Objective
The apolipoprotein E (APOE) ε4 allele is a major genetic risk factor for Alzheimer disease and dementia. However, it remains unclear whether plasma levels of apoE confer additional risk. We ...tested this hypothesis.
Methods
Using 75,708 participants from the general population, we tested whether low plasma levels of apoE at study enrollment were associated with increased risk of future Alzheimer disease and all dementia, and whether this association was independent of ε2/ε3/ε4 APOE genotype.
Results
Multifactorially adjusted hazard ratios (HRs) for Alzheimer disease and all dementia increased from the highest to the lowest apoE tertile (p for trends < 1 × 10−6). Multifactorially adjusted HRs for lowest versus highest tertile were 2.68 (95% confidence interval CI = 2.04–3.52) and 1.80 (95% CI = 1.52–2.13) for Alzheimer disease and all dementia, respectively. After further adjustment for ε2/ε3/ε4 APOE genotype, plasma apoE tertiles remained associated with Alzheimer disease (p for trend = 0.007) and all dementia (p for trend = 0.04). Plasma apoE tertiles did not interact with ε2/ε3/ε4 APOE genotype on risk of Alzheimer disease (p = 0.53) or all dementia (p = 0.79). In a subanalysis, the −219G>T GT promoter genotype, associated with low plasma apoE levels, remained significantly associated with increased risk of Alzheimer disease after adjustment for ε2/ε3/ε4 APOE genotype (HR = 1.56, 95% CI = 1.05–2.30).
Interpretation
Low plasma levels of apoE are associated with increased risk of future Alzheimer disease and all dementia in the general population, independent of ε2/ε3/ε4 APOE genotype. This is clinically relevant, because no plasma biomarkers are currently implemented. Hence, plasma levels of apoE may be a new, easily accessible preclinical biomarker. Ann Neurol 2015;77:301–311
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.
Abstract Introduction The adenosine triphosphate-binding cassette transporter A1 ( ABCA1 ) is a major cholesterol transporter highly expressed in the liver and brain. In the brain, ABCA1 lipidates ...apolipoprotein E (apoE), facilitates clearance of amyloid-β, and may be involved in maintenance of the blood-brain barrier via apoE-mediated pathways. Methods We tested whether a loss-of-function mutation in ABCA1 , N1800H, is associated with plasma levels of apoE and with risk of Alzheimer's disease (AD) in 92,726 individuals and with risk of cerebrovascular disease in 64,181 individuals. Results N1800H AC (0.2%) versus AA (99.8%) was associated with a 13% lower plasma level of apoE ( P = 1 × 10−11 ). Multifactorially adjusted hazard ratios for N1800H AC versus AA were 4.13 (95% confidence interval, 1.32–12.9) for AD, 2.46 (1.10–5.50) for cerebrovascular disease, and 8.28 (2.03–33.7) for the hemorrhagic stroke subtype. Discussion A loss-of-function mutation in ABCA1 , present in 1:500 individuals, was associated with low plasma levels of apoE and with high risk of AD and cerebrovascular disease in the general population.
Abstract Epidemiological studies consistently demonstrate a strong inverse association between low levels of high-density lipoprotein (HDL) cholesterol and increased risk of ischemic heart disease ...(IHD). This review focuses on whether both rare and common genetic variation in ABCA1 contributes to plasma levels of HDL cholesterol and to risk of IHD in the general population, and further seeks to understand whether low levels of HDL cholesterol per se are causally related to IHD. Studies of the ABCA1 gene demonstrate a general strategy for detecting functional genetic variants, and show that both common and rare ABCA1 variants contribute to levels of HDL cholesterol and risk of IHD in the general population. The association between ABCA1 variants and risk of IHD appears, however, to be independent of plasma levels of HDL cholesterol. With the recent identification of the largest number of individuals heterozygous for loss-of-function mutations in ABCA1 worldwide, population studies suggests that genetically low HDL cholesterol per se does not predict an increased risk of IHD, and thus questions the causality of isolated low levels of HDL cholesterol for the development of IHD.
Through seven decades the inverse association between HDL cholesterol concentrations and risk of atherosclerotic cardiovascular disease (ASCVD) has been observed in case-control and prospective ...cohort studies. This robust inverse association fuelled the enthusiasm towards development of HDL cholesterol increasing drugs, exemplified by the cholesteryl ester transfer protein (CETP) inhibitor trials and the extended-release niacin HPS2-THRIVE trial. These HDL cholesterol increasing trials were launched without conclusive evidence from human genetics, and despite discrepant species dependent evidence from animal studies. Evidence from human genetics and from randomized clinical trials over the last 13 years now point in the direction that concentrations of HDL cholesterol, do not appear to be a viable future path to target therapeutically for prevention of ASCVD. A likely explanation for the strong observational association between low HDL cholesterol and high ASCVD risk is the concomitant inverse association between HDL cholesterol and atherogenic triglyceride-rich lipoproteins. The purpose of the present review is to bring HDL cholesterol increasing trials into a human genetics context exemplified by candidate gene studies of key players in HDL biogenesis as well as by HDL cholesterol related genome-wide association studies.
Graphical abstract summarizing conclusions: Observational epidemiology, randomized clinical trials and human genetics suggesting noncausality between low HDL cholesterol concentrations and increased ASCVD risk.
Left upper image: 1. Low HDL cholesterol is associated with increased risk of ASCVD, confirmed in numerous case-control and prospective studies.
Right upper image: 2. Genetic evidence from consortia and candidate gene studies have shown that the inverse association between HDL cholesterol concentrations and risk of ASCVD may not be of a causal nature.
Left lower image: 3. HDL cholesterol concentration increasing trials have so far not shown to reduce risk of ASCVD.
Right lower image: 4. Despite lack of support of a causal role, the HDL cholesterol concentration can be used as a biomarker for ASCVD risk prediction.
ASCVD = atherosclerotic cardiovascular disease; HDL = high-density lipoprotein. Display omitted
Objectives This study tested whether genetic variation in the CETP gene is consistent with a protective effect of cholesteryl ester transfer protein (CETP) inhibition on risk of ischemic events and ...on total mortality, without the adverse effects reported for torcetrapib. Background Torcetrapib, an inhibitor of CETP, increased risk of death and ischemic cardiovascular disease of those randomized to the drug, despite improving the lipid profile. Methods The Copenhagen City Heart Study is a prospective cohort study of 10,261 individuals, aged 20 to 93 years, who were followed for up to 34 years (1976 to 2010). Of these, 2,087 developed ischemic heart disease, 1,064 developed ischemic cerebrovascular disease, and 3,807 died during follow-up. We selected 2 common genetic variants in CETP previously associated with reductions in CETP activity, thus mimicking the effect of pharmacological CETP inhibition. Results In individuals carrying 4 versus 0 high-density lipoprotein cholesterol–increasing alleles, there was an increase in levels of high-density lipoprotein cholesterol of up to 14% (0.2 mmol/l), and concomitant decreases in triglycerides, low-density lipoprotein cholesterol, and non–high-density lipoprotein cholesterol of, respectively, 6% (0.1 mmol/l), 3% (0.1 mmol/l), and 4% (0.2 mmol/l) (p for trend 0.004 to <0.001). Corresponding hazard ratios were 0.76 (95% confidence interval CI: 0.68 to 0.85) for any ischemic vascular event, 0.74 (95% CI: 0.65 to 0.85) for ischemic heart disease, 0.65 (95% CI: 0.54 to 0.79) for myocardial infarction, 0.77 (95% CI: 0.65 to 0.93) for ischemic cerebrovascular disease, 0.71 (95% CI: 0.58 to 0.88) for ischemic stroke, and 0.88 (95% CI: 0.80 to 0.97) for total mortality. CETP genotypes did not associate with variation in markers of possible side effects previously reported for torcetrapib. Conclusions Genetic CETP inhibition associates with reductions in risk of ischemic heart disease, myocardial infarction, ischemic cerebrovascular disease, and ischemic stroke, with a corresponding antiatherogenic lipid profile, and with increased longevity, without adverse effects.
In recent prospective studies, low plasma levels of apolipoprotein E (apoE) are associated with high risk of dementia. Whether this reflects a causal association remains to be established.
Using a ...Mendelian randomization approach, we studied 106,562 and 75,260 individuals from the general population in observational and genetic analyses, respectively.
In observational analyses risk of Alzheimer's disease and all dementia increased stepwise as a function of stepwise lower apoE levels (P for trend, 2 × 10−17 and 9 × 10−21). APOE-weighted allele scores were associated with stepwise decreases in apoE (P for trend, <1 × 10−300). In instrumental variable analysis, the causal risk ratios for a 1 mg/dL genetically determined lower apoE were 1.41 (1.27–1.57) for Alzheimer's disease and 1.33 (1.25–1.43) for all dementia (F-statistics = 3821).
Genetic and hence lifelong low apoE is associated with high risk of dementia in the general population. The concordance between observational and genetic estimates suggests a potential causal relationship.
•Observationally low plasma apolipoprotein E is associated with risk of dementia.•We studied 106,562 and 75,260 individuals using a Mendelian randomization approach.•Genetically low plasma apolipoprotein E is associated with high risk of dementia.•Taken together the observational and genetic estimates suggest a causal relationship.
Abstract
Aims
Preclinical evidence has indicated that HDL may play an important role in the immune system; however, very little is known about the role of HDL in the immune system in humans. We ...tested the hypothesis that low and high concentrations of HDL cholesterol are associated with risk of infectious disease in the general population.
Methods and results
We included 97 166 individuals from the Copenhagen General Population Study and 9387 from the Copenhagen City Heart Study with measurements of HDL cholesterol at baseline. The primary endpoint was any infectious disease requiring hospital admission, ascertained in the Danish health registries from baseline in 2003–13 or 1991–94 through 2014; 9% and 31% of individuals in the two studies experienced one or more infectious disease events. Using restricted cubic splines, there was a U-shaped association between concentrations of HDL cholesterol and risk of any infection. Following multifactorial adjustment, individuals with HDL cholesterol below 0.8 mmol/L (31 mg/dL) and above 2.6 mmol/L (100 mg/dL) had hazard ratios for any infection of 1.75 (95% confidence interval 1.31–2.34) and 1.43 (1.16–1.76), compared to those with HDL cholesterol of 2.2–2.3 mmol/L (85–95 mg/dL). In the Copenhagen City Heart Study, corresponding hazard ratios for any infection were 2.00 (1.16–3.43) and 1.13 (0.80–1.60).
Conclusion
Low and high HDL cholesterol concentrations found in 21% and 8% of individuals were associated with higher risk of infectious disease in the general population. These findings do not necessarily indicate causality.
Introduction
Hypophosphataemia is common in critically ill patients, but neither its prevalence nor its association with outcome have been investigated specifically in patients with aneurysmal ...subarachnoid haemorrhage (aSAH).
Methods
Patients with aSAH and at least one phosphate measurement were included from two independent cohorts; an American cohort extracted from two open‐access databases (Medical Information Mart for Intensive Care‐III and eICU Collaborative Research Database v. 2.0) and a Danish cohort consisting of patients with aSAH admitted to Rigshospitalet, Denmark over a 4‐year period. In each cohort, we calculated the prevalence of mild (0.32–0.80 mmol/L) and severe (<0.32 mmol/L) hypophosphataemia and their association with in‐hospital mortality before and after propensity‐score matching.
Results
Hypophosphataemia occurred in 72.4% (95% CI: 68.1–76.3) of patients in the American cohort (n = 471) and 54.9% (50.0–59.7) in the Danish cohort (n = 419). However, it was not associated with mortality in neither full (American: Mild, Odds ratio (OR) 0.99 (0.91–1.07), Severe OR 1.20 (0.95–1.51); Danish: Mild, OR 1.01 (0.95–1.08), Severe OR 1.20 (0.95–1.51)) nor propensity‐score matched cohorts (American (n = 168): Mild, OR 1.06 (0.88–1.28), Severe OR 1.46 (0.96–2.12); Danish (n = 44): Mild, OR 1.16 (0.82–1.65), Severe OR 0.45 (0.13–1.55)).
Conclusion
In this retrospective study of patients with aSAH, hypophosphataemia was common.
Aim
The voltage‐gated potassium channel Kv11.1 is important for repolarizing the membrane potential in excitable cells such as myocytes, pancreatic α‐ and β‐cells. Moxifloxacin blocks the Kv11.1 ...channel and increases the risk of hypoglycaemia in patients with diabetes. We investigated glucose regulation and secretion of glucoregulatory hormones in young people with and without moxifloxacin, a drug known to block the Kv11.1 channel.
Materials and Methods
The effect of moxifloxacin (800 mg/day for 4 days) or placebo on glucose regulation was assessed in a randomized, double‐blind, crossover study of young men and women (age 20‐40 years and body mass index 18.5‐27.5 kg/m2) without chronic disease, using 6‐h oral glucose tolerance tests and continuous glucose monitoring.
Results
Thirty‐eight participants completed the study. Moxifloxacin prolonged the QTcF interval and increased heart rate. Hypoglycaemia was more frequently observed with moxifloxacin, both during the 8 days of continuous glucose monitoring and during the oral glucose tolerance tests. Hypoglycaemia questionnaire scores were higher after intake of moxifloxacin. Moxifloxacin reduced the early plasma‐glucose response (AUC0‐30 min) by 7% (95% CI: −9% to −4%, p < .01), and overall insulin response (AUC0‐360 min) decreased by 18% (95% CI: −24% to −11%, p < .01) and plasma glucagon increased by 17% (95% CI: 4%‐33%, p = .03). Insulin sensitivity calculated as the Matsuda index increased by 11%, and MISI, an index of muscle insulin sensitivity, increased by 34%.
Conclusions
In young men and women, moxifloxacin, a drug known to block the Kv11.1 channel, increased QT interval, decreased glucose levels and was associated with increased muscle insulin sensitivity and more frequent episodes of hypoglycaemia.
PDF
