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Aims Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. We tested the hypotheses that high BMI causally influences heart failure incidence and mortality. Methods and results Using observational and Mendelian randomization causal, genetic analyses, we studied 106 121 individuals from the Copenhagen General Population Study, 18 407 from the Copenhagen City Heart Study, and 977 323 from publicly available databases. In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m2 increment of BMI were 1.06 (95% confidence interval: 1.05–1.07; P < 0.001; n = 124 528; events = 6589) for heart failure incidence, 1.04 (1.03–1.06; P < 0.001; n = 124 528; events = 1237) for heart failure mortality, and 1.01 (1.00–1.01; P < 0.001; n = 124 528; events = 24 144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.19 (1.05–1.36; P = 0.008; n = 118 200; events = 6541) for heart failure incidence, 1.27 (0.82–1.98; P = 0.28; n = 118 200; events = 889) for heart failure mortality, and 1.11 (1.02–1.22; P = 0.022; n = 118 200; events = 16 814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits, the Heart Failure Molecular Epidemiology for Therapeutic Targets, and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.39 (1.27–1.52; P < 0.001; n = 1 095 523; events = 53 850) for heart failure incidence, 1.18 (1.00–1.38; P = 0.05; n = 576 853; events = 2373) for heart failure mortality, and 1.02 (1.00–1.04; P = 0.03; n = 576 853; events = 44 734) for all-cause mortality. Conclusion High BMI causally increases the risk of both heart failure incidence and mortality. [ABSTRACT FROM AUTHOR]

Background: Reduced low-density lipoprotein (LDL) cholesterol due to inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) reduces cardiovascular events and may therefore also reduce cardiovascular and all-cause mortality.Objectives: This study tested the hypothesis that genetically low LDL cholesterol due to PCSK9 variation is causally associated with low cardiovascular and all-cause mortality in the general population.Methods: A total of 109,566 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study were genotyped for PCSK9 R46L (rs11591147), R237W (rs148195424), I474V (rs562556), and E670G (rs505151). During a median follow-up of 10 years (range 0 to 42 years) and 1,247,225 person-years, there were 3,828 cardiovascular deaths and 16,373 deaths from any cause. Results were validated using data on 431,043 individuals from the UK Biobank.Results: An increasing number of weighted PCSK9 alleles were associated with stepwise lower LDL cholesterol of up to 0.61 mmol/l (24 mg/dl; 18.2%; p for trend <0.001) and with lower cardiovascular mortality (p = 0.001), but not with lower all-cause mortality (p = 0.11). In causal, genetic analyses, a 0.5-mmol/l (19.4-mg/dl) lower LDL cholesterol was associated with risk ratios for cardiovascular and all-cause mortality of 0.79 (95% confidence interval [CI]: 0.63 to 0.99; p = 0.04) and 1.02 (95% CI: 0.94 to 1.12; p = 0.63) in the Copenhagen studies, 0.79 (95% CI: 0.58 to 1.08; p = 0.14) and 0.98 (95% CI: 0.87 to 1.10; p = 0.75) in the UK Biobank, and of 0.79 (95% CI: 0.65 to 0.95; p = 0.01) and 1.01 (95% CI: 0.94 to 1.08; p = 0.85), respectively, in studies combined.Conclusions: Genetically low LDL cholesterol due to PCSK9 variation was causally associated with low risk of cardiovascular mortality, but not with low all-cause mortality in the general population. [ABSTRACT FROM AUTHOR]

Aims Adiponectin may play an important protective role in heart failure and associated cardiovascular diseases. We hypothesized that plasma adiponectin is associated observationally and causally, genetically with risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. Methods and results In the Copenhagen General Population Study, we examined 30 045 individuals with plasma adiponectin measurements observationally and 96 903 individuals genetically in one-sample Mendelian randomization analyses using five genetic variants explaining 3% of the variation in plasma adiponectin. In the HERMES, UK Biobank, The Nord-Trøndelag Health Study (HUNT), deCODE, the Michigan Genomics Initiative (MGI), DiscovEHR, and the AFGen consortia, we performed two-sample Mendelian randomization analyses in up to 1 030 836 individuals using 12 genetic variants explaining 14% of the variation in plasma adiponectin. In observational analyses modelled linearly, a 1 unit log-transformed higher plasma adiponectin was associated with a hazard ratio of 1.51 (95% confidence interval: 1.37–1.66) for heart failure, 1.63 (1.50–1.78) for atrial fibrillation, 1.21 (1.03–1.41) for aortic valve stenosis, and 1.03 (0.93–1.14) for myocardial infarction; levels above the median were also associated with an increased risk of myocardial infarction, and non-linear U-shaped associations were more apparent for heart failure, aortic valve stenosis, and myocardial infarction in less-adjusted models. Corresponding genetic, causal risk ratios were 0.92 (0.65–1.29), 0.87 (0.68–1.12), 1.55 (0.87–2.76), and 0.93 (0.67–1.30) in one-sample Mendelian randomization analyses, and no significant associations were seen for non-linear one-sample Mendelian randomization analyses; corresponding causal risk ratios were 0.99 (0.89–1.09), 1.00 (0.92–1.08), 1.01 (0.79–1.28), and 0.99 (0.86–1.13) in two-sample Mendelian randomization analyses, respectively. Conclusion Observationally, elevated plasma adiponectin was associated with an increased risk of heart failure, atrial fibrillation, aortic valve stenosis, and myocardial infarction. However, genetic evidence did not support causality for these associations. [ABSTRACT FROM AUTHOR]

The Mendelian randomization approach is an epidemiological study design incorporating genetic information into traditional epidemiological studies to infer causality of biomarkers, risk factors, or lifestyle factors on disease risk. Mendelian randomization studies often draw on novel information generated in genome-wide association studies on causal associations between genetic variants and a risk factor or lifestyle factor. Such information can then be used in a largely unconfounded study design free of reverse causation to understand if and how risk factors and lifestyle factors cause cardiovascular disease. If causation is demonstrated, an opportunity for prevention of disease is identified; importantly however, before prevention or treatment can be implemented, randomized intervention trials altering risk factor levels or improving deleterious lifestyle factors needs to document reductions in cardiovascular disease in a safe and side-effect sparse manner. Documentation of causality can also inform on potential drug targets, more likely to be successful than prior approaches often relying on animal or cell studies mainly. The present review summarizes the history and background of Mendelian randomization, the study design, assumptions for using the design, and the most common caveats, followed by a discussion on advantages and disadvantages of different types of Mendelian randomization studies using one or more samples and different levels of information on study participants. The review also provides an overview of results on many of the risk factors and lifestyle factors for cardiovascular disease examined to date using the Mendelian randomization study design. [ABSTRACT FROM AUTHOR]

Background: Low plasma 25-hydroxyvitamin D [p-25(OH)D] is associated with increased risk of ischaemic heart disease and with the subgroup myocardial infarction. However, whether this association is causal or due to confounding or reverse causation is presently unknown. We tested the hypothesis that genetically reduced plasma 25(OH)D is associated with increased risk of ischaemic heart disease and myocardial infarction.Methods: We used a Mendelian randomization design in the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Copenhagen Ischaemic Heart Disease Study. Two 25(OH)D reducing genetic variants in the DCHR7 gene (rs7944926 and rs11234027) and two in the CYP2R1 gene (rs10741657 and rs12794714) were genotyped in 92 416 participants of Danish descent, of whom 14 455 developed ischaemic heart disease (ICD-8:410-414; ICD-10:I20-I25) and 7061 myocardial infarction (ICD-8:410: ICD-10:I21-I22) from 1977 through 2011. P-25(OH)D was measured in 36,089 participants. APOE genotype was included as a positive control for risk of ischaemic heart disease.Results: The multivariable adjusted hazard ratios for lowest vs highest quartile of 25(OH)D were 1.82 [95% confidence interval (CI): 1.42-2.32] for ischaemic heart disease. Each allele increase in a combined allele score was associated with a 1.9-nmol/l decrease in p-25(OH)D (P = 7 × 10(-55); R(2) = 0.9%). The genetic variants were, however, not associated with increased risk of ischaemic heart disease. In instrumental variable analysis, the odds ratio for ischaemic heart disease for a genetically 25-nmol/l decrease in p-25(OH)D was 0.98 (95% CI: 0.76-1.26), with a corresponding observational hazard ratio by Cox regression of 1.07 (1.01-1.13). Similarly, with myocardial infarction as the outcome, observational analyses suggested an increased risk with lower 25(OH)D, whereas genetic analyses suggested no causal effect. For APOE genotype, the odds ratio for ischaemic heart disease for a 1-mmol/l genetic increase in plasma total cholesterol concentrations was 1.23 (1.08-1.41), with a corresponding observational hazard ratio of 1.08 (1.04-1.14).Conclusion: We found no evidence to suggest that genetically reduced p-25(OH)D is associated with increased risk of ischaemic heart disease or myocardial infarction. [ABSTRACT FROM AUTHOR]

Background: The effect of alcohol consumption on liver function is difficult to determine because of reporting bias and potential residual confounding. Our aim was to determine this effect using genetic variants to proxy for the unbiased effect of alcohol. Methods: We used variants in ADH1B and ADH1C genes as instrumental variables (IV) to estimate the causal effect of long-term alcohol consumption on alanine aminotransferase (ALT), γ-glutamyl-transferase (γ-GT), alkaline phosphatase (ALP), bilirubin and prothrombin action. Analyses were undertaken on 58,313 Danes (mean age 56). Results: In both confounder adjusted multivariable and genetic-IV analyses greater alcohol consumption, amongst those who drank any alcohol, was associated with higher ALT [mean difference per doubling of alcohol consumption: 3.4% (95% CI: 3.1, 3.7) from multivariable analyses and 3.7% (−4.5, 11.9) from genetic-IV analyses] and γ-GT [8.2% (7.8, 8.5) and 6.8% (−2.8, 16.5)]. The point estimates from the two methods were very similar and statistically the results from the two methods were consistent with each other for effects with ALT and γ-GT (both pdiff>0.3). Results from the multivariable analyses suggested a weak inverse association of alcohol with ALP [−1.5% (−1.7, −1.3)], which differed from the strong positive effect found in genetic-IV analyses [11.6% (6.8, 16.4)] (pdiff<0.0001). In both multivariable and genetic-IV analyses associations with bilirubin and protrombin action were weak and close to the null. Conclusions: Our results suggest that greater consumption of alcohol is related to poorer liver function as indicated by higher ALT, γ-GT and ALP, but not to clotting or bilirubin. [ABSTRACT FROM AUTHOR]

Objective We tested the hypothesis that moderately elevated plasma creatinine levels and decreased levels of estimated glomerular filtration rate (eGFR) are associated with increased risk of myocardial infarction, ischemic heart disease, and early death in the general population. Methods We studied 10,489 individuals with a plasma creatinine measurement and calculated eGFR from the Danish general population, of which 1498 developed myocardial infarction, 3001 ischemic heart disease, and 7573 died during 32 years follow-up. Results Cumulative incidences of myocardial infarction and ischemic heart disease as a function of age increased with increasing levels of creatinine, and survival decreased (log-rank trends: <0.001). The median survival age was 78.7 (95%CI: 78.0–79.2) years for persons with creatinine levels <90th percentile, 78.1 (76.3–79.5) years for 90th–94th percentiles, and 74.8 (72.8–76.7) years for ≥95th percentile. Hazard ratios for myocardial infarction and plasma creatinine levels of 90th–94th percentiles and ≥95th percentile versus <50th percentile were 2.06 (95%CI: 1.67–2.56) and 1.90 (1.56–2.31) adjusted for gender and age, and 1.35 (1.09–1.68) and 1.11 (0.90–1.36) adjusted multifactorially, respectively. Corresponding estimates for creatinine and ischemic heart disease were 1.57 (1.33–1.85) and 1.64 (1.42–1.89) adjusted for gender and age, and 1.16 (0.98–1.37) and 1.11 (0.95–1.29) adjusted multifactorially. Finally, corresponding values for early death were 1.18 (1.06–1.32) and 1.43 (1.30–1.57), and 0.97 (0.87–1.09) and 1.13 (1.02–1.24), respectively. Low eGFR did not associate consistently with increased risk of these endpoints. Conclusion In the general population, moderately elevated plasma creatinine was associated with increased risk of myocardial infarction, ischemic heart disease, and early death, while low eGFR was not. [ABSTRACT FROM AUTHOR]

Abstract: 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. [Copyright &y& Elsevier]

Background--Elevated nonfasting remnant cholesterol and low-density lipoprotein (LDL) cholesterol are causally associated with ischemic heart disease (IHD), but whether elevated nonfasting remnant cholesterol and LDL cholesterol both cause low-grade inflammation is currently unknown. Methods and Results--We studied 60 608 individuals from the Copenhagen General Population Study, the Copenhagen City Heart Study, and the Copenhagen Ischemic Heart Disease study, of whom 10 668 had IHD diagnosed between 1977 and 2011. We genotyped for variants affecting levels of nonfasting remnant cholesterol, LDL cholesterol, C-reactive protein by CRP alleles, and C-reactive protein by IL6R alleles. Using a multidirectional mendelian randomization design, we investigated possible causal associations between the lipoproteins and C-reactive protein and between the lipoproteins and IHD. A 1-mmol/L(39 mg/dL) higher level of nonfasting remnant cholesterol was associated observationally with a 37% (95% confidence interval, 35-39) higher C-reactive protein level and causally with a 28% (95% confidence interval, 10-48) higher level. For LDL cholesterol, a 1-mmol/L (39-mg/dL) higher level was associated observationally with a 7% (95% confidence interval, 6-7) higher C-reactive protein level, but we found no causal association. Likewise, higher levels of C-reactive protein did not associate causally with elevated nonfasting remnant cholesterol or LDL cholesterol. Finally, the causal risk ratio for IHD for a 1-mmol/L (39-mg/dL) higher level was 3.3 (95% confidence interval, 2.1-5.2) for nonfasting remnant cholesterol and 1.8 (95% confidence interval, 1.5-2.2) for LDL cholesterol. The causal associations for remnant cholesterol were present even in those without diabetes mellitus and obesity. Conclusions--Elevated nonfasting remnant cholesterol is causally associated with low-grade inflammation and with IHD, whereas elevated LDL cholesterol is associated causally with IHD without inflammation. [ABSTRACT FROM AUTHOR]

Abstract: Background: Atrial fibrillation is associated with inflammation. In contrast to inflammatory markers like C-reactive protein (CRP) and fibrinogen produced in the liver, YKL-40 is produced at the site of inflammation including in the myocardium. We hypothesized that elevated plasma YKL-40 levels associate with increased risk of atrial fibrillation. Method and results: We measured plasma YKL-40 in 8731 participants from the prospective Copenhagen City Heart Study including 896 individuals who developed atrial fibrillation during up to 18years of follow-up. Additionally, we measured YKL-40 in 6621 individuals from the cross-sectional Copenhagen General Population Study including 337 cases with atrial fibrillation. A YKL-40 level >95% percentile (>204μg/L) versus <25% percentile (<36μg/L) associated prospectively with a 2.10-fold (95%CI:1.43–3.09) increased risk of atrial fibrillation. Hazard ratios attenuated slightly after multifactorial adjustment to 2.01 (1.35–2.98), and further after additional adjustment for heart failure to 1.89 (1.27–2.80), for plasma CRP to 1.79 (1.20–2.67), and for fibrinogen levels to 1.89 (1.27–2.81). Adjusting multifactorially including both heart failure, CRP, and fibrinogen attenuated the risk of atrial fibrillation to 1.79 (1.20–2.67). These findings were supported in the cross-sectional study with an odds ratio of 2.73 (1.46–5.11) for a YKL-40 level >95% percentile versus <25% percentile, attenuating to an odds ratio of 2.13 (1.09–4.18) when adjusting multifactorially including heart failure, CRP, and fibrinogen. Conclusions: Elevated plasma YKL-40 levels robustly associated with increased risk of atrial fibrillation originating from hospital admissions or visits to the emergency department, independent of heart failure, and CRP and fibrinogen levels. These findings need to be confirmed in other independent studies. [Copyright &y& Elsevier]

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. [Copyright &y& Elsevier]

Background: Several risk factors for asthma have been proposed; however, the causality of these associations is sometimes unclear. Mendelian randomization is a powerful epidemiological approach that can help elucidate the causality of risk factors. The aim of the present study was to identify causal risk factors for asthma through Mendelian Randomization studies. Methods: A systematic search of PubMed and EMBASE was conducted, to identify studies investigating risk factors for asthma or respiratory allergies through Mendelian Randomization. When two or more studies investigated the same risk factor a meta‐analysis was conducted. Of 239 studies initially identified, 41 were included. Results: A causal association between adiposity and adult asthma risk was found in 10 out of 12 studies with a summary risk ratio of 1.05 per kg/m2 increase in BMI (95% CI: 1.03–1.07). Puberty timing (n = 3), alcohol (n = 2), and linoleic acid (n = 1) had causal effects on asthma risk, while vitamins/minerals (n = 6) showed no consistent effect on asthma. The effect of smoking on adult asthma conflicted between studies. Several of the significant associations of asthma with immune related proteins (n = 5) and depression (n = 2) investigated through multiple traits analyses could generally benefit from replications in independent datasets. Conclusion: This systematic review and meta‐analysis found evidence for causal effects of adiposity, puberty timing, linoleic acid, alcohol, immune related proteins, and depression on risk of asthma. [ABSTRACT FROM AUTHOR]

Objective. To improve the pathophysiological understanding of cardioinhibitory and vasodepressor reflex syncope, by evaluating orthostatic effects on electrical and hemodynamic variables. To unravel the pathogeneses further, we studied these effects during both the passive head-up tilt test and the active standing test. Background. The current knowledge of the compromised autonomic balance in patients with reflex syncope is limited. The orthostatic responses to head-up tilt test in cardioinhibitory and vasodepressor patients differ, suggesting different pathogeneses; however, the more physiological active standing test represents daily life situations better. Methods. We included 74 patients; 36 cardioinhibitory and 38 vasodepressor. Patients were compared with respect to vascular hemodynamics and heart rate variability during the change from supine to upright position. Resting electrolytes, brain natriuretic peptide (BNP), pro-atrial natriuretic peptide (pro-ANP), and the C-terminal of pro-vasopressin, copeptin were measured. Results. Resting systolic blood pressure was higher in cardioinhibitory (117.8 ± 15.7 mmHg) than in vasodepressor patients (109.1 ± 15.3 mmHg, p < 0.001). Changes in heart rate tended to be smaller in cardioinhibitory patients (6.7 ± 9.8vs. 10.7 ± 8.9 bpm, p = 0.056). Heart rate variability was lower and changed less in cardioinhibitory patients ( p < 0.05). Cardioinhibitory patients had higher pro-ANP levels (63.5 ± 18.8pM) compared to vasodepressor patients (54.2 ± 31.4 pM, p = 0.018). Responses during active standing were attenuated compared to head-up tilt in both groups. Conclusions. This study demonstrated that cardioinhibitory patients had higher blood pressure, attenuated hemodynamic responses, and reduced autonomic regulation compared to vasodepressor patients. Furthermore, cardioinhibitory patients showed a sympathetic predominance in their modulation of autonomic responses. Orthostatic responses induced by active standing were modest and did not sufficiently explain potential pathophysiological differences between cardioinhibitory and vasodepressor patients. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to test whether elevated nonfasting glucose levels associate with and cause ischemic heart disease (IHD) and myocardial infarction (MI). Background: Elevated fasting plasma glucose levels associate with increased risk of IHD, but whether this is also true for nonfasting levels and whether this is a causal relationship is unknown. Methods: Using a Mendelian randomization approach, we studied 80,522 persons from Copenhagen, Denmark. Of those, IHD developed in 14,155, and MI developed in 6,257. Subjects were genotyped for variants in GCK (rs4607517), G6PC2 (rs560887), ADCY5 (rs11708067), DGKB (rs2191349), and ADRA2A (rs10885122) associated with elevated fasting glucose levels in genome-wide association studies. Results: Risk of IHD and MI increased stepwise with increasing nonfasting glucose levels. The hazard ratio for IHD in subjects with nonfasting glucose levels ≥11 mmol/l (≥198 mg/dl) versus <5 mmol/l (<90 mg/dl) was 6.9 (95% confidence interval [CI]: 4.2 to 11.2) adjusted for age and sex, and 2.3 (95% CI: 1.3 to 4.2) adjusted multifactorially; corresponding values for MI were 9.2 (95% CI: 4.6 to 18.2) and 4.8 (95% CI: 2.1 to 11.2). Increasing number of glucose-increasing alleles was associated with increasing nonfasting glucose levels and with increased risk of IHD and MI. The estimated causal odds ratio for IHD and MI by instrumental variable analysis for a 1-mmol/l (18-mg/dl) increase in nonfasting glucose levels due to genotypes combined were 1.25 (95% CI: 1.03 to 1.52) and 1.69 (95% CI: 1.28 to 2.23), and the corresponding observed hazard ratio for IHD and MI by Cox regression was 1.18 (95% CI: 1.15 to 1.22) and 1.09 (95% CI: 1.07 to 1.11), respectively. Conclusions: Like common nonfasting glucose elevation, plasma glucose-increasing polymorphisms associate with increased risk of IHD and MI. These data are compatible with a causal association. [Copyright &y& Elsevier]

Background Low plasma levels of low-density lipoprotein (LDL) cholesterol are associated with an increased risk of cancer, but whether this association is causal is unclear. Methods We studied 10 613 participants in the Copenhagen City Heart Study (CCHS) and 59 566 participants in the Copenhagen General Population Study, 6816 of whom had developed cancer by May 2009. Individuals were genotyped for PCSK9 R46L (rs11591147), ABCG8 D19H (rs11887534), and APOE R112C (rs429358) and R158C (rs7412) polymorphisms, all of which are associated with lifelong reduced plasma LDL cholesterol levels. Plasma LDL cholesterol was calculated using the Friedewald equation in samples in which the triglyceride level was less than 354 mg/dL and measured directly by colorimetry for samples with higher triglyceride levels. Risk of cancer was estimated prospectively using Cox proportional hazards regression analyses and cross-sectionally by logistic regression analyses. Causality was studied using instrumental variable analysis. All statistical tests were two-sided. Results In the CCHS, compared with plasma LDL cholesterol levels greater than the 66th percentile (>158 mg/dL), those lower than the 10th percentile (<87 mg/dL) were associated with a 43% increase (95% confidence interval [CI] = 15% to 79% increase) in the risk of cancer. The polymorphisms were associated with up to a 38% reduction (95% CI = 36% to 41% reduction) in LDL cholesterol levels but not with increased risk of cancer. The causal odds ratio for cancer for a 50% reduction in plasma LDL cholesterol level due to all the genotypes in both studies combined was 0.96 (95% CI = 0.87 to 1.05), whereas the hazard ratio of cancer for a 50% reduction in plasma LDL cholesterol level in the CCHS was 1.10 (95% CI = 1.01 to 1.21) (P for causal odds ratio vs observed hazard ratio = .03). Conclusion Low plasma LDL cholesterol levels were robustly associated with an increased risk of cancer, but genetically decreased LDL cholesterol was not. This finding suggests that low LDL cholesterol levels per se do not cause cancer. [ABSTRACT FROM PUBLISHER]

Objectives: The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. Background: The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. Methods: We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). Results: In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). Conclusions: The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life. [Copyright &y& Elsevier]

Objectives: Mutations in genes encoding desmosomal proteins have been linked to arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D). We hypothesized that a Scandinavian ARVC/D population would have a different spectrum of plakophilin-2 (PKP2) mutations and that some of the reported missense mutations may not be pathogenic. Methods: We screened 53 unrelated patients fulfilling Task Force criteria for ARVC/D for mutations in PKP2 by direct sequencing. Results: Seven different mutations were identified: two insertion/deletions (E329fsX352, P401fsX406), 1 splice site (2146–2A>T), 1 non-sense (R79X) and 4 missense mutations (Q62K in 2 patients, G489R, G673V) of undeterminable pathogeneity. None of these mutations was present in 650 controls. Five of the mutations were novel. Seven patients carried reported missense mutations (D26N, S140F, V587I); however, these mutations were identified in our healthy controls, although at a lower frequency. Evaluation of all reported missense mutations in PKP2 showed unclear pathogeneity of several reported mutations. Conclusions: Fifteen percent of Danish ARVC/D patients carried PKP2 mutations. Our finding of reported disease-causing mutations at a low frequency among healthy controls suggests that these variants are disease modifying but not directly disease causing. We recommend conservative interpretation of missense variants in PKP2, functional characterization and large-scale sequencing to clarify normal variation in the gene. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Apolipoprotein B is a key component in lipid metabolism. Subendothelial retention of apolipoprotein B containing lipoproteins is a necessary initiating event in atherogenesis, and high plasma levels of apolipoprotein B is a risk factor for atherosclerosis, whereas low levels may provide protection. The present review examines, with focus on general population studies, apolipoprotein B levels as a predictor of ischemic cardiovascular disease, as well as the association of mutations and polymorphisms in APOB with plasma apolipoprotein B levels, and risk of ischemic cardiovascular disease. The studies can be summarized as follows: (1) apolipoprotein B predicts ischemic cardiovascular events in both genders, and is better than LDL cholesterol in this respect; (2) linkage disequilibrium structure in APOB is more complex than expected from HapMap data, because a minimal set of tag single nucleotide polymorphisms capturing the entire variation in APOB cannot be identified, and thus most polymorphisms must be evaluated separately in association studies; (3) APOB mutations and polymorphisms are associated with a range of apolipoprotein B and LDL cholesterol levels, although the magnitude of effect sizes of common polymorphisms are modest; (4) both mutations and polymorphisms are associated with LDL metabolism in vivo; (5) association of APOB mutations and polymorphisms with lipid and disease phenotype cannot be predicted in silico using evolutionary conservation or existing prediction programs; and finally, (6) except for the E4154K polymorphism that possibly predicts a reduction in risk of ischemic cerebrovascular disease and ischemic stroke, common APOB polymorphisms with modest effect sizes on lipid levels do not predict risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, or ischemic stroke in the general population. [Copyright &y& Elsevier]

The renin-angiotensin system may play a role in the pathogenesis of atrial fibrillation, and renin-angiotensin system blockers reduce the risk of atrial fibrillation. We hypothesized that polymorphisms in the angiotensinogen and angiotensin-converting enzyme (ACE) genes encoding proteins in this system predict risk of atrial fibrillation.We genotyped 9235 individuals from the Danish general population, The Copenhagen City Heart Study, for the a-20c, g-6a, T174M, and M235T polymorphisms in the angiotensinogen gene and the insertion/deletion (I/D) polymorphism in the ACE gene; rare allele frequencies were 0.16, 0.40, 0.12, 0.41, and 0.49, respectively. Participants had sinus rhythm at inclusion. During 26 years of follow-up, 968 individuals developed atrial fibrillation. Multifactorially adjusted hazard ratios for atrial fibrillation for a-20c ac and cc versus aa genotype were 1.1(95% confidence interval: 1.0-1.3; P=0.05) and 1.5(1.1-2.1; P=0.01). Compared with double noncarriers (angiotensinogen -20aa and ACE II), double heterozygotes (ac-I/D genotype), and double homozygotes (cc-DD) had hazard ratios for atrial fibrillation of 1.2(0.9-1.6; P=0.06) and 2.4(1.4-4.1; P=0.001). a-20c cc homozygotes above 70 years of age who were overweight, severely hypertensive, and had heart failure, had an absolute 10-year risk of atrial fibrillation of 61%.Angiotensinogen a-20c genotype alone and in combination with ACE I/D genotype predicts an increased risk of atrial fibrillation. Therefore, genetic variation in the renin-angiotensin system may influence effect of renin-angiotensin system blockers on atrial fibrillation. [ABSTRACT FROM AUTHOR]

This article reports on a clinical trial on nonfasting triglycerides and the risk of myocardial infarction, ischemic heart disease, and death in men and women. The objective of the trial was to test the hypothesis that very high levels of nonfasting triglycerides predict myocardial infarction (MI), ischemic heart disease (IHD) and death. The study found that with increasing levels of nonfasting triglycerides, levels of lipoprotein cholesterol increased. The study concluded that in this general population cohort, elevated nonfasting triglyceride levels were associated with increased risk of MI, IHD and death in both men and women.

Mutations in apolipoprotein B (APOB) may reduce binding of low density lipoprotein (LDL) to the LDL receptor and cause hypercholesterolemia. We showed that heterozygotes for a new mutation in APOB have hypobetalipoproteinemia, despite a reduced binding of LDL to the LDL receptor. APOB R3480P heterozygotes were identified among 9,255 individuals from the general population and had reduced levels of apoB-containing lipoproteins. Most surprisingly, R3480P LDL bound with lower affinity to the LDL receptor than non-carrier LDL in vitro, and these results were confirmed by turnover studies of LDL in vivo. In very low density lipoprotein (VLDL) turnover studies, the amount of VLDL converted to LDL in R3480P heterozygotes was substantially reduced, suggesting that this was the explanation for the hypobetalipoproteinemia observed in these individuals. Our findings emphasized the importance of combining in vitro studies with both human in vivo and population-based studies, as in vitro studies often have focused on very limited aspects of complex mechanisms taken out of their natural context. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that low plasma adiponectin is associated observationally and causally with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization (MR) analyses are much less influenced by these biases. We examined 30,045 individuals from the Copenhagen General Population Study observationally (plasma adiponectin [1,751 individuals with type 2 diabetes]), 96,903 Copenhagen individuals using one-sample MR (5 genetic variants [5,012 individuals with type 2 diabetes]), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample MR (10 genetic variants [62,892 individuals type 2 diabetes]). Observationally, and in comparisons with individuals with median plasma adiponectin of 28.9 μg/mL (4th quartile), multivariable adjusted hazard ratios (HRs) for type 2 diabetes were 1.42 (95% CI 1.18-1.72) for 19.2 μg/mL (3rd quartile), 2.21 (1.84-2.66) for 13.9 μg/mL (2nd quartile), and 4.05 (3.38-4.86) for 9.2 μg/mL (1st quartile). Corresponding cumulative incidence for type 2 diabetes at age 70 years was 3%, 7%, 11%, and 20%, respectively. A 1 μg/mL lower plasma adiponectin conferred an HR for type 2 diabetes of 1.07 (1.06-1.09), while genetic, causal risk ratio per 1 unit log-transformed lower plasma adiponectin was 1.13 (95% CI 0.83-1.53) in one-sample MR and 1.26 (1.01-1.57) in two-sample MR. In conclusion, low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to describe the rationale and design of Project FOREVER (Finding Ophthalmic Risk and Evaluating the Value of Eye exams and their predictive Reliability). Design: Project FOREVER will build a comprehensive database of clinical eye and vision data collected from ~280 000 adults at 100 optician stores across Denmark. The FOREVER database (FOREVERdb) includes detailed data from refraction, visual acuity, intraocular pressure, corneal thickness, visual field assessments and retinal fundus images. Linkage to the comprehensive Danish national registries with, that is diagnostic and prescribing data permits investigation of rare associations and risk factors. 30 000 individuals over 50 also provide a saliva sample for later genetic studies and blood pressure measurements. Of these 30 000, 10 000 will also get optical coherence tomography (OCT) nerve and retinal scans. This subpopulation data is reviewed by ophthalmologists for disease detection. All participants will be asked to complete a questionnaire assessing lifestyle, self‐perceived eye health and general health. Enrolment of participants began in April 2022. Perspective: The FOREVERdb is a powerful tool to answer a wide range of research questions that can pave the way for better eye health. This database will provide valuable insights for future studies investigating the correlations between eye and general health in a Danish population cohort, enabling research to identify potential risk factors for a range of diseases. [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have reported a higher risk of dementia in individuals with type 2 diabetes and high glucose concentrations have been associated with dementia independent of type 2 diabetes. However, is not known whether glucose per se has a causal effect on risk of dementia. Hypothesis: High plasma glucose due to genetic variation is causally associated with risk of Alzheimer's dementia, vascular dementia, and unspecified dementia in the general population. Methods: We examined observational associations of plasma glucose concentration with risk of disease; genetic variants with plasma glucose concentrations; and genetic variants with risk of disease as an indication of a causal effect of high plasma glucose on disease, using a Mendelian randomization design largely free of confounding and reverse causation in 125,875 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study. Results: In observational multifactorially adjusted analyses hazard ratio for Alzheimer's dementia was 1.18 (95% confidence interval: 0.89-1.56; p=0.25), for vascular dementia 1.74 (1.02-2.96; p=0.043), and 1.50 (1.15-1.95; p=0.003) for unspecified dementia in individuals with a glucose above 9 mmol/L versus between 5-6 mmol/L. Corresponding hazard ratios were 1.13 (0.96-1.32; p=0.14), 1.66 (1.25-2.21; p<0.001) and 1.39 (1.21-1.60; p<0.001) in individuals with type 2 diabetes versus without. A weighted allele score of glucose increasing alleles was associated with a 4.1% higher plasma glucose. In genetic, causal analyses a 1 mmol/L higher plasma glucose had risk ratios of 0.85 (0.70-1.04; p=0.11) for Alzheimer's dementia, of 1.03 (0.74-1.89; p=0.87) for vascular dementia, and of 1.17 (0.64-2.13; p=0.61) for unspecified dementia. Summary level data from the International Genomics of Alzheimer's Project using Egger Mendelian randomisation analysis gave a risk ratio for Alzheimer's dementia of 1.09 (0.60-1.96; p=0.79). Conclusions: Genetically high plasma glucose had no causal effect on risk of Alzheimer's dementia, vascular dementia, or unspecified dementia, suggesting that the increased observational risk of vascular and unspecified dementia is likely due to confounding and/or reverse causation. [ABSTRACT FROM AUTHOR]

Aims Treatment with sodium-glucose co-transporter 2 (SGLT2)-inhibitors reduces the risk of cardiovascular disease and mortality, but the mechanism is unclear. We hypothesized that a functional genetic variant in solute carrier family 5 member 2 (SLC5A2), known to be associated with familial renal glucosuria, would mimic pharmacological SGLT2-inhibition, and thus provide an opportunity to examine potential mediators of the effects on lower risk of cardiovascular disease and mortality. Methods and results We examined 112 712 individuals from the Copenhagen City Heart Study and Copenhagen General Population Study (CCHS + CGPS), 488 687 from the UK Biobank, and 342 499 from FinnGen, genotyped for SLC5A2 rs61742739, c.1961A > G; p.(Asn654Ser). The 2.0% heterozygotes and 0.01% homozygotes were pooled as carriers and compared with the 98% non-carriers. First, we examined the risk of cardiovascular disease and mortality; second, whether carrying the variant was associated with potential mediators of the effect; and third, whether identified potential mediators could explain the observed reduced risk of cardiovascular disease and mortality. In the CCHS + CGPS, carriers vs. non-carries had a 31% lower risk of heart failure, 21% lower risk of myocardial infarction, 16% lower risk of ischaemic heart disease, and 22% lower risk of all-cause mortality. Corresponding values in meta-analyses of the three studies combined were lower risk by 10%, 6%, 6%, and 10%, respectively. The SLC5A2 rs61742739 variant was not associated with a risk of ischaemic stroke or cardiovascular mortality. Of the lower risks observed in CCHS + CGPS, lower plasma glucose mediated 2.0%(P = 0.004) on heart failure, 3.1%(P = 0.09) on myocardial infarction, 4.1%(P = 0.02) on ischaemic heart disease, and 6.0%(P = 0.39) on all-cause mortality; corresponding values in the UK Biobank were 2.9%(P = 0.70), 1.5%(P = 0.77), 4.1%(P = 0.23), and 3.1%(P = 0.21), respectively. Conclusion A functional genetic variant in SLC5A2 , mimicking SGLT2-inhibition, was associated with a lower risk of heart failure, myocardial infarction, ischaemic heart disease, and all-cause mortality. These effects were at most minimally mediated through lower plasma glucose. [ABSTRACT FROM AUTHOR]

A response by Anette Varbo, Marianne Benn and colleagues to letters to the editor about their paper "Elevated Remnant Cholesterol Causes Both Low-Grade Inflammation and Ischemic Heart Disease, Whereas Elevated Low-Density Lipoprotein Cholesterol Causes Ischemic Heart Disease Without Inflammation" published in "Circulation" is presented.

Red blood cell parameters are frequently used biomarkers when assessing clinical status in newborns and in early childhood. Cell counts, amounts, and concentrations of these parameters change through gestation and after birth. Robust age-specific reference intervals are needed to optimize clinical decision making. The Copenhagen Baby Heart Study (CBHS) and the COMPARE study are prospective cohort studies including red blood cell parameters from 7,938 umbilical cord blood samples and 295 parallel venous blood samples from newborns with follow-up at two and at 14–16 months after birth. For venous blood at birth, reference intervals for hemoglobin, erythrocytes, and hematocrit were 145–224 g/L, 4.1–6.4 × 1012/L, and 0.44–0.64, respectively. Hemoglobin, erythrocytes, and hematocrit were lower at birth in children delivered by prelabor cesarean section compared to vaginal delivery. Conversion algorithms based on term newborns were: venous hemoglobin=(umbilical cord hemoglobin˗86.4)/0.39; venous erythrocytes=(umbilical cord erythrocytes-2.20)/0.44; and venous hematocrit=(umbilical cord hematocrit-0.24)/0.45. This study presents new reference intervals for red blood cell parameters in early childhood, describes the impact of delivery mode, and provide exact functions for converting umbilical cord to venous blood measurements for term newborns. These findings may improve clinical decision making within neonatology and infancy and enhance our clinical understanding of red blood cell parameters for health and diseases in early life. [ABSTRACT FROM AUTHOR]

A reply is presented by Drs. Børge G. Nordestgaard and Anne Tybjærg-Hansen to letters to the editor about their article "Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women."

The letter discusses the quality demands for arterial partial pressure of oxygen (pO2) and the lack of criteria available for defining necessary limits for bias and coefficient of variation (CV%). The authors propose quality specifications based on clinical judgments and known information on normal ranges. They suggest that the quality demands for arterial pO2 should include a bias of less than 0.2 kPa, a CV of less than 4%, and a total error of less than 0.5 kPa at levels below 5 kPa. These specifications have been implemented in their laboratories until more scientifically based data becomes available. [Extracted from the article]

Sodium glucose co-transporter 2 (SGLT2)-inhibitors were developed as glucose-lowering drugs. Surprisingly, SGLT2-inhibitors also reduced risk of cardiovascular disease. The impact of SGLT2-inhibitors on lipids and lipoproteins is unclear, but an effect might contribute to the observed lower cardiovascular risk. We conducted a meta-analysis to examine this, overall and by dose, ethnicity, and drug type. PubMed, EMBASE and Web of Science were searched for randomized controlled trials examining all available SGLT2-inhibitors. Studies with available lipid measurements were included. Quantitative data synthesis was performed using random and fixed effects models. We identified 60 randomized trials, including 147,130 individuals. Overall, using random effects models, SGLT2-inhibitor treatment increased total cholesterol by 0.09 mmol/L (95% CI: 0.06, 0.13), low-density lipoprotein (LDL) cholesterol by 0.08 mmol/L (0.05, 0.10), and high-density lipoprotein (HDL) cholesterol by 0.06 mmol/L (0.05, 0.07), while it reduced triglycerides by 0.10 mmol/L (0.06, 0.14). Fixed effects estimates were similar but with smaller effect sizes for HDL cholesterol and triglycerides. For higher SGLT2-inhibitor doses, there was a nominally higher non-significant effect on lipids and lipoproteins. In Asian compared to non-Asian populations, a slightly larger increase in HDL cholesterol and a decrease in triglycerides were observed, but with similar results for total and LDL cholesterol. Treatment effects on lipids and lipoproteins were generally robust across different SGLT2-inhibitor drugs. In meta-analyses, SGLT2-inhibition increased total, LDL, and HDL cholesterol and decreased triglycerides. Effect sizes varied slightly by drug dose and ethnicity but were generally robust by drug type. [Display omitted] • SGLT2-inhibitor treatment increases total, LDL, and HDL cholesterol slightly. • SGLT2-inhibitor treatment lowers triglycerides slightly. • Higher vs. lower treatment dose had minimal influence on the results. • Results were generally robust across different types of SGLT2-inhibitors. • Overall, changes were modest and not likely to be of clinical relevance. [ABSTRACT FROM AUTHOR]

The healthcare system of Ukraine was already suffering from several shortfalls before February 2022, but the war of aggression started by the Russian leadership is poised to inflict a further severe blow that will have long-lasting consequences for the health of all Ukrainians. In pre-war Ukraine, noncommunicable diseases (NCDs) contributed to 91% of deaths, especially cardiovascular diseases (67%). Ukrainians have a high prevalence of risk factors for NCDs ranking among the highest levels reported by the World Health Organization (WHO) in the European (EU) Region. Cardiovascular disease is one of the key health risks for the conflict-affected Ukrainian population due to significant limitations in access to health care and interruptions in the supply of medicines and resources. The excess mortality observed during the COVID-19 pandemic, due to a combination of viral illness and chronic disease states, is bound to increase exponentially from poorly treated NCDs. In this report, we discuss the impact of the war on the public health of Ukraine and potential interventions to provide remote health assistance to the Ukrainian population. [ABSTRACT FROM AUTHOR]

Background & Aims: Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone disease. Methods: We used a Mendelian randomization approach and genotyped 63,051 individuals from a prospective cohort study of the general Danish population, including 3323 subjects with symptomatic gallstones. We selected eight genetic variants in APOE, APOB, LDLR, and PCSK9 affecting LDL-C. Furthermore, studies of APOE rs429358/rs7412 (defining ε2/ε3/ε4 alleles; 12 studies) and APOB rs693 (eight studies) were included in meta-analyses. Results: The observational hazard ratio (HR) for symptomatic gallstone disease for the fifth versus first quintile of LDL-C was 0.94 (95% confidence interval: 0.76–1.17), despite a corresponding 134% increase in LDL-C. Furthermore, although individual genetic variants in APOE, APOB, LDLR, and PCSK9 associated with stepwise increases/decreases in LDL-C of up to +59% compared with non-carriers (p <0.001), none predicted the risk of symptomatic gallstone disease. Combining all variants into 10 genotypes, carriers of 9 versus ⩽3 LDL-C increasing alleles associated with 41% increased LDL-C (p <0.001), but predicted a HR for symptomatic gallstone disease of 1.09 (0.70–1.69). Finally, in meta-analyses, random effects odds ratios for gallstone disease were 0.91 (0.78–1.06) for carriers of APOE ε4 versus non-carriers, and 1.25 (0.95–1.63) for APOB rs693 CT+TT versus CC. Conclusions: Results from the observational study, genetic studies, and meta-analyses suggest that elevated plasma levels of LDL-C are not causally associated with increased risk of symptomatic gallstone disease. [ABSTRACT FROM AUTHOR]

Background: 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. Methods and Findings: 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/m² increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m² (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/m² 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/m² increase in BMI was 1.52 (95% CI 1.12-2.05). Conclusions: For every 4 kg/m² 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. [ABSTRACT FROM AUTHOR]

Background: Sinus node dysfunction (SND) is a heterogeneous disorder of unknown etiology characterized by a variety of supraventricular arrhythmias with symptoms of syncope, palpitations, and dizziness. The mechanism underlying the abnormal rhythm is incompletely understood. Objective: Because vagal stimulation and acetylcholine (ACh) affect the function of pacemaker cells, we hypothesized that genetic variation in the genes encoding the ACh-activated K+ channels, the KACh channels, could be involved in the pathogenesis of SND. Methods and Results: We screened 184 patients listed in the pacemaker registry of the Copenhagen University Hospital aged <60 years at pacemaker implantation for SND in the period 1982–2005. Forty-three patients fulfilled the following inclusion criteria: documented sinus arrest, asystole, or extreme sinus bradycardia. The coding sequences of KCNJ3 and KCNJ5, encoding the main subunits of the KACh channels, were re-sequenced. We identified several known single nucleotide polymorphisms in KCNJ3 and KCNJ5, but no mutations in either of the genes. Conclusions: Genetic variation in KCNJ3 and KCNJ5 encoding the subunits of the KACh channels is apparently not involved in the pathogenesis of SND. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

This pharmacogenetics substudy from the Losartan Intervention for Endpoint reduction in Hypertension study in patients with hypertension and left ventricular hypertrophy (LVH) treated with the angiotensin receptor blocker losartan versus the β-blocker atenolol for 4.8 years tested whether the insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene and 12 other previously well-characterized polymorphisms of hypertension susceptibility genes affected blood pressure reduction, heart rate reduction, cardiovascular events, and/or response to treatment. These polymorphisms were chosen because they could affect blood pressure control or the pharmacological action of losartan or atenolol.We genotyped 3503 patients, 1774 on losartan and 1729 on atenolol.ACE and the 12 other genotypes did not affect the reduction in systolic blood pressure, diastolic blood pressure, pulse pressure, mean arterial pressure, or heart rate, or treatment differences between losartan and atenolol on these endpoints, as assessed by general linear models. Also, ACE and the 12 other genotypes did not affect risk of the primary composite endpoint or its components stroke, myocardial infarction, and cardiovascular death, or treatment differences between losartan and atenolol on these endpoints, as assessed by Cox proportional hazards models including baseline Framingham risk score and LVH.ACE insertion/deletion and 12 other polymorphisms of hypertension susceptibility genes did not affect blood pressure reduction, heart rate reduction, or cardiovascular events in patients with hypertension and LVH, or treatment differences between losartan and atenolol on these endpoints. These results suggest that the observed effects of losartan versus atenolol in the Losartan Intervention for Endpoint reduction in hypertension study do not depend on ACE and 12 other polymorphisms of hypertension susceptibility genes. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether high glucose levels in the normoglycemic range and higher have a causal genetic effect on risk of retinopathy, neuropathy, nephropathy, chronic kidney disease (CKD), peripheral arterial disease (PAD), and myocardial infarction (MI; positive control) in the general population.Research Design and Methods: This study applied observational and one-sample Mendelian randomization (MR) analyses to individual-level data from 117,193 Danish individuals, and validation by two-sample MR analyses on summary-level data from 133,010 individuals from the Meta-Analyses of Glucose and Insulin-Related Traits Consortium (MAGIC), 117,165 from the CKDGen Consortium, and 452,264 from the UK Biobank.Results: Observationally, glucose levels in the normoglycemic range and higher were associated with high risks of retinopathy, neuropathy, diabetic nephropathy, PAD, and MI (all P for trend <0.001). In genetic causal analyses, the risk ratio for a 1 mmol/L higher glucose level was 2.01 (95% CI 1.18-3.41) for retinopathy, 2.15 (1.38-3.35) for neuropathy, 1.58 (1.04-2.40) for diabetic nephropathy, 0.97 (0.84-1.12) for estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, 1.19 (0.90-1.58) for PAD, and 1.49 (1.02-2.17) for MI. Summary-level data from the MAGIC, the CKDGen Consortium, and the UK Biobank gave a genetic risk ratio of 4.55 (95% CI 2.26-9.15) for retinopathy, 1.48 (0.83-2.66) for peripheral neuropathy, 0.98 (0.94-1.01) for eGFR <60 mL/min/1.73 m2, and 1.23 (0.57-2.67) for PAD per 1 mmol/L higher glucose level.Conclusions: Glucose levels in the normoglycemic range and higher were prospectively associated with a high risk of retinopathy, neuropathy, diabetic nephropathy, eGFR <60 mL/min/1.73 m2, PAD, and MI. These associations were confirmed in genetic causal analyses for retinopathy, neuropathy, diabetic nephropathy, and MI, but they could not be confirmed for PAD and seemed to be refuted for eGFR <60 mL/min/1.73 m2. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown.Objectives: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population.Methods: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed.Results: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy.Conclusions: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]

Background: Familial hypercholesterolemia (FH) is a condition with very high concentrations of low-density lipoprotein (LDL) cholesterol and high risk of ischemic heart disease including myocardial infarction. However, there is limited and contradictory information on whether FH and high LDL cholesterol per se confer high risk of ischemic stroke. We tested the hypotheses that individuals in the general population with FH and/or high LDL cholesterol have higher risk of ischemic stroke.Methods: The associations of FH and high LDL cholesterol with ischemic stroke risk were tested in both causal, genetic, and observational analyses using 106 412 individuals from the CGPS (Copenhagen General Population Study; 2823 ischemic strokes and 3792 myocardial infarctions) and/or 10 372 individuals from the CCHS (Copenhagen City Heart Study; 945 ischemic strokes and 1142 myocardial infarctions). FH causative mutations were LDLR W23X(rs267607213), W66G(rs121908025) and W556S, and APOB R3500Q(rs5742904). A Mendelian randomization design tested whether high LDL cholesterol per se has a causal effect on ischemic stroke risk, using a combination of the FH causative mutations and common genetic variants associated with high LDL cholesterol.Results: The cumulative incidences in individuals in the CGPS with and without FH causative mutations were similar for ischemic stroke ( P=0.50) but not for myocardial infarction ( P<0.001): at age 80 years, 4% and 7% of these individuals developed ischemic stroke and 20% and 8% myocardial infarction, with similar results in the CCHS. There was no association between clinical FH and ischemic stroke, except if personal premature ischemic heart disease was included in the clinical FH criteria. Ischemic heart disease at baseline was associated with higher ischemic stroke risk, explaining the higher ischemic stroke risk in those with high LDL cholesterol. For a 1 mmol/L higher LDL cholesterol, the genetic causal risk ratio was 1.11 (0.62-2.02) for ischemic stroke and 1.45 (1.08-1.93) for myocardial infarction.Conclusions: FH and high LDL cholesterol did not confer an increased risk of ischemic stroke. A positive association with ischemic stroke observed for some clinical FH criteria and high LDL cholesterol appears to be due to previous ischemic heart disease, rather than to high LDL cholesterol per se. [ABSTRACT FROM AUTHOR]

Background The aetiology of ischaemic heart disease (IHD) is complex and is influenced by a spectrum of environmental factors and susceptibility genes. Traditional statistical modelling considers such factors to act independently in an additive manner. The Patient Rule-Induction Method (PRIM) is a multi-model building strategy for evaluating risk attributable to context-dependent gene and environmental effects.Methods PRIM was applied to 9073 participants from the prospective Copenhagen City Heart Study (CCHS). Gender-specific cumulative incidences were estimated for subgroups defined by categories of age, smoking, hypertension, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol and triglycerides and by 94 single nucleotide variants (SNVs).Cumulative incidences for subgroups were validated using an independently ascertained sample of 58 240 participants from the Copenhagen General Population Study (CGPS).Results In the CCHS the overall cumulative incidences were 0.17 in women and 0.21 in men. PRIM identified six and four mutually exclusive subgroups in women and men, respectively, with cumulative incidences of IHD ranging from 0.02 to 0.34. Cumulative incidences of IHD generated by PRIM in the CCHS were validated in four of the six subgroups of women and two of the four subgroups of men in the CGPS.Conclusions PRIM identified high-risk subgroups characterized by specific contexts of selected values of traditional risk factors and genetic variants. These subgroups were validated in an independently ascertained cohort study. Thus, a multi-model strategy may identify groups of individuals with substantially higher risk of IHD than the overall risk for the general population. [ABSTRACT FROM PUBLISHER]

In this article, the authors focus on Mendelian randomisation analysis of two cohort studies related to the association of uric acid and hyperuricaemia with blood pressure and ischaemic heart disease. They inform that uric acid is not associated with ischaemic heart disease and blood pressure but uric acid levels are affected by body mass index. They also reflect on casual relation of the solute carrier family 2 (facilitated glucose transporter) member 9 (SLC2A9) gene with uric acid.

Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10−6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10−9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH. [ABSTRACT FROM AUTHOR]

Background Sun exposure is the single most important risk factor for skin cancer, but sun exposure may also have beneficial effects on health. We tested the hypothesis that individuals with skin cancer (non-melanoma skin cancer and cutaneous malignant melanoma) have less myocardial infarction, hip fracture and death from any cause, compared with general population controls.Methods We examined the entire Danish population above age 40 years from 1980 through 2006, comprising 4.4 million individuals. Diagnoses of non-melanoma skin cancer (n = 129 206), cutaneous malignant melanoma (n = 22107), myocardial infarction (n = 327 856), hip fracture (n = 129 419), and deaths from any cause (n = 1 629 519) were drawn from national registries.Results In individuals with vs without non-melanoma skin cancer, multifactorially adjusted odds ratios were 0.96 (95% confidence interval: 0.94–0.98) for myocardial infarction and 1.15 (1.12–1.18) for hip fracture, and the multifactorially adjusted hazard ratio was 0.52 (0.52–0.53) for death from any cause. Risk of hip fracture was reduced (odds ratios were below 1.0) in individuals below age 90 years. In individuals with vs without cutaneous malignant melanoma, corresponding odds ratios were 0.79 (0.74–0.84) for myocardial infarction and 0.84 (0.76–0.93) for hip fracture, and the corresponding hazard ratio for death from any cause was 0.89 (0.87–0.91); however, cutaneous malignant melanoma was associated positively with death from any cause in some individuals.Conclusions In this nationwide study, having a diagnosis of skin cancer was associated with less myocardial infarction, less hip fracture in those below age 90 years and less death from any cause. Causal conclusions cannot be made from our data. A beneficial effect of sun exposure per se needs to be examined in other studies. [ABSTRACT FROM AUTHOR]

Aims Activation of the angiotensin II type 1 (AT1) receptor has been shown to mediate the structural and electrical remodelling of the atrial myocardium associated with atrial fibrillation. We hypothesized that AT1 genotypic variation is associated with atrial fibrillation or diseases predisposing to atrial fibrillation, such as hypertension, heart failure, ischaemic heart disease and myocardial infarction, in the general population. Methods We resequenced the AT1 gene in 760 individuals with atrial fibrillation and identified two nonsynonymous variants ( I103 T and A244 S), which were subsequently genotyped in the prospective Copenhagen City Heart Study ( n = 10 603) and the prospective Copenhagen General Population Study ( n = 60 647). Results Risk of atrial fibrillation for heterozygotes for AT1 genetic variants A244 S and I103 T/ A244 S vs. noncarriers was increased by 2.7-fold (95% confidence interval 1.5- to 5.1-fold) and 2.6-fold (95% confidence interval 1.6- to 4.2-fold), respectively, for men. Conclusions Heterozygosity for the nonsynonymous AT1 genetic variants A244 S and I103 T/ A244 S was associated with increased risk of atrial fibrillation in men. The AT1 recptor might be a target for the pharmaceutical industry. This finding needs to be validated in independent studies. [ABSTRACT FROM AUTHOR]

Objective: We tested the hypothesis that low plasma concentrations of 25-hydroxyvitamin D are associated with increased risk of symptomatic ischemic stroke in the general population. Methods: We measured plasma 25-hydroxyvitamin D in 10,170 individuals from the general population, the Copenhagen City Heart Study. During 21 years of follow-up, 1,256 and 164 persons developed ischemic and hemorrhagic stroke, respectively. In a meta-analysis of ischemic stroke, we included 10 studies, 58,384 participants, and 2,644 events. Results: Stepwise decreasing plasma 25-hydroxyvitamin D concentrations were associated with stepwise increasing risk of ischemic stroke both as a function of seasonally adjusted percentile categories and as a function of clinical categories of 25-hydroxyvitamin D ( p for trend ≤ 2 × 10−3). In a Cox regression model comparing individuals with plasma 25-hydroxyvitamin D concentrations between the 1st and 4th percentiles to individuals with 25-hydroxyvitamin D concentrations between the 50th and 100th percentiles, multivariate adjusted hazard ratio of ischemic stroke was 1.82 (95% confidence interval, 1.41-2.34). Comparing individuals with clinical categories of severe vitamin D deficiency (<25.0nmol/l [<10.0ng/ml]) to individuals with optimal vitamin D status (≥75.0nmol/l [≥30.0ng/ml]), the multivariate adjusted hazard ratio of ischemic stroke was 1.36 (1.09-1.70). 25-Hydroxyvitamin D concentrations were not associated with risk of hemorrhagic stroke. In a meta-analysis comparing lowest versus highest quartile of 25-hydroxyvitamin D concentrations, the multivariate adjusted odds ratio of ischemic stroke was 1.54 (1.43-1.65) with a corresponding hazard ratio of 1.46 (1.35-1.58) in prospective general population studies. Interpretation: In this large population-based prospective study, we observed stepwise increasing risk of symptomatic ischemic stroke with decreasing plasma 25-hydroxyvitamin D concentrations. This finding was substantiated in a meta-analysis. ANN NEUROL 2013. [ABSTRACT FROM AUTHOR]

Objective: We used genetic variants that are robustly associated with adiposity to examine the causal association of adiposity with psychological distress. Methods: We examined the association of adiposity with psychological distress in a large (N = 53,221) general population cohort of 20- to 99-year-old adults from Copenhagen, Denmark. Psychological distress was assessed using four questions that asked about: feeling stressed; not accomplishing very much; wanting to give up; and regular use of antidepressants/sedatives. We used the genetic loci FTO rs9939609 and MC4R rs17782313 as instrumental variables for adiposity quantified by body mass index (BMI) and waist to hip ratio (WHR). Results: In conventional multivariable analyses, BMI and WHR were positively associated with distress. For example, the odds ratio of reporting not accomplishing for each additional standard deviation increase for BMI was 1.11 (95% CI: 1.09, 1.13) and for WHR was 1.10 (95% CI: 1.08, 1.13) in the fully adjusted analyses. In contrast, instrumental variable analyses showed an inverse association of adiposity on distress; corresponding odds ratio in instrumental variable analyses was 0.64 (95% CI: 0.46, 0.89) for BMI and 0.49 (95% CI: 0.25, 0.94) for WHR (P-values for difference between the two approaches both = 0.001). Conclusion: The inverse associations of adiposity and psychological distress when genetic variants are used as instrumental variables could be explained by biological pathways linking adiposity and distress. The positive associations of adiposity with distress in multivariable analyses might be explained by residual confounding or reverse causality. [ABSTRACT FROM AUTHOR]

Lawlor DA, Harbord RM, Tybjaerg-Hansen A, Palmer TM, Zacho J, Benn M, Timpson NJ, Smith GD, Nordestgaard BG (MRC Centre for Causal Analyses in Translational Epidemiology, University of Bristol, UK; The Department of Social Medicine, University of Bristol, UK; Department of Clinical Biochemistry, Rigshospitalet, Copenhagen, Denmark; The Copenhagen General Population Study, Herlev Hospital, Copenhagen, Denmark; Copenhagen University Hospital, Faculty of Health Sciences, University of Copenhagen, Denmark; Department of Clinical Biochemistry, Herlev Hospital, Copenhagen, Denmark) Using genetic loci to understand the relationship between adiposity and psychological distress: a Mendelian Randomization study in the Copenhagen General Population Study of 53 221 adults. J Intern Med 2011; : 525-537. We used genetic variants that are robustly associated with adiposity to examine the causal association of adiposity with psychological distress. We examined the association of adiposity with psychological distress in a large ( N = 53 221) general population cohort of 20- to 99-year-old adults from Copenhagen, Denmark. Psychological distress was assessed using four questions that asked about: feeling stressed; not accomplishing very much; wanting to give up; and regular use of antidepressants/sedatives. We used the genetic loci FTO rs9939609 and MC4R rs17782313 as instrumental variables for adiposity quantified by body mass index (BMI) and waist to hip ratio (WHR). In conventional multivariable analyses, BMI and WHR were positively associated with distress. For example, the odds ratio of reporting not accomplishing for each additional standard deviation increase for BMI was 1.11 (95% CI: 1.09, 1.13) and for WHR was 1.10 (95% CI: 1.08, 1.13) in the fully adjusted analyses. In contrast, instrumental variable analyses showed an inverse association of adiposity on distress; corresponding odds ratio in instrumental variable analyses was 0.64 (95% CI: 0.46, 0.89) for BMI and 0.49 (95% CI: 0.25, 0.94) for WHR ( P-values for difference between the two approaches both = 0.001). The inverse associations of adiposity and psychological distress when genetic variants are used as instrumental variables could be explained by biological pathways linking adiposity and distress. The positive associations of adiposity with distress in multivariable analyses might be explained by residual confounding or reverse causality. [ABSTRACT FROM AUTHOR]

The article focuses on the study conducted to examine the nonfasting triglycerides, cholesterol, and ischemic stroke. It compares the compare the increasing levels of nonfasting triglycerides and cholesterol for their association with risk of ischemic stroke in the general population. It concludes that the increasing levels of nonfasting triglycerides in women were associated with increasing risk of ischemic stroke.

Objectives: The purpose of this study was to test whether the association of C-reactive protein (CRP) with increased risk of atrial fibrillation is a robust and perhaps even causal association. Background: Elevated levels of CRP previously have been associated with increased risk of atrial fibrillation. Methods: We studied 10,276 individuals from the prospective Copenhagen City Heart Study, including 771 individuals who had atrial fibrillation during follow-up, and another 36,600 persons from the cross-sectional Copenhagen General Population Study, including 1,340 cases with atrial fibrillation. Individuals were genotyped for 4 CRP gene polymorphisms and had high-sensitivity CRP levels measured. Results: A CRP level in the upper versus lower quintile associated with a 2.19-fold (95% confidence interval [CI]: 1.54- to 3.10-fold) increased risk of atrial fibrillation. Risk estimates attenuated slightly after multifactorial adjustment to 1.77 (95% CI: 1.22 to 2.55), and after additional adjustment for heart failure and plasma fibrinogen level to 1.47 (95% CI: 1.02 to 2.13) and 1.63 (95% CI: 1.21 to 2.20), respectively. Genotype combinations of the 4 CRP polymorphisms associated with up to a 63% increase in plasma CRP levels (p < 0.001), but not with increased risk of atrial fibrillation. The estimated causal odds ratio for atrial fibrillation by instrumental variable analysis for a doubling in genetically elevated CRP levels was lower than the odds ratio for atrial fibrillation observed for a doubling in plasma CRP on logistic regression (0.94 [95% CI: 0.70 to 1.27] vs. 1.36 [95% CI: 1.30 to 1.44]; p < 0.001). Conclusions: Elevated plasma CRP robustly associated with increased risk of atrial fibrillation; however, genetically elevated CRP levels did not. This suggests that elevated plasma CRP per se does not increase atrial fibrillation risk. [ABSTRACT FROM AUTHOR]