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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: 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]

Supplemental Digital Content is Available in the Text. [ABSTRACT FROM AUTHOR]

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87).Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. [ABSTRACT FROM AUTHOR]