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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]

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke., Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank., Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min -1 ·1.73 m -2 , compared with those with eGFR between 60 and 105 mL·min -1 ·1.73 m -2 . Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min -1 ·1.73 m -2 , with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min -1 ·1.73 m -2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min -1 ·1.73 m -2 . Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD., Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.

Background: Lipid profiles are usually measured after fasting. We tested the hypotheses that these levels change only minimally in response to normal food intake and that nonfasting levels predict cardiovascular events., Methods and Results: We cross-sectionally studied 33 391 individuals 20 to 95 years of age from the Copenhagen General Population Study. We also studied 9319 individuals 20 to 93 years of age from the Copenhagen City Heart Study, 1166 of whom developed cardiovascular events during 14 years of follow-up. Compared with fasting levels, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, and albumin levels were reduced up to 3 to 5 hours after the last meal; triglycerides levels were increased up to 6 hours after the last meal; and non-HDL cholesterol level, apolipoprotein A1 level, apolipoprotein B level, ratio of total cholesterol to HDL cholesterol, and ratio of apolipoprotein B to apolipoprotein A1 did not change in response to normal food intake. The maximum changes after normal food and fluid intake from fasting levels were -0.2 mmol/L for total cholesterol, -0.2 mmol/L for low-density lipoprotein cholesterol, -0.1 mmol/L for HDL cholesterol, and 0.3 mmol/L for triglycerides. Highest versus lowest tertile of nonfasting total cholesterol, non-HDL cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, triglycerides, ratio of total cholesterol to HDL cholesterol, and ratio of apolipoprotein B/apolipoprotein A1 and lowest versus highest tertile of nonfasting HDL cholesterol and apolipoprotein A1 predicted 1.7- to 2.4-fold increased risk of cardiovascular events., Conclusions: Lipid profiles at most change minimally in response to normal food intake in individuals in the general population. Furthermore, nonfasting lipid profiles predicted increased risk of cardiovascular events.

Background: Rare mutations in the mitochondrial genome may cause disease. Mitochondrial haplogroups defined by common polymorphisms have been associated with risk of disease and longevity. We tested the hypothesis that common haplogroups predict risk of ischemic cardiovascular disease, morbidity from other causes, mortality, and longevity in a general population of European descent., Methods and Results: We followed 9254 individuals from the Danish general population, in the Copenhagen City Heart Study, prospectively for risk of ischemic cardiovascular disease, morbidity from other causes, and mortality during 25 and 11 years, respectively. Haplogroup frequencies were as follows: H (45.9%), U (15.9%), T (9.9%), J (9.1), K (6.2%), V (4.5%), W/I (3.8%), and Z (3.5%). Hazard ratios for hospitalization due to all cardiovascular disorders (haplogroup U: 1.0 [95% confidence interval{CI}, 0.9 to 1.1]; T: 0.9 [95% CI, 0.8 to 1.0]; J: 1.0 [95% CI, 0.9 to 1.1]; K: 1.0 [95% CI, 0.9 to 1.2]; V: 1.0 [95% CI, 0.9 to 1.2]; W/I: 0.8 [95% CI, 0.7 to 1.0]; Z: 1.0 [95% CI, 0.8 to 1.2]), ischemic heart disease (U: 0.9 [95% CI, 0.8 to 1.1]; T: 0.9 [95% CI, 0.7 to 1.0]; J: 1.1 [95% CI, 0.9 to 1.2]; K: 1.1 [95% CI, 0.9 to 1.3]; V: 1.1 [95% CI, 0.9 to 1.4]; W/I: 1.1 [95% CI, 0.8 to 1.4]; Z: 1.1 [95% CI, 0.8 to 1.4]), and ischemic cerebrovascular disease (U: 1.1 [95% CI, 0.9 to 1.4]; T: 0.9 [95% CI, 0.7 to 1.2]; J: 1.1 [95% CI, 0.9 to 1.4]; K: 1.0 [95% CI, 0.8 to 1.4]; V: 1.1 [95% CI, 0.8 to 1.5]; W/I: 0.8 [95% CI, 0.5 to 1.3]; Z: 0.9 [95% CI, 0.6 to 1.4]) did not differ from 1.0 for any haplogroup versus the most common haplogroup H. Results were similar for hospitalization due to infectious and parasitic diseases, respiratory infections, respiratory disorders, malignant neoplasms, digestive disorders, musculoskeletal disorders, neuropsychiatric disorders, and miscarriages. Likewise, hazard ratios for death from all causes were not different from 1.0 for any haplogroup versus haplogroup H (U: 1.0 [95% CI, 0.8 to 1.1]; T: 0.9 [95% CI, 0.8 to 1.1]; J: 0.9 [95% CI, 0.8 to 1.1]; K: 1.0 [95% CI, 0.8 to 1.2]; V: 1.1 [95% CI, 0.9 to 1.3]; W/I: 0.8 [95% CI, 0.7 to 1.1]; Z: 0.9 [95% CI, 0.7 to 1.2]). Finally, after stratification by major causes of death, hazard ratios remained insignificant., Conclusions: Our results do not support an association of mitochondrial haplogroups with risk of ischemic cardiovascular disease, morbidity from other causes, mortality, or longevity in a large general population of European descent.

Background: We hypothesized that the estrogen receptor alpha (ESR1) IVS1-397T/C polymorphism affects high-density lipoprotein cholesterol response to hormone replacement therapy and risk of cardiovascular disease (CVD), cancer of reproductive organs, and hip fracture., Methods and Results: We studied cross-sectionally 9244 individuals from the Danish general population and followed them up for 23 to 25 years. End points were CVD (ischemic heart disease, myocardial infarction, angina pectoris, ischemic cerebrovascular disease, ischemic stroke, other ischemic cerebrovascular disease, venous thromboembolism, deep vein thrombosis, and pulmonary embolism), cancer of reproductive organs (breasts, ovaries, uterus, and prostate), and hip fracture. We also studied patients with ischemic heart disease (n=2495), ischemic cerebrovascular disease (n=856), and breast cancer (n=1256) versus general population controls. The CC, CT, and TT genotypes had general population frequencies of 21%, 50%, and 29%, respectively. Cross-sectionally, genotype did not influence high-density lipoprotein cholesterol response to hormone replacement therapy. In the cohort study, there were no differences in risks of CVD, cancer of reproductive organs, or hip fracture between genotypes. In case-control studies, risk of CVD did not differ between genotypes; however, the odds ratio for breast cancer in women with TT versus CC genotypes was 1.4 (95% CI, 1.1 to 1.7). Meta-analysis in men of 6 previous and the present 2 studies, including 4799 cases and 12,190 controls, showed odds ratios in CC versus CT and TT genotypes for fatal and nonfatal myocardial infarction of 0.81 (95% CI, 0.59 to 1.12) and 1.08 (95% CI, 0.97 to 1.21)., Conclusions: ESR1 IVS1-397T/C polymorphism does not influence high-density lipoprotein cholesterol response to hormone replacement therapy or risk of CVD, most cancers of reproductive organs, or hip fracture.

Background: We tested the hypothesis that the hereditary hemochromatosis genotypes C282Y/C282Y, C282Y/H63D, or C282Y/wild-type are risk factors for ischemic heart disease (IHD) and myocardial infarction (MI)., Methods and Results: We performed a prospective study of 9178 individuals from the Danish general population followed up for 24 years, during which 1035 and 511 developed IHD and MI, respectively, and a case-control study of 2441 and 1113 IHD and MI cases versus 8080 controls. C282Y/C282Y, C282Y/H63D, and C282Y/wild-type versus wild-type/wild-type individuals were not associated with increased risk of IHD or MI in prospective studies, overall or stratified by gender. We had 90% power to detect a hazard ratio for IHD of 3.4 for C282Y/C282Y, 1.9 for C282Y/H63D, and 1.3 for C282Y/wild-type versus wild-type/wild-type. Furthermore, these genotypes were not associated with increased risk of IHD or MI in case-control studies, overall or stratified by gender. We had 90% power to detect an odds ratio for IHD of 3.6 for C282Y/C282Y, 1.8 for C282Y/H63D, and 1.3 for C282Y/wild-type versus wild-type/wild-type., Conclusions: In these studies, hereditary hemochromatosis C282Y/C282Y, C282Y/H63D, and C282Y/wild-type genotypes were not associated with IHD or MI; however, the study lacked the power to exclude the possibility that C282Y/C282Y and C282Y/H63D individuals have a modestly increased risk of IHD or MI.

Background: Extracellular superoxide dismutase (EC-SOD) is an antioxidative enzyme found in high concentrations in the arterial wall. Two to three percent of all people in Denmark carry an R213G substitution, which increases plasma concentration 10-fold. This may reduce arterial wall EC-SOD concentrations, increase intimal LDL oxidation, and therefore may accelerate atherogenesis. Our primary hypothesis was that EC-SOD-R213G predisposes to ischemic heart disease (IHD). The secondary hypothesis was that EC-SOD-R213G offers predictive ability with respect to IHD beyond that offered by measurements of plasma EC-SOD and autoantibodies against oxidized LDL (oxLDL)., Methods and Results: The primary hypothesis was tested in a prospective, population-based study of 9188 participants from The Copenhagen City Heart Study with 956 incident IHD events during 23 years of follow-up and retested cross-sectionally with independent case populations of patients with IHD (n=943) or ischemic cerebrovascular disease (ICVD) (n=617). Case populations were compared with unmatched IHD/ICVD-free control subjects from The Copenhagen City Heart Study (n=7992). The secondary hypothesis was tested by using a nested case-control study comparing patients with IHD (n=956) with age- and gender-matched control subjects (n=956). Age- and gender-adjusted relative risk for IHD in heterozygotes (n=221, 2.4%) versus noncarriers (n=8965, 97.6%) was 1.5 (95% CI, 1.1 to 2.1). Retesting confirmed this: Age- and gender-adjusted odds ratios for IHD was 1.4 (1.0 to 2.0) and for ICVD 1.7 (1.1 to 2.7). Additional adjustment for plasma EC-SOD produced an odds ratio for IHD in heterozygotes versus noncarriers of 9.2 (1.2 to 72), whereas adjustment for autoantibodies against oxLDL produced an odds ratio of 2.5 (1.2 to 5.3)., Conclusions: Heterozygosity for EC-SOD-R213G is associated with increased IHD risk. Genotyping offers predictive ability with respect to IHD beyond that offered by plasma EC-SOD and autoantibodies against oxLDL.