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.

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.

Nonfasting cholesterol and triglycerides and association with risk of myocardial infarction and total mortality: the Copenhagen City Heart Study with 31 years of follow-up.

Objectives: We compared the ability of very high levels of nonfasting cholesterol and triglycerides to predict risk of myocardial infarction and total mortality.

Design: Prospective study from 1976 to 1978 until 2007.

Setting: Danish general population.

Plasma levels of 27-hydroxycholesterol in humans and mice with monogenic disturbances of high density lipoprotein metabolism.

Secretion of 27-hydroxycholesterol (27OHC) from macrophages is considered as an alternative to HDL-mediated reverse transport of excess cholesterol. We investigated 27OHC-concentrations in plasma of humans and mice with monogenic disorders of HDL metabolism. As compared to family controls mutations in the genes for apolipoprotein A-I, ATP binding cassette transporter (ABC) A1 and lecithin:cholesterol acylstransferase (LCAT) were associated with reduced concentrations of both HDL-cholesterol and HDL-27OHC whereas mutations in the genes for cholesterylester transfer protein (CETP), scavenger receptor type BI and hepatic lipase were associated with elevated HDL concentrations of either sterol.

Serum soluble CD163 predicts risk of type 2 diabetes in the general population.

Background: Activation of adipose tissue macrophages with concomitant low-grade inflammation is believed to play a central role in the development of type 2 diabetes. We tested whether a new macrophage-derived biomarker, soluble CD163 (sCD163), identifies at-risk individuals before overt disease has developed.

Methods: A prospective cohort study of 8849 study participants from the general population, the Copenhagen City Heart Study, was followed for 18 years for incidence of type 2 diabetes.

Scavenger receptor AI/II truncation, lung function and COPD: a large population-based study.

Objectives: The scavenger receptor A-I/II (SRA-I/II) on alveolar macrophages is involved in recognition and clearance of modified lipids and inhaled particulates. A rare variant of the SRA-I/II gene, Arg293X, truncates the distal collagen-like domain, which is essential for ligand recognition. We tested whether the Arg293X variant is associated with reduced lung function and risk of chronic obstructive pulmonary disease (COPD) in the general population.

TRIB1 and GCKR polymorphisms, lipid levels, and risk of ischemic heart disease in the general population.

Objective: The goal of this study was to test whether TRIB1-rs2954029 and GCKR-rs1260326 associate with lipid levels and risk of ischemic heart disease (IHD) and myocardial infarction (MI) in the general population.

Methods And Results: We genotyped >71 000 individuals. Lipid levels were studied cross-sectionally.

C reactive protein and chronic obstructive pulmonary disease: a Mendelian randomisation approach.

Background: It is unclear whether elevated plasma C reactive protein (CRP) is causally related to chronic obstructive pulmonary disease (COPD). The authors tested the hypothesis that genetically elevated plasma CRP causes COPD using a Mendelian randomisation design.

Methods: The authors measured high-sensitivity CRP in plasma, genotyped for four single nucleotide polymorphisms in the CRP gene, and screened for spirometry-defined COPD and hospitalisation due to COPD in 7974 individuals from the Copenhagen City Heart Study and in 32,652 individuals from the Copenhagen General Population Study.

Lipoprotein(a) as a cardiovascular risk factor: current status.

Aims: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.

Methods And Results: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels.

Wide spectrum of desmosomal mutations in Danish patients with arrhythmogenic right ventricular cardiomyopathy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a lethal condition characterised by ventricular tachyarrhythmias, right and/or left ventricular involvement and fibrofatty infiltrations in the myocardium. The disease has been associated with mutations in genes encoding desmosomal proteins.

Objective: To thoroughly evaluate an ARVC cohort for desmosomal mutations and large genomic rearrangements and characterise the phenotype associated with double-mutation carrier status.

Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease.

Context: Epidemiologically, levels of high-density lipoprotein (HDL) cholesterol and its major protein constituent, apolipoprotein A-I (apoA-I), are inversely related to risk of ischemic heart disease (IHD).

Objective: We tested whether common genetic variation in the apolipoprotein A1 gene (APOA1) contributes to apoA-I and HDL cholesterol levels and risk of IHD in the general population.

Design: We resequenced the regulatory and coding regions of APOA1 in 190 individuals from the Copenhagen City Heart Study with the lowest 1% (n=95) and highest 1% (n=95) apoA-I levels.

Plasma YKL-40 and total and disease-specific mortality in the general population.

Background: Increased plasma YKL-40 is associated with short-term survival in patients with cardiovascular disease and cancer. We tested the hypothesis that increased plasma YKL-40 is associated with total and disease-specific mortality in the general population.

Methods: We measured plasma YKL-40 in 8899 study participants, aged 20-95 years, in the Copenhagen City Heart Study from the Danish general population who were followed for 16 years: 3059 died, 2158 had ischemic cardiovascular disease, 2271 had cancer, and 2820 had other diseases associated with increased YKL-40.

Does elevated C-reactive protein increase atrial fibrillation risk? A Mendelian randomization of 47,000 individuals from the general population.

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.

Common clinical practice versus new PRIM score in predicting coronary heart disease risk.

Objectives: To compare the new Patient Rule Induction Method (PRIM) Score and common clinical practice with the Framingham Point Score for classification of individuals with respect to coronary heart disease (CHD) risk.

Methods And Results: PRIM Score and the Framingham Point Score were estimated for 11,444 participants from the Copenhagen City Heart Study. Gender specific cumulative incidences and 10 year absolute CHD risks were estimated for subsets defined by age, total cholesterol, high-density lipoprotein (HDL) cholesterol, blood pressure, diabetes and smoking categories.

C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization.

Context: The assignment of direction and causality within networks of observational associations is problematic outside randomized control trials, and the presence of a causal relationship between body mass index (BMI) and C-reactive protein (CRP) is disputed.

Objective: Using reciprocal Mendelian randomization, we aim to assess the direction of causality in relationships between BMI and CRP and to demonstrate this as a promising analytical technique.

Participants And Methods: The study was based on a large, cross-sectional European study from Copenhagen, Denmark.

PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses.

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).

Copy number variation in glutathione-S-transferase T1 and M1 predicts incidence and 5-year survival from prostate and bladder cancer, and incidence of corpus uteri cancer in the general population.

Glutathione-S-transferase T1 (GSTT1) and GSTM1 detoxify carcinogens and thus potentially contribute to inter-individual susceptibility to cancer. We determined the ability of GST copy number variation (CNV) to predict the risk of cancer in the general population. Exact copy numbers of GSTT1 and GSTM1 were measured by real-time PCR in 10 247 individuals, of whom 2090 had cancer.

High pre-beta1 HDL concentrations and low lecithin: cholesterol acyltransferase activities are strong positive risk markers for ischemic heart disease and independent of HDL-cholesterol.

Background: We hypothesized that patients with high HDL-cholesterol (HDL-C) and ischemic heart disease (IHD) may have dysfunctional HDL or unrecognized nonconventional risk factors.

Methods: Individuals with IHD (Copenhagen University Hospital) and either high HDL-C (n = 53; women >or=735 mg/L; men >or=619 mg/L) or low HDL-C (n = 42; women View Article and Find Full Text PDF

[Fatal course of a patient during in vitro fertilisation treatment].

Chylomicronaemia syndrome is a rare disorder primarily caused by a genetic defect which increases triglycerides, combined with a secondary inducing factor. We describe the fatal course of a 33-year-old, pregnant woman with known dyslipidaemia who had been treated with in vitro fertilisation and developed chylomicronaemia syndrome with severe hypertriglyceridaemia, hypertriglyceridaemia-induced acute pancreatitis and septic shock. Appropriate treatment including close monitoring, severe restriction of dietary fat intake and early plasmapheresis is emphasized - especially during pregnancy.

Hyperhomocysteinemia, methylenetetrahydrofolate reductase c.677C>T polymorphism and risk of cancer: cross-sectional and prospective studies and meta-analyses of 75,000 cases and 93,000 controls.

Global DNA hypomethylation associates with development of cancer. DNA hypomethylation also associates with hyperhomocysteinemia and MTHFR c.677C>T homozygosity, both of which may associate with increased risk of cancer.

C-reactive protein and risk of venous thromboembolism in the general population.

Objective: To examine the robustness of the association between C-reactive protein (CRP) levels and increased risk of venous thromboembolism (VTE) and to examine whether genetically elevated CRP levels cause VTE.

Methods And Results: In the prospective Copenhagen City Heart Study, we observed 10 388 participants for longer than 16 years, of whom 484 developed a VTE. In the cross-sectional Copenhagen General Population Study, we studied 36 616 participants, of whom 903 previously had a VTE.

Novel mutations in leukotriene C4 synthase and risk of cardiovascular disease based on genotypes from 50,000 individuals.

Background: Atherosclerosis is an inflammatory condition where cysteinyl leukotrienes have been identified to play an important role. Furthermore, cysteinyl leukotrienes may also affect thrombus formation. Using prospective, cross-sectional and case-control designs, we tested the hypothesis that hitherto unknown genetic variation, likely to affect the function of leukotriene C(4) synthase, is associated with risk of venous thromboembolism, ischemic stroke and myocardial infarction.

C-reactive protein and all-cause mortality--the Copenhagen City Heart Study.

Aims: We tested whether elevated levels of C-reactive protein is robustly and causally associated with all-cause mortality.

Methods And Results: We studied 10 388 white persons from the general population. During 16 years 3124 persons died.

Penetrance of NOD2/CARD15 genetic variants in the general population.

Background: In case-control studies of Europeans, heterozygosity for Arg702Trp(rs2066844), Gly908Arg(rs2066845) and Leu1007fsinsC(rs5743293) on the NOD2/CARD15 gene is associated with a 2-fold greater risk of Crohn disease, whereas homozygosity or compound heterozygosity is associated with a 17-fold greater risk. However, the importance of these genetic variants if identified in particular individuals within the general population is unknown. We undertook this study to estimate the penetrance of these variants in the general population.

Haemochromatosis genotype and iron overload: association with hypertension and left ventricular hypertrophy.

Objective: We hypothesized that there is an association between haemochromatosis genotype C282Y/C282Y and/or iron overload and risk of hypertension and/or left ventricular hypertrophy (LVH).

Methods: We analysed data from a cross-sectional study of the general population including 8992 individuals from the Copenhagen City Heart Study (CCHS), a follow-up study of 36,480 individuals from the Copenhagen General Population Study (CGPS), and a case-only study of 3815 Scandinavians from the Losartan Intervention For End-point Reduction in Hypertension Genetic Substudy (LIFEGEN) with LVH and hypertension.

Results: In the CCHS, individuals with C282Y/C282Y versus wild type/wild type had an odds ratio for antihypertensive medication use of 4.

Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables.

Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable.