for an FH mutation were 439 (95% CI: 170-1 138) for definite FH, 90 (53-152) for probable FH, and 18 (13-25) for possible FH vs. unlikely FH. Using the Simon Broome criteria, the odds ratio was 27 (20-36) for possible vs. unlikely FH, and using the Make Early Diagnosis to Prevent Early Death (MEDPED) criteria, 40 (28-58) for probable vs. unlikely FH. Odds ratios for an FH mutation were 17 (9-31) for LDL-cholesterol of 4-4.9 mmol/L, 69 (37-126) for LDL-cholesterol of 5-5.9 mmol/L, 132 (66-263) for LDL-cholesterol of 6-6.9 mmol/L, 264 (109-637) for LDL-cholesterol of 7-7.9 mmol/L, and 320 (129-798) for LDL-cholesterol above 7.9 mmol/L vs. LDL-cholesterol below 4 mmol/L. The most optimal threshold for LDL-cholesterol concentration to discriminate between mutation carriers and non-carriers was 4.4 mmol/L.
Familial hypercholesterolaemia-causing mutations are estimated to occur in 1:217 in the general population and are best identified by a definite or probable phenotypic diagnosis of FH based on the DLCN criteria or an LDL-cholesterol above 4.4 mmol/L.
Elevated lipoprotein(a) levels are associated with myocardial infarction (MI) in some but not all studies. Limitations of previous studies include lack of risk estimates for extreme lipoprotein(a) ...levels, measurements in long-term frozen samples, no correction for regression dilution bias, and lack of absolute risk estimates in the general population. We tested the hypothesis that extreme lipoprotein(a) levels predict MI in the general population, measuring levels shortly after sampling, correcting for regression dilution bias, and calculating hazard ratios and absolute risk estimates.
We examined 9330 men and women from the general population in the Copenhagen City Heart Study. During 10 years of follow-up, 498 participants developed MI. In women, multifactorially adjusted hazard ratios for MI for elevated lipoprotein(a) levels were 1.1 (95% CI, 0.6 to 1.9) for 5 to 29 mg/dL (22nd to 66th percentile), 1.7 (1.0 to 3.1) for 30 to 84 mg/dL (67th to 89th percentile), 2.6 (1.2 to 5.9) for 85 to 119 mg/dL (90th to 95th percentile), and 3.6 (1.7 to 7.7) for > or =120 mg/dL (>95th percentile) versus levels <5 mg/dL (<22nd percentile). Equivalent values in men were 1.5 (0.9 to 2.3), 1.6 (1.0 to 2.6), 2.6 (1.2 to 5.5), and 3.7 (1.7 to 8.0). Absolute 10-year risks of MI were 10% and 20% in smoking, hypertensive women aged >60 years with lipoprotein(a) levels of <5 and > or =120 mg/dL, respectively. Equivalent values in men were 19% and 35%.
We observed a stepwise increase in risk of MI with increasing levels of lipoprotein(a), with no evidence of a threshold effect. Extreme lipoprotein(a) levels predict a 3- to 4-fold increase in risk of MI in the general population and absolute 10-year risks of 20% and 35% in high-risk women and men.
Objectives The aim of this study was to test the hypothesis that elevated nonfasting remnant cholesterol is a causal risk factor for ischemic heart disease independent of reduced high-density ...lipoprotein (HDL) cholesterol. Background Elevated remnant cholesterol is associated with elevated levels of triglyceride-rich lipoproteins and with reduced HDL cholesterol, and all are associated with ischemic heart disease. Methods A total of 73,513 subjects from Copenhagen were genotyped, of whom 11,984 had ischemic heart disease diagnosed between 1976 and 2010. Fifteen genetic variants were selected, affecting: 1) nonfasting remnant cholesterol alone; 2) nonfasting remnant cholesterol and HDL cholesterol combined; 3) HDL cholesterol alone; or 4) low-density lipoprotein (LDL) cholesterol alone as a positive control. The variants were used in a Mendelian randomization design. Results The causal odds ratio for a 1 mmol/l (39 mg/dl) genetic increase of nonfasting remnant cholesterol was 2.8 (95% confidence interval CI: 1.9 to 4.2), with a corresponding observational hazard ratio of 1.4 (95% CI: 1.3 to 1.5). For the ratio of nonfasting remnant cholesterol to HDL cholesterol, corresponding values were 2.9 (95% CI: 1.9 to 4.6) causal and 1.2 (95% CI 1.2 to 1.3) observational for a 1-U increase. However, for HDL cholesterol, corresponding values were 0.7 (95% CI: 0.4 to 1.4) causal and 1.6 (95% CI: 1.4 to 1.7) observational for a 1 mmol/l (39 mg/dl) decrease. Finally, for LDL cholesterol, corresponding values were 1.5 (95% CI: 1.3 to 1.6) causal and 1.1 (95% CI: 1.1 to 1.2) observational for a 1 mmol/l (39 mg/dl) increase. Conclusions A nonfasting remnant cholesterol increase of 1 mmol/l (39 mg/dl) is associated with a 2.8-fold causal risk for ischemic heart disease, independent of reduced HDL cholesterol. This implies that elevated cholesterol content of triglyceride-rich lipoprotein particles causes ischemic heart disease. However, because pleiotropic effects of the genetic variants studied cannot be totally excluded, these findings need to be confirmed using additional genetic variants and/or randomized intervention trials.
This review focuses on remnant cholesterol as a causal risk factor for ischemic heart disease (IHD), on its definition, measurement, atherogenicity, and levels in high risk patient groups; in ...addition, present and future pharmacological approaches to lowering remnant cholesterol levels are considered. Observational studies show association between elevated levels of remnant cholesterol and increased risk of cardiovascular disease, even when remnant cholesterol levels are defined, measured, or calculated in different ways. In-vitro and animal studies also support the contention that elevated levels of remnant cholesterol may cause atherosclerosis same way as elevated levels of low-density lipoprotein (LDL) cholesterol, by cholesterol accumulation in the arterial wall. Genetic studies of variants associated with elevated remnant cholesterol levels show that an increment of 1mmol/L (39mg/dL) in levels of nonfasting remnant cholesterol associates with a 2.8-fold increased risk of IHD, independently of high-density lipoprotein cholesterol levels. Results from genetic studies also show that elevated levels of remnant cholesterol are causally associated with both low-grade inflammation and IHD. However, elevated levels of LDL cholesterol are associated with IHD, but not with low-grade inflammation. Such results indicate that elevated LDL cholesterol levels cause atherosclerosis without a major inflammatory component, whereas an inflammatory component of atherosclerosis is driven by elevated remnant cholesterol levels. Post-hoc subgroup analyses of randomized trials using fibrates in individuals with elevated triglyceride levels, elevated remnant cholesterol levels, show a benefit of lowering triglycerides or remnant cholesterol levels; however, large randomized trials with the primary target of lowering remnant cholesterol levels are still missing.
We tested the hypothesis that the contrasting results for the effect of high-dose, purified omega-3 fatty acids on the prevention of atherosclerotic cardiovascular disease (ASCVD) in two randomized ...trials, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) vs. Long-Term Outcomes Study to Assess Statin Residual Risk with Epanova in High Cardiovascular Risk Patients with Hypertriglyceridaemia (STRENGTH), can be explained by differences in the effect of active and comparator oils on lipid traits and C-reactive protein.
In the Copenhagen General Population Study (CGPS) with 106 088 individuals, to mimic trial designs we analysed those who met key inclusion criteria in REDUCE-IT (n = 5684; ASCVD = 852) and STRENGTH (n = 6862; ASCVD = 697). Atherosclerotic cardiovascular disease incidence was followed for the median durations of REDUCE-IT and STRENGTH (4.9 and 3.5 years), respectively. When combining changes in plasma triglycerides, low-density lipoprotein cholesterol, and C-reactive protein observed in the active oil groups of the original studies, estimated hazard ratios for ASCVD in the CGPS were 0.96 95% confidence interval 0.93-0.99 mimicking REDUCE-IT and 0.94 (0.91-0.98) mimicking STRENGTH. In the comparator oil groups, corresponding hazard ratios were 1.07 (1.04-1.10) and 0.99 (0.98-0.99). Combining these results, the active oil vs. comparator oil hazard ratio was 0.88 (0.84-0.93) in the CGPS mimicking REDUCE-IT compared to 0.75 (0.68-0.83) in the REDUCE-IT. The corresponding hazard ratio was 0.96 (0.93-0.99) in the CGPS mimicking STRENGTH compared to 0.99 (0.90-1.09) in STRENGTH.
The contrasting results of REDUCE-IT vs. STRENGTH can partly be explained by a difference in the effect of comparator oils (mineral vs. corn), but not of active oils eicosapentaenoic acid (EPA) vs. EPA + docosahexaenoic acid, on lipid traits and C-reactive protein. The unexplained additional 13% risk reduction in REDUCE-IT likely is through other effects of EPA or mineral oil.
Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that ...positive observational associations between BMI and IHD are causal.
In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19-1.34) for every 4 kg/m(2) increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m(2) (95 CI% 0.20-0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01-1.05) (corresponding to an average 1.68 kg/m(2) BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m(2) increase in BMI was 1.52 (95% CI 1.12-2.05).
For every 4 kg/m(2) increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias.
High plasma levels of nonfasting triglycerides are associated with an increased risk of ischemic cardiovascular disease. Whether lifelong low levels of nonfasting triglycerides owing to mutations in ...the gene encoding apolipoprotein C3 (APOC3) are associated with a reduced risk of ischemic cardiovascular disease in the general population is unknown.
Using data from 75,725 participants in two general-population studies, we first tested whether low levels of nonfasting triglycerides were associated with reduced risks of ischemic vascular disease and ischemic heart disease. Second, we tested whether loss-of-function mutations in APOC3, which were associated with reduced levels of nonfasting triglycerides, were also associated with reduced risks of ischemic vascular disease and ischemic heart disease. During follow-up, ischemic vascular disease developed in 10,797 participants, and ischemic heart disease developed in 7557 of these 10,797 participants.
Participants with nonfasting triglyceride levels of less than 1.00 mmol per liter (90 mg per deciliter) had a significantly lower incidence of cardiovascular disease than those with levels of 4.00 mmol per liter (350 mg per deciliter) or more (hazard ratio for ischemic vascular disease, 0.43; 95% confidence interval CI, 0.35 to 0.54; hazard ratio for ischemic heart disease, 0.40; 95% CI, 0.31 to 0.52). Heterozygosity for loss-of-function mutations in APOC3, as compared with no APOC3 mutations, was associated with a mean reduction in nonfasting triglyceride levels of 44% (P<0.001). The cumulative incidences of ischemic vascular disease and ischemic heart disease were reduced in heterozygotes as compared with noncarriers of APOC3 mutations (P=0.009 and P=0.05, respectively), with corresponding risk reductions of 41% (hazard ratio, 0.59; 95% CI, 0.41 to 0.86; P=0.007) and 36% (hazard ratio, 0.64; 95% CI, 0.41 to 0.99; P=0.04).
Loss-of-function mutations in APOC3 were associated with low levels of triglycerides and a reduced risk of ischemic cardiovascular disease. (Funded by the European Union and others.).
Abstract
Objective
The incidence of acute pancreatitis is rising worldwide and currently no curative treatment exists. Clarification of preventable risk factors is important for the reduction of ...morbidity and mortality from acute pancreatitis. In this study, we tested the hypothesis that the risk of acute pancreatitis associated with body mass index (BMI) is partly mediated through elevated triglycerides.
Design
We included 118 085 individuals from 2 prospective cohort studies, the Copenhagen City Heart Study and the Copenhagen General Population Study, with BMI measured at baseline. Diagnosis of acute pancreatitis was assessed from the national Danish registries, as hospitalization or death due to acute pancreatitis.
Results
Higher BMI was associated with higher risk of acute pancreatitis with a multivariable-adjusted hazard ratio of 1.4 (95% CI, 1.1–1.8) for BMI of 25–29.9, 2.1 (1.6–2.9) for BMI of 30–34.9, and 2.8 (1.8–4.3) for BMI > 35, compared with individuals with BMI of 18.5–24.9. Triglycerides mediated 29% (95% CI, 12%–46%; P = 0.001) of the association between BMI and risk of acute pancreatitis in the age- and sex-adjusted model and 22% (6%–39%; P = 0.008) in the multivariable-adjusted model.
Conclusion
Higher BMI is associated with higher risk of acute pancreatitis in individuals from the general population, partly mediated through higher triglycerides. This indicates a potential for preventing acute pancreatitis by reducing BMI and triglycerides in individuals with high values.
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