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Objective: For decades, it has been suggested that small dense low‐density lipoprotein (sdLDL) may be particularly atherogenic. High levels of sdLDL are associated with an increased risk of ischemic heart disease; however, the association of sdLDL with ischemic stroke has not been explored in a large prospective study on the general population. We tested the hypothesis that high sdLDL cholesterol levels are associated with an increased risk of ischemic stroke. Methods: This prospective study included 38,319 individuals from the Copenhagen General Population Study with fresh sample measurements of sdLDL cholesterol. Median follow‐up time was 3.1 years. We observed 302 and 74 ischemic and hemorrhagic strokes from baseline in 2013 to 2017 to the end of follow‐up in 2018. For comparison, we included estimates for large buoyant LDL cholesterol and total LDL cholesterol. Results: Higher levels of sdLDL cholesterol were log‐linearly associated with increased risk of ischemic stroke. Compared with individuals with sdLDL cholesterol in the lowest tertile (≤0.60 mmol/l; ≤23 mg/dl) the multivariable adjusted hazard ratio for ischemic stroke was 1.79 (95% confidence interval = 1.31–2.43) for the highest tertile (≥0.86 mmol/l; ≥33 mg/dl). Multivariable adjusted hazard ratios for ischemic stroke per 1 mmol/l (38.7 mg/dl) higher levels were 1.69 (1.28–2.22) for sdLDL cholesterol, 0.95 (0.78–1.16) for large buoyant LDL cholesterol, and 1.08 (0.93–1.25) for total LDL cholesterol. Hazard ratios were similar when further adjusting for body mass index (BMI) and diabetes mellitus in the biological pathway in combination with related lipids and lipoproteins. Interpretation: Higher sdLDL cholesterol levels were robustly associated with increased risk of ischemic stroke. ANN NEUROL 2023;93:952–964 [ABSTRACT FROM AUTHOR]

This article discusses the results of six randomized trials that examined the effects of fibrates and gemfibrozil on the prevention of atherosclerotic cardiovascular disease (ASCVD). The trials showed inconsistent results, and the authors sought to understand these discrepancies by examining the effects of mass changes in remnant cholesterol and LDL cholesterol. Using the Copenhagen General Population Study (CGPS) to mimic the study population of these trials, the authors compared estimated changes in ASCVD risk through mass changes in cholesterol with the observed changes in the original trials. The results suggest that mass changes in total atherogenic cholesterol can explain the results of these trials, regardless of whether statins were used or not. The authors conclude that to reduce ASCVD, cholesterol-lowering agents should aim to reduce the total mass of atherogenic cholesterol. [Extracted from the article]

Objective: High remnant cholesterol concentrations are associated with high risk of ischemic heart disease, but whether this is also the case for ischemic stroke is unknown. We tested the hypothesis that high remnant cholesterol concentrations are associated with increased risk of ischemic stroke in the general population.Methods: A total of 102,964 individuals from the Copenhagen General Population Study with information on remnant cholesterol at baseline in 2003-2015 were included in a prospective, observational association study. Individuals were followed for up to 14 years, during which time 2,488 were diagnosed with an ischemic stroke. Hazard ratios were estimated using Cox proportional hazard regression models. Results were independently confirmed in 9,548 individuals enrolled in the Copenhagen City Heart Study in 1991-1994; 983 ischemic strokes developed during up to 26 years of follow-up.Results: Step-wise higher remnant cholesterol concentrations were associated with step-wise higher ischemic stroke risk in the Copenhagen General Population Study, with multivariable adjusted hazard ratios up to 1.99 (95%confidence interval: 1.49-2.67) for individuals with remnant cholesterol concentrations ≥1.5 mmol/l (58 mg/dl), compared to individuals with remnant cholesterol <0.5 mmol/l (19 mg/dl). Results were similar in the Copenhagen City Heart Study. Cumulative incidence of ischemic stroke at age 80 in the Copenhagen General Population Study ranged from 7.3% for individuals with remnant cholesterol <0.5 mmol/l (19 mg/dl) to 11.5% for individuals with remnant cholesterol ≥1.5 mmol/l (58 mg/dl).Interpretation: Individuals with high remnant cholesterol concentrations had higher risk of ischemic stroke. These results indicate that randomized clinical trials with remnant cholesterol lowering in individuals with high concentrations, with the aim of preventing ischemic strokes, are needed. Ann Neurol 2019;85:550-559. [ABSTRACT FROM AUTHOR]

Objective: Urate is a potent antioxidant, and high plasma urate has been associated with lower incidence of Parkinson's disease (PD) in epidemiological studies. We tested the hypothesis that high concentrations of plasma urate are associated with low incidence of PD.Methods: We performed observational and genetic analyses using plasma urate and the urate SLC2A9 rs7442295 and ABCG2 rs2231142 genotype in >102,000 individuals from the CGPS (Copenhagen General Population Study). Information on PD and mortality was from national patient and death registries. Incidences of PD were calculated using Cox regression, Fine and Gray competing-risks regression, and instrumental variable analyses.Results: In total, 398 individuals were diagnosed with PD, of which 285 were incident cases. The multivariable adjusted hazard ratio for PD was 0.56 (95% confidence interval [CI], 0.41-0.77) for the highest versus the lowest tertile of plasma urate (p for trend across 3 groups, 8 × 10-5 ). Each one-allele increase in the combined allele score was associated with 19μmol/l (95% CI, 18.5-19.9) higher plasma urate. In observational analyses, a 50μmol/l higher plasma urate was associated with a hazard ratio of 0.85 (0.77-0.92) for PD; in instrumental variable analyses, 50μmol/l higher plasma urate was associated with an odds ratio of 1.20 (0.85-1.71) for PD.Interpretation: High plasma urate was associated with lower risk of PD in observational analyses; however, in instrumental variable analysis, high plasma urate was not associated with low risk of PD. Thus, our data do not support a causal relationship between high plasma urate and low risk of PD. Ann Neurol 2018;84:178-190. [ABSTRACT FROM AUTHOR]

Background & Aims: Fatty liver disease has been associated with higher all‐cause as well as liver‐related, ischemic heart disease (IHD)‐related and extrahepatic cancer‐related mortality in observational epidemiological studies. We tested the hypothesis that fatty liver disease is a causal risk factor for higher mortality. Methods: We genotyped seven genetic variants known to be associated with fatty liver disease (in PNPLA3, TM6SF2, HSD17B13, MTARC1, MBOAT7, GCKR, and GPAM) in 110 913 individuals from the Danish general population. Hepatic steatosis was measured by hepatic computed tomography in n = 6965. Using a Mendelian randomization framework, we tested whether genetically proxied hepatic steatosis and/or elevated plasma alanine transaminase (ALT) was associated with liver‐related mortality. Results: During a median follow‐up of 9.5 years, 16 119 individuals died. In observational analyses, baseline elevated plasma ALT was associated with higher all‐cause (1.26‐fold), liver‐related (9‐fold), and extrahepatic cancer‐related (1.25‐fold) mortality. In genetic analyses, the risk alleles in PNPLA3, TM6SF2, and HSD17B13 were individually associated with higher liver‐related mortality. The largest effects were seen for the PNPLA3 and TM6SF2 risk alleles, for which homozygous carriers had 3‐fold and 6‐fold, respectively, higher liver‐related mortality than non‐carriers. None of the risk alleles, individually or combined into risk scores, were robustly associated with all‐cause, IHD‐related, or extrahepatic cancer‐related mortality. In instrumental variable analyses, genetically proxied hepatic steatosis and higher plasma ALT were associated with liver‐related mortality. Conclusions: Human genetic data support that fatty liver disease is a causal driver of liver‐related mortality. [ABSTRACT FROM AUTHOR]

Said differently, LDL cholesterol cannot be too low after a myocardial infarction and all patients with a myocardial infarction should receive LDL cholesterol-lowering medication post myocardial infarction irrespective of their LDL cholesterol levels at the time of the infarct. Just as age - these comorbidities increase the risk of dying during follow-up for patients with low LDL cholesterol at myocardial infarction compared with those with high LDL cholesterol at myocardial infarction. Elevated low-density lipoprotein (LDL) cholesterol is a causal risk factor for the development of atherosclerosis and drives an increased risk of both myocardial infarction and early death. [Extracted from the article]

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]

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.

An abstract of the article "Scavenger receptor AI/II truncation, lung function and COPD in 48,700 individuals," by Mette Thomsen and colleagues is presented.

Abstract: Objective: ATP‐binding‐cassette transporter A7(ABCA7) is suggested to be involved in lipid transport as well as in phagocytosis of amyloid‐β in the brain. We tested the hypothesis that a common genetic variant in ABCA7 is associated with dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels in the general population, independent of the common apolipoprotein E(APOE) genotype. Methods: For this purpose, we genotyped a common genetic variant in ABCA7, identified in genome‐wide‐association‐studies of Alzheimer's disease, in 104,258 individuals from the Danish general population, and also meta‐analyzed our results with publicly available consortia data. Results: Multifactorially adjusted hazard ratios for Alzheimer's disease were 1.07 (95% confidence interval:0.93–1.23) and 1.72 (1.24–2.40) for GA and AA versus GG genotype. Results were similar after APOE genotype adjustment and when only APOE ɛ33 carriers were studied. Including 178,304 individuals, the meta‐analyzed odds ratio for Alzheimer's disease per one allele ABCA7 rs4147929 increase was 1.15 (1.12–1.18). ABCA7 genotype was not convincingly associated with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, or with lipid levels. Including 288,563 individuals, meta‐analyzed odds ratios for ischemic heart disease per one allele ABCA7 rs4147929 increase was 1.01 (0.99–1.03). Interpretation: A common genetic variant in ABCA7 was associated with high risk of Alzheimer's disease independent of APOE genotype. The lack of association with vascular dementia, ischemic heart disease, ischemic cerebrovascular disease, and with lipid levels suggests that ABCA7 is not important for atherosclerosis. Thus, our findings support the suggested role of ABCA7 in Alzheimer's disease pathology and phagocytic clearance of amyloid‐β in the brain. [ABSTRACT FROM AUTHOR]

The myeloproliferative neoplasms are associated with chronic kidney disease but whether clonal haematopoiesis of indeterminate potential (CHIP) is associated with impaired kidney function is unknown. In the Danish General Suburban Population Study (N = 19 958) from 2010 to 2013, 645 individuals were positive for JAK2V617F (N = 613) or CALR (N = 32) mutations. Mutation‐positive individuals without haematological malignancy were defined as having CHIP (N = 629). We used multiple and inverse probability weighted (IPW)‐adjusted linear regression analysis to estimate adjusted mean (95% confidence interval) differences in estimated glomerular filtration rate (eGFR; ml/min/1.73 m2) by mutation status, variant allele frequency (VAF%), blood cell counts, and neutrophil‐to‐lymphocyte ratio (NLR). We performed 11‐year longitudinal follow‐up of eGFR in all individuals. Compared to CHIP‐negative individuals, the mean differences in eGFR were −5.6 (−10.3, −0.8, p =.02) for CALR, −11.9 (−21.4, −2.4, p = 0.01) for CALR type 2, and −10.1 (−18.1, −2.2, p =.01) for CALR with VAF ≥ 1%. The IPW‐adjusted linear regression analyses showed similar results. NLR was negatively associated with eGFR. Individuals with CALR type 2 had a worse 11‐year longitudinal follow‐up on eGFR compared to CHIP‐negative individuals (p =.004). In conclusion, individuals with CALR mutations, especially CALR type 2, had impaired kidney function compared to CHIP‐negative individuals as measured by a lower eGFR at baseline and during 11‐year follow‐up. [ABSTRACT FROM AUTHOR]

Objective: Conflicting results have been reported on the association between lipids and risk of ischemic stroke. We tested the hypothesis that the burden of ischemic stroke attributable to either elevated apolipoprotein B (apoB) or non‐high‐density lipoprotein (non‐HDL) cholesterol is higher than that attributable to elevated low‐density lipoprotein (LDL) cholesterol. Methods: We included 104,618 individuals from an ongoing cohort study, the Copenhagen General Population Study. The associations of quintiles of apoB, non‐HDL cholesterol, and LDL cholesterol with risk of ischemic stroke were estimated by Cox proportional hazards regressions with 95% confidence intervals. With 1st quintile as reference, the proportion of ischemic stroke attributable to the 2nd, 3rd, 4th, and 5th quintiles of apoB, non‐HDL cholesterol, and LDL cholesterol were estimated by population attributable fractions. Results: Higher quintiles of apoB and non‐HDL cholesterol were associated with increased risk of ischemic stroke (both trends: p < 0.0001), whereas for LDL cholesterol this association was somewhat attenuated (trend: p = 0.0005). A similar pattern was seen for population attributable fraction values. Compared to individuals in the 1st quintile, the combined proportion of ischemic stroke attributable to individuals in the 2nd to 5th quintiles was 16.3% for apoB (levels >82 mg/dL), 14.7% for non‐HDL cholesterol (>3.0 mmol/L; >117 mg/dL), and 6.8% for LDL cholesterol (>2.4 mmol/L; >94 mg/dL). Interpretation: The proportion of ischemic stroke attributable to either elevated apoB or non‐HDL cholesterol was double that attributable to elevated LDL cholesterol. ANN NEUROL 2022;92:379–389 [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Thus, the CLL clone was detectable 8 years and not 18 years prior to the diagnosis of CLL for this patient (CLL no. 6, Table SI, Fig 1). No specific CLL characteristics were noted for the four (24%) patients without detectable pre-diagnostic CLL clones; two of those patients had normal fluorescence I in situ i hybridisation (FISH) while two had del(13q), one was I IGHV i unmutated. [Extracted from the article]

The JAK2 V617 F somatic mutation is present in the majority of patients with myeloproliferative cancer (polycythaemia vera, essential thrombocytosis, and primary myelofibrosis). However, the diagnostic value of the JAK2 V617 F somatic mutation for myeloproliferative cancer in the general population is unknown. We examined this question in 49 488 individuals from the Copenhagen General Population Study. We also examined the association between JAK2 V617 F somatic mutation, rs10974944 germline genotype, haematological phenotype, any cancer, haematological cancer, myeloproliferative cancer, ischaemic heart disease, and venous thromboembolism. The JAK2 V617 F somatic mutation was present in 0·1% ( n = 68), increasing across rs10974944 germline genotypes ( P-trend = 0·001). JAK2 V617 F somatic mutation positives versus negatives had higher erythrocyte ( P = 2 × 10−5), thrombocyte ( P = 2 × 10−16), and leucocyte ( P = 4 × 10−9) counts, and had 2·7-/2·5-fold risk of cancer (prevalent/incident), 44-/28-fold risk of haematological cancer, 221-/97-fold risk of myeloproliferative cancer, 2·2-/1·2-fold risk of ischaemic heart disease, and 3·1-/1·0-fold risk of venous thromboembolism. By combining conventional haematological parameters with a test for the JAK2 V617 F somatic mutation, myelo;?>proliferative cancer could be identified or ruled out with a sensitivity of 47-100% and a specificity of 98-100%. In conclusion, in the general population the JAK2 V617 F somatic mutation has a high diagnostic value for myeloproliferative cancer when combined with conventional haematological parameters. [ABSTRACT FROM AUTHOR]

Whether there is an association between measured and genetically predicted telomere length and melanoma mortality is unclear. We tested the hypothesis that measured and genetically predicted telomere length is associated with mortality after a melanoma diagnosis. We followed 2,101 patients with melanoma from hospital clinics and the general population for risk of death for up to 26 years. All had telomere length measured in DNA from leukocytes, and 2052 of these were genotyped for the three single nucleotide polymorphisms rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1); all three genotypes are associated with telomere length and combined into an allele count from 0 to 6. For each telomere‐lengthening allele, the hazard ratios (HRs) for mortality in the age‐adjusted and multivariable‐adjusted Cox analysis were 1.12 (95% confidence interval: 1.02–1.23) and 1.11 (1.01–1.23). However, for each standard deviation increase in measured telomere length, HR for mortality was 0.97 (0.88–1.08). In conclusion, in more than 2000 melanoma patients from hospital clinics and from the general population, genetically predicted long telomeres were associated with increased mortality, but measured leukocyte telomere length was not. [ABSTRACT FROM AUTHOR]

Meta‐analyses and Mendelian randomization (MR) may clarify the associations of smoking, blood cells and myeloproliferative neoplasms (MPN). We investigated the association of smoking with blood cells in the Danish General Suburban Population Study (GESUS, n = 11 083), by meta‐analyses (including GESUS) of 92 studies (n = 531 741) and MR of smoking variant CHRNA3 (rs1051730[A]) in UK Biobank, and with MPN in a meta‐analysis of six studies (n (total/cases):1 425 529/2187), totalling 2 307 745 participants. In the meta‐analysis the random‐effects standardized mean difference (SMD) in current smokers versus non‐smokers was 0·82 (0·75–0·89, P = 2·0 * 10−108) for leukocytes, 0·09 (−0·02 to 0·21, P = 0·12) for erythrocytes, 0·53 (0·42–0·64, P = 8·0 * 10−22) for haematocrit, 0·42 (0·34–0·51, P = 7·1 * 10−21) for haemoglobin, 0·19 (0·08–0·31, P = 1·2 * 10−3) for mean corpuscular haemoglobin (MCH), 0·29 (0·19–0·39, P = 1·6 * 10−8) for mean corpuscular volume (MCV), and 0·04 (−0·04 to 0·13, P = 0·34) for platelets with trends for ever/ex‐/current smokers, light/heavy smokers and female/male smokers. Analyses presented high heterogeneity but low publication bias. Per allele in CHRNA3, cigarettes per day in current smokers was associated with increased blood cell counts (leukocytes, neutrophils), MCH, red cell distribution width (RDW) and MCV. The pooled fixed‐effects odds ratio for MPN was 1·44 [95% confidence interval (CI): 1·33–1·56; P = 1·8 * 10−19; I2 = 0%] in current smokers, 1·29 (1·15–1·44; P = 8·0 * 10−6; I2 = 0%) in ex‐smokers, 1·49 (1·26–1·77; P = 4·4 * 10−6; I2 = 0%) in light smokers and 2·04 (1·74–2·39, P = 2·3 * 10−18; I2 = 51%) in heavy smokers compared with non‐smokers. Smoking is observationally and genetically associated with increased leukocyte counts and red blood cell indices (MCH, MCV, RDW) and observationally with risk of MPN in current and ex‐smokers versus non/never‐smokers. [ABSTRACT FROM AUTHOR]

Objective: Short telomere length is a known risk factor for developing clonal haematopoietic stem cell disorders, probably due to chromosomal instability. We tested the hypotheses that bone marrow mononuclear cell telomere length change from diagnosis through chemotherapy‐induced remission and relapse, and that long telomere length is associated with low risk of relapse and all‐cause mortality in patients with acute myeloid leukaemia or high‐risk myelodysplastic syndrome. Methods: We measured telomere length in bone marrow mononuclear cells from 233 patients at diagnosis, 112 patients at chemotherapy‐induced remission and 58 patients at relapse of disease. Results: In patients with acute myeloid leukaemia or high‐risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length was similar at diagnosis and relapse, but increased after chemotherapy‐induced remission. Furthermore, bone marrow mononuclear cell telomere length was longer in patients with higher age at diagnosis. There was no association between telomere length at diagnosis, remission or relapse and all‐cause mortality, nor did we find any association between telomere length at diagnosis or remission and risk of relapse. Conclusion: In patients with acute myeloid leukaemia or high‐risk myelodysplastic syndrome, bone marrow mononuclear cell telomere length increased from diagnosis to remission. Furthermore, telomere length paradoxically was longer at higher age at diagnosis, even after adjusting for known risk factors of disease severity. Finally, we did not detect any prognostic information in telomere length. [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]

Objective: We hypothesized that elevated plasma YKL-40 levels are associated with increased risk of ischemic cardiovascular disease in the general population. In contrast to C-reactive protein (CRP) produced in the liver in response to inflammation, YKL-40 is produced by lipid-laden macrophages inside the vessel wall. Methods: We measured plasma YKL-40 in 8,899 21- to 93-year-old participants of the Copenhagen City Heart Study 1991-1994 examination, and followed them for up to 18 years. Endpoints were ischemic stroke, ischemic cerebrovascular disease, myocardial infarction, and ischemic heart disease. Hazard ratios were calculated for plasma YKL-40 levels in 10-year age percentile categories of 34 to 66%, 67 to 90%, and 91 to 100% versus 0 to 33%. Results: Multifactorially and CRP-adjusted hazard ratios for ischemic stroke were 1.2 (95% confidence interval, 0.9-1.6) for 33 to 66%, 1.8 (1.3-2.4) for 67 to 90%, and 2.3 (1.5-3.3) for 91 to 100% versus the 0 to 33% percentile category ( p-trend < 0.001). Corresponding hazard ratios for ischemic cerebrovascular disease were 1.2 (0.9-1.5), 1.6 (1.2-2.0), and 2.2 (1.6-3.2) ( p-trend < 0.001). Hazard ratios for myocardial infarction were not significant, whereas corresponding hazard ratios for ischemic heart disease were 1.0 (0.8-1.2), 1.2 (1.0-1.5), and 1.3 (1.0-1.6) ( p-trend = 0.01). Stratifying for CRP or other risk factors gave similar results. A doubling in plasma YKL-40 was associated with multifactorially and CRP-adjusted increased risk of 20% (95% confidence interval, 11%-30%) for ischemic stroke, 16% (8%-24%) for ischemic cerebrovascular disease, 3% (-5%-11%) for myocardial infarction, and 7% (1%-12%) for ischemic heart disease. Interpretation: In the general population, elevated plasma YKL-40 levels are associated with increased risk of ischemic stroke and ischemic cerebrovascular disease, independent of plasma CRP levels.Ann Neurol 2010;68:672-680 [ABSTRACT FROM AUTHOR]