Search

Background: Lipids influence brain function and mental health. Understanding the role of apolipoproteins in affective disorders could provide valuable insights and potentially pave the way for novel therapeutic approaches. Methods: We examined the apolipoprotein E genotype and ApoE-levels, lipid profiles, and the correlation with cognition in 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected, AT), their unaffected co-twins (high-risk, HR), and twins with no personal or family history of affective disorder (low-risk, LR). Results: The APOE genotype was not associated with affective disorders. No significant group differences in ApoE levels were found between the three risk groups. Post hoc analysis group-wise comparisons showed higher ApoE levels in the AT than HR twins and in the concordant AT twin pairs relative to the discordant twin pairs. Within the discordant twin pairs, higher ApoE levels were observed in the affected twins (AT = 39.4 mg/L vs. HR = 36.8 mg/L, p = 0.037). Limitations: The present study could benefit from a larger sample size. We did not assess dietary habits. Conclusions: The results did not support our main hypothesis. However, exploratory post hoc analysis suggests a role for plasma ApoE and triglycerides in affective disorders. Future research is needed. [ABSTRACT FROM AUTHOR]

The association between thyroid stimulating hormone (TSH) and cardiovascular disease has mainly been determined using clinical categories of disease. We tested the hypothesis that TSH on a continuous scale is associated with risk of atrial fibrillation (AF), myocardial infarction (MI), stroke, heart failure (HF), aortic valve stenosis (AVS), and major adverse cardiovascular events (MACE) and whether these associations are likely to be causal. We first tested whether plasma TSH on a continuous scale was observationally associated with incident cardiovascular events in a prospective cohort study of 105,224 individuals from the Copenhagen General Population Study followed for a median 7 years. Next, we tested whether a genetic risk score weighted on TSH was associated with cardiovascular endpoints. Finally, using Mendelian randomization, we tested whether the observed associations were likely to be causal. Using restricted cubic splines, lower concentrations of TSH relative to the population median (=1.53 mIU/L) were associated with higher risk of AF, MI, stroke, HF, AVS, and MACE. Comparing individuals with TSH ≤5th percentile (≤0.54 mIU/L) versus >50th percentile (>1.53 mIU/L), hazard ratios (HRs) ranged from 1.12 (1.00–1.26) for stroke to 1.27 (1.11–1.46) for HF. Genetic risk estimates per standard deviation decrease in TSH were 1.28 (1.08–1.52) for AF, 1.35 (1.06–1.71) for MI, 1.06 (0.89–1.26) for stroke, 1.19 (0.94–1.52) for HF, 1.53 (1.03–2.26) for AVS, and 1.09 (0.97–1.23) for MACE. In 105,224 individuals from the general population low plasma TSH was observationally and genetically associated with increased risk of AF, MI, and AVS suggesting that these observations may reflect causal pathways. [Display omitted] • We tested the hypothesis that TSH was associated with cardiovascular disease (CVD). • 105,224 individuals from the general population were followed for a median of 7 years. • Observationally, TSH below the median was associated with increased risk of CVD. • Genetically, Mendelian randomization suggested possible causal associations. [ABSTRACT FROM AUTHOR]

Apolipoprotein E (apoE) plays a crucial role in cholesterol metabolism, and high levels of apoE in plasma are associated with cardiovascular disease and all-cause mortality. We aimed to assess if HIV is independently associated with high plasma apoE and to determine HIV-related risk factors for high plasma apoE. We included 661 people with HIV (PWH) from the Copenhagen Comorbidity in HIV (COCOMO) study with available measurement of plasma apoE. COCOMO participants were frequency matched 1:1 on age and sex with controls from the Copenhagen General Population Study. High plasma apoE was defined as levels above the 90th percentile (66.2 mg/L). The association between HIV and high plasma apoE was assessed using logistic regression models. Among PWH, both linear and logistic regression models were used to determine HIV-specific risk factors for high plasma apoE. Mean age was 52 years and 89 % were male. Median plasma apoE was 49.0 mg/L in PWH and 43.3 mg/L in controls, p < 0.001. HIV was associated with higher plasma apoE after adjusting for potential confounders, including triglycerides (odds ratio 2.14 [95 % CI: 1.39–3.29], p < 0.001). In PWH, higher plasma apoE was associated with a previous AIDS-defining condition in linear models before adjustment for triglycerides and integrase strand transfer inhibitor use in fully adjusted linear models. PWH had higher plasma apoE than controls even after adjusting for triglycerides. Further studies are needed to elucidate the clinical impact of high plasma apoE in PWH. [Display omitted] • People with HIV had higher plasma apoE levels than controls from the general population. • Plasma apoE was consistently higher in people with HIV when stratifying by triglyceride levels. • People with HIV also had higher apoE/apoB ratio compared to controls. • Thus, the association between HIV status and apoE was independent of changes in other lipid parameters. [ABSTRACT FROM AUTHOR]

Background Werner syndrome, a premature genetic aging syndrome, shares many clinical features reminiscent of normal physiological aging, and ischemic vascular disease is a frequent cause of death. We tested the hypothesis that genetic variation in the WRN gene was associated with risk of ischemic vascular disease in the general population. Methods We included 58,284 participants from two general population cohorts, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). Of these, 6,312 developed ischemic vascular disease during follow-up. In the CCHS ( n = 10,250), we genotyped all non-synonymous variants in WRN with reported minor allele frequencies ≥ 0.5% in Caucasians. Second, variants which were associated with ischemic vascular disease in the CCHS or in previous studies, were genotyped in the CGPS ( n = 48,034). Results A total of 11 non-synonymous variants were identified in the CCHS. In C1367R (rs1346044) TT homozygotes versus CC/CT, hazard ratios for ischemic stroke were 1.09 (95% confidence interval: 0.95–1.24; P = 0.22) in the CCHS, 1.16 (1.00–1.33; P = 0.04) in the CGPS, and 1.12 (1.01–1.23; P = 0.02) in studies combined (CCHS + CGPS), with similar trends for ischemic cerebrovascular disease ( P = 0.06). In meta-analyses including 59,190 individuals in 5 studies, the hazard ratio for ischemic stroke for C1367R TT homozygotes versus CC/CT was 1.14 (1.04–1.25; P = 0.008). Conclusions This study suggests that common genetic variation in WRN is associated with increased risk of ischemic stroke in the general population. [ABSTRACT FROM AUTHOR]

Background The aetiology of ischaemic heart disease (IHD) is complex and is influenced by a spectrum of environmental factors and susceptibility genes. Traditional statistical modelling considers such factors to act independently in an additive manner. The Patient Rule-Induction Method (PRIM) is a multi-model building strategy for evaluating risk attributable to context-dependent gene and environmental effects.Methods PRIM was applied to 9073 participants from the prospective Copenhagen City Heart Study (CCHS). Gender-specific cumulative incidences were estimated for subgroups defined by categories of age, smoking, hypertension, diabetes, body mass index, total cholesterol, high-density lipoprotein cholesterol and triglycerides and by 94 single nucleotide variants (SNVs).Cumulative incidences for subgroups were validated using an independently ascertained sample of 58 240 participants from the Copenhagen General Population Study (CGPS).Results In the CCHS the overall cumulative incidences were 0.17 in women and 0.21 in men. PRIM identified six and four mutually exclusive subgroups in women and men, respectively, with cumulative incidences of IHD ranging from 0.02 to 0.34. Cumulative incidences of IHD generated by PRIM in the CCHS were validated in four of the six subgroups of women and two of the four subgroups of men in the CGPS.Conclusions PRIM identified high-risk subgroups characterized by specific contexts of selected values of traditional risk factors and genetic variants. These subgroups were validated in an independently ascertained cohort study. Thus, a multi-model strategy may identify groups of individuals with substantially higher risk of IHD than the overall risk for the general population. [ABSTRACT FROM PUBLISHER]

Background Conflicting evidence exists on whether smoking acts as an effect modifier of the association between APOE genotype and risk of coronary heart disease (CHD). Methods and results We searched PubMed and EMBASE to June 11, 2013 for published studies reporting APOE genotype, smoking status and CHD events and added unpublished data from population cohorts. We tested for presence of effect modification by smoking status in the relationship between APOE genotype and risk of CHD using likelihood ratio test. In total 13 studies (including unpublished data from eight cohorts) with 10,134 CHD events in 130,004 individuals of European descent were identified. The odds ratio (OR) for CHD risk from APOE genotype (ε4 carriers versus non-carriers) was 1.06 (95% confidence interval (CI): 1.01, 1.12) and for smoking (present vs. past/never smokers) was OR 2.05 (95%CI: 1.95, 2.14). When the association between APOE genotype and CHD was stratified by smoking status, compared to non-ε4 carriers, ε4 carriers had an OR of 1.11 (95%CI: 1.02, 1.21) in 28,789 present smokers and an OR of 1.04 (95%CI 0.98, 1.10) in 101,215 previous/never smokers, with no evidence of effect modification ( P -value for heterogeneity = 0.19). Analysis of pack years in individual participant data of >60,000 with adjustment for cardiovascular traits also failed to identify evidence of effect modification. Conclusions In the largest analysis to date, we identified no evidence for effect modification by smoking status in the association between APOE genotype and risk of CHD. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the association of the loss-of-function mutations in the gene encoding apolipoprotein C3 (APOC3) with the risk of ischemic vascular disease and nonfasting triglyceride levels. Study results provided show the hazard ratio and confidence interval for ischemic vascular disease. The heterozygosity for loss-of-function mutations and the incidences of ischemic vascular disease and ischemic heart disease are compared in APOC3 carriers and noncarriers.

Objectives: The study sought to test the hypothesis that genetic variation in ABCG5/8, the transporter responsible for intestinal and hepatobiliary cholesterol efflux, may simultaneously influence plasma and biliary cholesterol levels, and hence risk of myocardial infarction (MI) and gallstone disease in opposite directions. Background: High plasma levels of low-density lipoprotein (LDL) cholesterol are a causal risk factor for MI, whereas high levels of biliary cholesterol promote gallstone formation. Methods: A total of 60,239 subjects from Copenhagen were included, including 5,647 with MI and 3,174 with symptomatic gallstone disease. Subjects were genotyped for 6 common, nonsynonymous and functional variants in ABCG5/8, and a combined weighted genotype score was calculated. Results: Combined, weighted genotype scores were associated with stepwise decreases in LDL cholesterol of up to 5.9% (0.20 mmol/l) for individuals with a score ≥8.0 (prevalence = 11%) versus <2.0 (prevalence = 9%; p for trend across 5 groups = 2 × 10E-35). The cumulative incidences of MI and gallstone disease as a function of age and increasing genotype score were decreased and increased (log-rank ps for trend: 6 × 10E-4 and 9 × 10E-45), respectively. The multifactorially adjusted odds ratios were 0.83 (95% confidence interval: 0.73 to 0.94) for MI and 2.85 (95% confidence interval: 2.39 to 3.39) for symptomatic gallstone disease for individuals with a genotype score ≥8.0 versus <2.0. Conclusions: Genetic variation in ABCG5/8, which associates with decreased levels of plasma LDL cholesterol protects against MI, but increases the risk of symptomatic gallstone disease. These results suggest that MI and gallstones, 2 seemingly unrelated diseases, are intrinsically linked via the function of the ABCG5/8 cholesterol transporter. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age. METHODS AND RESULTS: 10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20-1.62) for IHD and 1.57 (1.28-1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (P for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs. CONCLUSIONS: Male pattern baldness, earlobe crease, and xanthelasmata-alone or in combination-associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health. [ABSTRACT FROM AUTHOR]

Background--Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemie heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age. Methods and Results--10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20-1.62) for IHD and 1.57(1.28-1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (P for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs. Conclusions--Male pattern baldness, earlobe crease, and xanthelasmata--alone or in combination--associate with increased risk of ischemie heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health. [ABSTRACT FROM AUTHOR]

Background & Aims: Drugs which reduce plasma low-density lipoprotein cholesterol (LDL-C) may protect against gallstone disease. Whether plasma levels of LDL-C per se predict risk of gallstone disease remains unclear. We tested the hypothesis that elevated LDL-C is a causal risk factor for symptomatic gallstone disease. Methods: We used a Mendelian randomization approach and genotyped 63,051 individuals from a prospective cohort study of the general Danish population, including 3323 subjects with symptomatic gallstones. We selected eight genetic variants in APOE, APOB, LDLR, and PCSK9 affecting LDL-C. Furthermore, studies of APOE rs429358/rs7412 (defining ε2/ε3/ε4 alleles; 12 studies) and APOB rs693 (eight studies) were included in meta-analyses. Results: The observational hazard ratio (HR) for symptomatic gallstone disease for the fifth versus first quintile of LDL-C was 0.94 (95% confidence interval: 0.76–1.17), despite a corresponding 134% increase in LDL-C. Furthermore, although individual genetic variants in APOE, APOB, LDLR, and PCSK9 associated with stepwise increases/decreases in LDL-C of up to +59% compared with non-carriers (p <0.001), none predicted the risk of symptomatic gallstone disease. Combining all variants into 10 genotypes, carriers of 9 versus ⩽3 LDL-C increasing alleles associated with 41% increased LDL-C (p <0.001), but predicted a HR for symptomatic gallstone disease of 1.09 (0.70–1.69). Finally, in meta-analyses, random effects odds ratios for gallstone disease were 0.91 (0.78–1.06) for carriers of APOE ε4 versus non-carriers, and 1.25 (0.95–1.63) for APOB rs693 CT+TT versus CC. Conclusions: Results from the observational study, genetic studies, and meta-analyses suggest that elevated plasma levels of LDL-C are not causally associated with increased risk of symptomatic gallstone disease. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Rare genetic variants, identified by in-detail resequencing of loci, may contribute to complex traits. We used the apolipoprotein A-I gene (APOA1), a major high-density lipoprotein (HDL) gene, and population-based resequencing to determine the spectrum of genetic variants, the phenotypic characteristics of these variants, and how these results compared with results based on resequencing only the extremes of the apolipoprotein A-I (apoA-I) distribution. First, we resequenced APOA1 in 10,330 population-based participants in the Copenhagen City Heart Study. The spectrum and distribution of genetic variants was determined as a function of the number of individuals resequenced. Second, apoA-I and HDL cholesterol phenotypes were determined for nonsynonymous (NS) and synonymous (S) variants and were validated in the Copenhagen General Population Study (n = 45,239). Third, observed phenotypes were compared with those predicted using an extreme phenotype approach based on the apoA-I distribution. Our results are as follows: First, population-based resequencing of APOA1 identified 40 variants of which only 7 (18%) had minor allele frequencies >1%, and most were exceedingly rare. Second, 0.27% of individuals in the general population were heterozygous for NS variants which were associated with substantial reductions in apoA-I (up to 39 mg/dL) and/or HDL cholesterol (up to 0.9 mmol/L) and, surprisingly, 0.41% were heterozygous for variants predisposing to amyloidosis. NS variants associated with a hazard ratio of 1.72 (1.09-2.70) for myocardial infarction (MI), largely driven by A164S, a variant not associated with apoA-I or HDL cholesterol levels. Third, using the extreme apoA-I phenotype approach, NS variants correctly predicted the apoA-I phenotype observed in the population-based resequencing. However, using the extreme approach, between 79% (screening 0-1st percentile) and 21% (screening 0-20th percentile) of all variants were not identified; among these were variants previously associated with amyloidosis. Population-based resequencing of APOA1 identified a majority of rare NS variants associated with reduced apoA-1 and HDL cholesterol levels and/or predisposing to amyloidosis. In addition, NS variants associated with increased risk of MI. [ABSTRACT FROM AUTHOR]

Abstract: 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. PRIM defined seven mutually exclusive subsets in women and men, with cumulative incidences of CHD from 0.01 to 0.22 in women, and from 0.03 to 0.26 in men. PRIM versus Framingham Point Score found 11% versus 4% of all women, and 31% versus 35% of all men to have 10 year CHD risks>20%. Among women≥65 years with hypertension and/or with diabetes, 10 year CHD risk>20% was found for 100% with PRIM scoring but for only 18% with the Framingham Point Score. Conclusion: Compared to the PRIM Score, common clinical practice with the Framingham Point Score underestimates CHD risk in women, especially in women≥65 years with hypertension and/or with diabetes. [ABSTRACT FROM AUTHOR]

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. [Copyright &y& Elsevier]

Abstract: Objectives: Characteristic for the genes encoding glutathione S-transferase (GST) M1 and GSTT1 is a null allele, suggested to increase susceptibility to chronic diseases. We report an optimized method for the determination of copy number variation (CNV) in GST genes. Design and methods: Real-time multiplex PCR reactions were optimized for quantification of GSTM1 and GSTT1 CNV using the ΔC t method, a fixed volume of diluted DNA, a total volume of 10 μL, 384-well formats, and single determinations of each sample. Results: Consistent genotyping was obtained using DNA in a range of 0.41 ng to 100 ng. In a general population sample of 20,687 individuals the genotype frequencies were concordant with other methods used as standards. Throughput was 4600 genotypes per day at a reagent price of 0.5 euros per sample. Conclusions: This high-throughput, low cost method accurately determines CNV in the GST genes enabling reliable estimates of disease prediction in large epidemiological samples. [Copyright &y& Elsevier]

Objectives: This study was designed to test the hypotheses that single nucleotide polymorphisms (SNPs), in zinc finger protein 202 (ZNF202), predict severe atherosclerosis and ischemic heart disease (IHD). Background: ZNF202 is a transcriptional repressor controlling promoter elements in genes involved in vascular maintenance and lipid metabolism. Methods: We first determined genotype association for 9 ZNF202 SNPs with severe atherosclerosis (ankle brachial index >0.7 vs. ≤0.7) in a cross-sectional study of 5,355 individuals from the Danish general population. We then determined genotype association with IHD in 10,431 individuals from the Danish general population, the CCHS (Copenhagen City Heart Study), including 1,511 incident IHD events during 28 years of follow-up. Results were verified in 2 independent case-control studies including, respectively, 942 and 1,549 cases with IHD and 8,998 controls. Finally, we determined whether g.−660A>G altered transcriptional activity of the ZNF202 promoter in vitro. Results: Cross-sectionally, ZNF202 g.−660 GG versus AA homozygosity predicted an odds ratio for severe atherosclerosis of 2.01 (95% confidence interval [CI]: 1.34 to 3.01). Prospectively, GG versus AA homozygosity predicted a hazard ratio for IHD of 1.21 (95% CI: 1.02 to 1.43). In the 2 case-control studies, the equivalent odds ratios for IHD were 1.29 (95% CI: 1.02 to 1.62) and 1.60 (95% CI: 1.34 to 1.92), confirming the results from the prospective study. Only 2 other SNPs, which were highly correlated with g.−660A>G, also predicted risk of severe atherosclerosis and IHD. Finally, ZNF202 g.−660G versus g.−660A was associated with a 60% reduction in transcriptional activity in vitro, whereas none of the 2 correlated SNPs were predicted to be functional. Conclusions: Homozygosity for a common functional promoter variant in ZNF202 predicts severe atherosclerosis and an increased risk of IHD. [Copyright &y& Elsevier]

The article presents a study seeking to determine whether genetically reduced high-density lipoprotein (HDL) due to heterozygosity for loss-of-function mutations in the adenosine triphosphate-binding cassette transporter A1 (ABCA1) gene causes increased risk of ischemic heart disease (IHD). The design and setting of the studies, which were drawn from the general population in Copenhagen, Denmark, are described. The outcomes measured the level of HDL cholesterol in the population, cellular cholesterol efflux, and the link between IHD, HDL, and genotype. Results suggest that lower levels of HDL related to loss-of-function mutations in the ABCA1 gene were not associated with an increased risk of IHD.

Single nucleotide polymorphisms (SNPs) are hypothesized to explain the genetic predisposition to ischemic heart disease (IHD) in the general population. Lack of evidence for a role of such variation is fostering pessimism about the utility of genetic information in the practice of medicine. In this study we determined the utility of exonic and 5′ SNPs in apolipoprotein E ( APOE) and lipoprotein lipase ( LPL) when considered singly and in combination for predicting incidence of IHD in 8,456 individuals from the general population during 24 years of follow-up. In men, LPL D9N improved prediction of IHD ( P = 0.03) beyond smoking, diabetes and hypertension. The group of men heterozygous and homozygous for the rare D9N variant had a hazard ratio (HR) of 1.69 (95% confidence interval = 1.10–2.58) relative to the most common genotype. Pairwise combinations of D9N with −219G > T in APOE and N291S and S447X in LPL significantly improved the prediction of IHD ( P = 0.05 in women, P = 0.04 in men, P = 0.03 in men, respectively) beyond smoking, diabetes and hypertension, and identified subgroups of individuals ( n = 6–94) with highly significant HRs of 1.92–4.35. These results were validated in a case-control study ( n = 8,806). In conclusion, we present evidence that combinations of SNPs in APOE and LPL identify subgroups of individuals at substantially increased risk of IHD beyond that associated with smoking, diabetes and hypertension. [ABSTRACT FROM AUTHOR]

Abstract: Objective: Zinc Finger Protein 202 (ZNF202) is a transcriptional repressor of genes affecting the vascular endothelium as well as lipid metabolism. A phenotype associated with genetic variation in ZNF202 is presently unknown. We tested the hypothesis that a common variant in ZNF202, A154V, predicts risk of ischemic heart disease (IHD), myocardial infarction (MI), and ischemic cerebrovascular disease (ICVD). Methods and results: We conducted a prospective study of more than 9000 individuals from the general population with 24 years follow-up. In women, age-adjusted hazard ratios in heterozygotes and homozygotes versus non-carriers were 1.2 (95% CI: 1.0–1.5, P =0.04) and 1.5 (1.1–2.1, P =0.007) for IHD, 1.5 (1.1–2.1; P =0.01) and 1.7 (1.1–2.8, P =0.02) for MI, and 1.3 (1.0–1.8, P =0.07) and 1.3 (0.8–2.1; P =0.33) for ICVD. Adjustments for lipids and lipoproteins did not alter these hazard ratios substantially. Genotype did not predict risk in men. Finally, results for IHD were borderline significant (P =0.06) in an independent case–control study including 933 patients and 8068 controls. Conclusion: This is the first study to suggest that ZNF202 could be a new candidate gene for IHD and MI in the general population. [Copyright &y& Elsevier]

Objectives: We tested whether heterozygosity for the K776N mutation (frequency: 0.4%) in ATP-binding cassette transporter A1 (ABCA1) predicted ischemic heart disease (IHD) in the Copenhagen City Heart Study population. Background: In a complex trait like IHD, genetic variation is considered to be conferred by common DNA polymorphisms, although rare mutations may have a larger impact. Tangier disease, a rare high-density lipoprotein cholesterol (HDL-C) deficiency syndrome with IHD, is caused by homozygous ABCA1 mutations. Methods: We analyzed blood samples from a large cohort study of 9,076 Danish individuals followed for 24 years (167,287 person-years), during which 1,033 incident IHD events occurred. The hypothesis was retested in an independent case-control study comparing 562 IHD patients with 3,103 controls. Results: The cumulative incidence of IHD as a function of age was increased in K776N heterozygotes compared with non-carriers (log-rank test: p = 0.005). At the age of 80 years, 48% of heterozygotes and 23% of non-carriers had IHD. Incidence rates in non-carriers and K776N heterozygotes were 61 and 157 per 10,000 person-years. The age-adjusted hazard ratio for IHD in K776N heterozygotes versus non-carriers was 2.4 (95% confidence interval 1.3 to 4.5). Adjusting for HDL-C, or for smoking, diabetes, and hypertension did not change the result, suggesting that genotype predicted risk of IHD beyond that offered by HDL-C, and by other conventional risk factors. Similar trends were obtained in an independent case-control study. Conclusions: Heterozygosity for an ABCA1 mutation (K776N) conferred two- to three-fold risk of IHD in 37 participants in the Copenhagen City Heart study. [Copyright &y& Elsevier]

Homozygosity for mutations in ABC transporter A1 (ABCA1) causes Tangier disease, a rare HDL-deficiency syndrome. Whether heterozygosity for genetic variation in ABCA1 also contributes to HDL cholesterol (HDL-C) levels in the general population is presently unclear. We determined whether mutations or single-nucleotide polymorphisms (SNPs) in ABCA1 were overrepresented in individuals with the lowest 1% (n=95) or highest 1% (n=95) HDL-C levels in the general population by screening the core promoter and coding region of ABCA1. For all nonsynonymous SNPs identified, we determined the effect of genotype on lipid traits in 9,259 individuals from the general population. Heterozygosity for ABCA1 mutations was identified in 10% of individuals with low HDL-C only. Three of 6 nonsynonymous SNPs (V771M, V825I, and R1587K) were associated with increases or decreases in HDL-C in women in the general population and some with consistent trends in men, determined as isolated single-site effects varying only at the relevant SNP. Finally, these results were consistent over time. In conclusion, we show that at least 10% of individuals with low HDL-C in the general population are heterozygous for mutations in ABCA1 and that both mutations and SNPs in ABCA1 contribute to HDL-C levels in the general population. [ABSTRACT FROM AUTHOR]

In the present study of 9,000 individuals representative of the general population, we have considered whether the addition of common single nucleotide polymorphisms (SNPs) in the promoter region ofApolipoprotein E(APOE) improve the statistical explanation of variation in lipid traits and test the hypothesis that the estimated genotype effects are independent of factors indexed by gender and age. To address these questions, we have asked, for each gender and for each 20-year age strata (young: 20-39 years; middle-aged: 40-59 years; old: 60-79 years; very old: 80-100 years), how much trait variation is associated with the traditional e2, e3, and e4 allelic variations defined by the g.2059T?C and g.2197C?T SNPs in the fourth exon of theAPOEgene, and how much additional trait variation is associated with genotypes defined by combining the g.2059T?C and g.2197C?T SNPs with one, two, or three promoter SNPs. Our study demonstrates that the pleiotropic effects of genotype variation defined by the traditional e2, e3, and e4 alleles on five plasma measures of lipid metabolism manifest differently in women and men and change significantly during the life cycle for high-density lipoprotein cholesterol in women. Multi-site genotypes defined by adding SNPs located in the 5' promoter region to the traditional g.2059T?C and g.2197C?T SNPs doubled the estimate of genetic variance of high-density lipoprotein and apolipoprotein Al in middle-aged females. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is the most common form of dementia, and the prodromal phases of Alzheimer's disease can last for decades. Vascular dementia is the second most common form of dementia and is distinguished from Alzheimer's disease by evidence of previous stroke or hemorrhage and current cerebrovascular disease. A compiled group of vascular-related dementias (vascular dementia and unspecified dementia) is often referred to as non-Alzheimer dementia. Recent evidence indicates that preventing dementia by lifestyle interventions early in life with a focus on reducing cardiovascular risk factors is a promising strategy for reducing future risk. Approximately 40% of dementia cases is estimated to be preventable by targeting modifiable, primarily cardiovascular risk factors. The aim of this review is to describe the association between risk factors for atherosclerotic cardiovascular disease and the risk of Alzheimer's disease and non-Alzheimer dementia by providing an overview of the current evidence and to shed light on possible shared pathogenic pathways between dementia and cardiovascular disease. The included risk factors are body mass index (BMI); plasma triglyceride-, high-density lipoprotein (HDL) cholesterol-, low-density lipoprotein (LDL) cholesterol-, and total cholesterol concentrations; hypertension; diabetes; non-alcoholic fatty liver disease (NAFLD); physical inactivity; smoking; diet; the gut microbiome; and genetics. Furthermore, we aim to disentangle the difference between associations of risk factors in midlife as compared with in late life. [ABSTRACT FROM AUTHOR]

As solid organ transplant (SOT) recipients remain at risk of severe outcomes after SARS-CoV-2 infections, vaccination continues to be an important preventive measure. In SOT recipients previously vaccinated with at least three doses of BNT162b2, we investigated humoral responses to BNT162b2 booster doses. Anti-SARS-CoV-2 receptor binding domain (RBD) immunoglobulin G (IgG) was measured using an in-house ELISA. Linear mixed models were fitted to investigate the change in the geometric mean concentration (GMC) of anti-SARS-CoV-2 RBD IgG after vaccination in participants with intervals of more or less than six months between the last two doses of vaccine. We included 107 SOT recipients vaccinated with a BNT162b2 vaccine. In participants with an interval of more than six months between the last two vaccine doses, we found a 1.34-fold change in GMC per month (95% CI 1.25–1.44), while we found a 1.09-fold change in GMC per month (95% CI 0.89–1.34) in participants with an interval of less than six months between the last two vaccine doses, resulting in a rate ratio of 0.82 (95% CI 0.66 to 1.01, p = 0.063). In conclusion, the administration of identical COVID-19 mRNA vaccine boosters within six months to SOT recipients may result in limited humoral immunogenicity of the last dose. [ABSTRACT FROM AUTHOR]

• Immune dysregulation was present in patients with newly diagnosed bipolar disorder (BD) • Higher levels of pro-inflammatory markers in patients with BD compared with HC. • Higher levels of anti-inflammatory markers in patients with BD compared with HC. • MDC levels were higher in patients with BD compared with HC and UR. • A composite marker discriminated BD from HC with an AUC of 0.76. Substantial evidence emphasizes immune dysregulation in patients with bipolar disorder (BD). However, whether immune dysregulation is present already in the early illness stages of BD or even precedes development of BD is largely unknown. In this study we compared immune and vascular stress markers in patients newly diagnosed with BD, their unaffected first-degree relatives (UR) and healthy control individuals (HC) and investigated the ability a composite immune and vascular stress marker to discriminate between the three groups of participants. In a unique sample including 373 patients newly diagnosed with BD, 95 UR and 190 HC, we compared 47 immune and vascular stress markers at the baseline visit in the ongoing longitudinal Bipolar Illness Onset study. For comparison of individual immune and vascular stress markers between groups, we applied linear mixed models, whereas the composite immune and vascular stress marker was investigated using the SuperLearner ensemble-method. Compared with HC, patients newly diagnosed with BD had higher levels of the anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) and IL-10, and of the pro-inflammatory IL-6, eotaxin, monocyte chemoattractant protein-1 (MCP-1), MCP-4, Macrophage Derived Chemokine (MDC), and Thymus and Activation-Regulated Chemokine (TARC) in analyses adjusted for sex and age ranging from 26 % higher levels of IL-6 (1.26, 95 %CI: [1.12–1.43], p < 0.001, adjusted p = 0.009) and IL-10 (1.26, 95 %CI: [1.09–1.46], p = 0.002, adjusted p = 0.049), respectively, to 9 % higher eotaxin levels (1.09, 95 %CI: [1.04–1.15], p = 0.001, adjusted p = 0.024). Of these, MDC levels were 12 % higher in BD compared with UR (1.12, 95 %CI: [1.02–1.22], p = 0.001, adjusted p = 0.024). For all other markers, UR showed no difference from patients with BD or HC. Based on a data-driven model, a composite marker including all 47 immune and vascular stress markers, sex, age, BMI, smoking status, and alcohol intake, discriminated patients with BD from HC with a with an area under the receiver operating curve (AUC) of 0.76 (95 % CI: 0.75–0.77) Higher levels of pro-inflammatory and anti-inflammatory immune markers are present in patients newly diagnosed with BD but not in UR compared with HC, supporting immune dysregulation playing a role in the pathophysiology of BD. [ABSTRACT FROM AUTHOR]

Studies of self-reported coffee consumption and smoking on risk of dementia have shown results conflicting with two-sample Mendelian randomization studies. We tested the hypotheses that coffee consumption and smoking influence risk of dementia using observational and one-sample Mendelian randomization designs with individual level data. We included 114,551 individuals from two Danish general population cohorts (median age 58 years). First, we tested whether high self-reported coffee consumption/smoking were associated with risk of dementia. Second, whether genetically predicted high coffee consumption/smoking due to variation near CYP1A1/AHR/CHRNA3 genes were associated with risk of dementia. We observed 3,784 dementia events. Moderate self-reported coffee consumption was associated with low risk of all dementia and non-Alzheimer's dementia, with a similar trend for Alzheimer's disease. Genetically predicted high coffee consumption was associated with high risk of all dementia (hazard ratio [95% confidence interval] per +1 cup/day: 1.20 [1.01–1.42]), with a similar trend for non-Alzheimer's dementia (1.23 [0.95–1.53]). High self-reported smoking was associated with high risk of non-Alzheimer's dementia. High genetically predicted smoking was associated with a trend towards high risk of all dementia and Alzheimer's disease (hazard ratios per +1 pack-year: 1.04 [0.96–1.11]) and 1.06 [0.97–1.16]). Moderate self-reported coffee consumption was associated with low risk of all and non-Alzheimer's dementia, while high genetically predicted coffee consumption was associated with a trend towards the opposite. High self-reported smoking was associated with high risk of non-Alzheimer's dementia, with a similar trend for genetically predicted smoking on all dementia and Alzheimer's disease. [Display omitted] • Moderate self-reported coffee consumption was associated with low risk of dementia. • High genetic coffee consumption showed a trend towards high risk of some dementia. • High self-reported smoking was associated with some dementia. • High genetic smoking showed a trend towards high risk of dementia. • High coffee consumption and smoking are unlikely to protect against dementia. [ABSTRACT FROM AUTHOR]

Background: Heavy occupational lifting is prevalent in the general working population and is sparsely reported to associate with hypertension, especially among older and hypertensive workers. We investigated if heavy occupational lifting is associated with hypertension and blood pressure (BP) in both cross-sectional and prospective study designs in the Copenhagen General Population Study, stratified by age, and use of anti-hypertensives.Methods: Participation was conducted following the declaration of Helsinki and approved by the ethical committee (H-KF-01-144/01). By multivariable logistic and linear regression models, we investigated the association between heavy occupational lifting and hypertension, in a cross-sectional design (n = 67,363), using anti-hypertensives or BP ≥140/≥90 mmHg as outcome, and in a prospective design (n = 7020) with an above-median change in systolic BP (SBP) from baseline to follow-up and/or a shift from no use to use of anti-hypertensives as outcome, with and without stratification by age and use of anti-hypertensives.Results: The odds ratio for hypertension was estimated at 0.97 (99% CI: 0.93-1.00) in the cross-sectional analysis, and at 1.08 (99% CI: 0.98-1.19) in the prospective analysis. The difference in SBP among workers with versus without heavy occupational lifting was estimated at - 0.29 mmHg (99% CI -0.82 - 0.25) in the cross-sectional and at 1.02 mmHg (99% CI -0.41 - 2.45) in the prospective analysis. No significant interaction between heavy occupational lifting and age, nor use of anti-hypertensives were shown.Conclusions: Only the prospective analysis indicated heavy occupational lifting to increase the risk of hypertension. Further research on the association between occupational lifting and hypertension are needed. [ABSTRACT FROM AUTHOR]

To accommodate waning COVID-19 vaccine immunity to emerging SARS-CoV-2 variants, variant-adapted mRNA vaccines have been introduced. Here, we examine serological responses to the BA.1 and BA.4-5 Omicron variant-adapted BNT162b2 COVID-19 vaccines in people with lymphoid malignancies. We included 233 patients with lymphoid malignancies (chronic lymphocytic B-cell leukemia: 73 (31.3%), lymphoma: 89 (38.2%), multiple myeloma/amyloidosis: 71 (30.5%)), who received an Omicron-adapted mRNA-based COVID-19 vaccine. IgG and neutralizing antibodies specific for the receptor-binding domain (RBD) of SARS-CoV-2 were measured using ELISA-based methods. Differences in antibody concentrations and neutralizing capacity and associations with risk factors were assessed using mixed-effects models. Over the period of vaccination with an Omicron-adapted COVID-19 vaccine, the predicted mean concentration of anti-RBD IgG increased by 0.09 log10 AU/mL/month (95% CI: 0.07; 0.11) in patients with lymphoid malignancies across diagnoses. The predicted mean neutralizing capacity increased by 0.9 percent points/month (95% CI: 0.2; 1.6). We found no associations between the increase in antibody concentration or neutralizing capacity and the variant included in the adapted vaccine. In conclusion, a discrete increase in antibody concentrations and neutralizing capacity was found over the course of Omicron-adapted vaccination in patients with lymphoid malignancies regardless of the adapted vaccine variant, indicating a beneficial effect of Omicron-adapted booster vaccination in this population. [ABSTRACT FROM AUTHOR]

Purpose: Patients who are successfully resuscitated following out-of-hospital cardiac arrest (OHCA) are still at a high risk of neurological damage and death. Inflammation and brain injury are components of the post-cardiac arrest syndrome, and can be assessed by systemic interleukin 6 (IL-6) and neuron-specific enolase (NSE). Anti-inflammatory treatment with methylprednisolone may dampen inflammation, thereby improving outcome. This study aimed to determine if prehospital high-dose methylprednisolone could reduce IL-6 and NSE in comatose OHCA patients. Methods: The STEROHCA trial was a randomized, blinded, placebo-controlled, phase II prehospital trial performed at two cardiac arrest centers in Denmark. Resuscitated comatose patients with suspected cardiac etiology were randomly assigned 1:1 to a single intravenous injection of 250 mg methylprednisolone or placebo. The co-primary outcome was reduction of IL-6 and NSE-blood levels measured daily for 72 h from admission. The main secondary outcome was survival at 180 days follow-up. Results: We randomized 137 patients to methylprednisolone (n = 68) or placebo (n = 69). We found reduced IL-6 levels (p < 0.0001) in the intervention group, with median (interquartile range, IQR) levels at 24 h of 2.1 pg/ml (1.0; 7.1) and 30.7 pg/ml (14.2; 59) in the placebo group. We observed no difference between groups in NSE levels (p = 0.22), with levels at 48 h of 18.8 ug/L (14.4; 24.6) and 14.8 ug/L (11.2; 19.4) in the intervention and placebo group, respectively. In the intervention group, 51 (75%) patients survived and 44 (64%) in the placebo group. Conclusion: Prehospital treatment with high-dose methylprednisolone to resuscitated comatose OHCA patients, resulted in reduced IL-6 levels after 24 h, but did not reduce NSE levels. [ABSTRACT FROM AUTHOR]

Objective. We aimed to assess the association between low N-terminal pro-brain natriuretic peptide (NT-proBNP) and body mass index (BMI), adipose tissue distribution, adiponectin, and HIV-specific risk factors among people with HIV (PWH). Methods. We included 811 PWH with measurement of height, weight and waist circumference, blood samples analyzed for NT-proBNP, and visceral-(VAT) and subcutaneous (SAT) adipose tissue areas measured from CT-scans. Low concentrations of NT-proBNP were defined as concentrations below the limit of quantification (5.9 pmol/L). Associations were explored with multivariable logistic regression analyses adjusted for relevant confounders. Results. We identified 471 (58%) individuals with low concentrations of NT-proBNP. Increasing BMI was associated with higher odds of low NT-proBNP (adjusted OR (aOR) 1.06 (95% CI: 1.01–1.11) per 1 kg/m2). Central obesity and large areas of VAT were associated with higher odds of low NT-proBNP (aOR 1.66 (1.16–2.36) and aOR 1.69 (1.09–2.62), respectively). Higher adiponectin was associated with lower odds of low NT-proBNP (aOR 0.86 (0.79–0.95) per 10% increase). No associations were found between low NT-proBNP and HIV-specific risk factors. Conclusions. In PWH, low NT-proBNP is associated with an adverse adipose tissue profile with high BMI, central obesity, accumulation of VAT, and low adiponectin. [ABSTRACT FROM AUTHOR]

Background: The calcium binding protein S100B and brain derived neurotrophic factor (BDNF) are both biomarkers implicated in neuronal processes in the central nervous system and seem to be associated with affective disorders. Here we investigated both markers in a sample of monozygotic (MZ) twins with, at risk of and without affective disorders, aiming to evaluate whether these markers have a role as causal factors- or trait markers for affective disorders.Method: We measured serum S100B and plasma BDNF levels in 204 monozygotic twins (MZ) with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk).Results: No significant group differences in S100B and BDNF levels were found between the three groups. Exploratory analysis revealed that higher S100B levels were correlated with lower cognitive performance.Limitations: The cross-sectional design cannot elucidate the two neuronal biomarkers role as causal factors. We would have preferred a higher sample size in the high- and low-risk groups.Conclusion: The present result did not support a role for S100B and BDNF as neither causal factors nor trait markers for affective disorders. Elevated S100B levels may associate with impaired cognition, but further studies are warranted. [ABSTRACT FROM AUTHOR]

Background: Metabolic syndrome (MetS) is associated with reduced life expectancy in patients with affective disorders, however, whether MetS also plays a role before the onset of affective disorder is unknown. We aimed to investigate whether MetS, inflammatory markers or oxidative stress act as risk factors for affective disorders, and whether MetS is associated with increased inflammation and oxidative stress. Methods: We conducted a high-risk study including 204 monozygotic (MZ) twins with unipolar or bipolar disorder in remission or partial remission (affected), their unaffected co-twins (high-risk) and twins with no personal or family history of affective disorder (low-risk). Metabolic Syndrome was ascertained according to the International Diabetes Federation (IDF) criteria. Inflammatory markers and markers of oxidative stress were analyzed from fasting blood and urine samples, respectively. Results: The affected and the high-risk group had a significantly higher prevalence of MetS compared to the low-risk group (20% v. 15% v. 2.5%, p = 0.0006), even after adjusting for sex, age, smoking and alcohol consumption. No differences in inflammatory and oxidative markers were seen between the three groups. Further, MetS was associated with alterations in inflammatory markers, and oxidative stress was modestly correlated with inflammation. Conclusion: Metabolic syndrome is associated with low-grade inflammation and may act as a risk factor and a trait marker for affective disorders. If confirmed in longitudinal studies, this suggests the importance of early intervention and preventive approaches targeted towards unhealthy lifestyle factors that may contribute to later psychopathology. [ABSTRACT FROM AUTHOR]

Objectives: Initial responses to coronavirus disease 2019 vaccination are impaired in patients with hematological malignancies. We investigated immune responses after three or four doses of BNT162b2 in patients with myeloid and lymphoid malignancies compared to controls, and identified risk factors for humoral and cellular nonresponse 1 year after first vaccination. Methods: In 407 hematological patients (45 myeloid, 362 lymphoid) and 98 matched controls, we measured immunoglobulin G (IgG) and neutralizing antibodies specific for the receptor‐binding domain of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) at baseline, 3 weeks, 2, 6, and 12 months, and interferon‐γ release at 12 months. Results: In patients with lymphoid malignancies, SARS‐CoV‐2 receptor‐binding domain IgG concentration and mean neutralizing capacity was lower than in controls at all time points. A diagnosis of chronic lymphocytic B‐cell leukemia (CLL) or lymphoma was associated with humoral nonresponse at 12 months compared to having multiple myeloma/amyloidosis (p <.001 and p =.013). Compared to controls, patients with lymphoid malignancies had increased risk of cellular nonresponse. A lymphoma diagnosis was associated with lower risk of cellular nonresponse compared to patients with multiple myeloma/amyloidosis, while patients with CLL had comparable response rates to patients with multiple myeloma/amyloidosis (p =.037 and p =.280). Conclusions: In conclusion, long‐term humoral and cellular immune responses to BNT162b2 were impaired in patients with lymphoid malignancies. [ABSTRACT FROM AUTHOR]

Background: Research suggests NT-proBNP (N-terminal pro-B-type natriuretic peptide) to be a strong predictor of incident atrial fibrillation (AF) and stroke. However, its utility in AF screening remains unknown. The aim of this study was to investigate NT-proBNP as a potential marker for screening efficacy with respect to AF yield and stroke prevention. Methods: In the LOOP Study (Atrial Fibrillation Detected by Continuous ECG Monitoring Using Implantable Loop Recorder to Prevent Stroke in High-Risk Individuals), 6004 AF-naïve individuals at least 70 years old and with additional stroke risk factors were randomized 1:3 to either screening with an implantable loop recorder (ILR) and initiation of anticoagulation upon detection of AF episodes lasting ≥6 minutes or usual care (control). This post hoc analysis included study participants with available NT-proBNP measurement at baseline. Results: A total of 5819 participants (96.9% of the trial population) were included. The mean age was 74.7 years (SD, 4.1 years) and 47.5% were female. The median NT-proBNP level was 15 pmol/L (interquartile range, 9–28 pmol/L) corresponding to 125 pg/mL (interquartile range, 76–233 pg/mL). NT-proBNP above median was associated with an increased risk of AF diagnosis both in the ILR group (hazard ratio, 1.84 [95% CI, 1.51–2.25]) and the control group (hazard ratio, 2.79 [95% CI, 2.30–3.40]). Participants with NT-proBNP above the median were also at higher risk of clinical events compared with those having lower levels (hazard ratio, 1.21 [95% CI, 0.96–1.54] for stroke or systemic embolism [SE], 1.60 [95% CI, 1.32–1.95] for stroke/SE/cardiovascular death, and 1.91 [95% CI, 1.61–2.26] for all-cause death). Compared with usual care, ILR screening was associated with significant reductions in stroke/SE and stroke/SE/cardiovascular death among participants with NT-proBNP above median (hazard ratio, 0.60 [95% CI, 0.40–0.90] and 0.70 [95% CI, 0.53–0.94], respectively) but not among those with lower levels (P interaction=0.029 for stroke/SE and 0.045 for stroke/SE/cardiovascular death). No risk reduction in all-cause death was observed in either NT-proBNP subgroup for ILR versus control (P interaction=0.68). Analyzing NT-proBNP as a continuous variable yielded similar findings. Conclusions: In an older population with additional stroke risk factors, ILR screening for AF was associated with a significant reduction in stroke risk among individuals with higher NT-proBNP levels but not among those with lower levels. These findings should be considered hypothesis generating and warrant further study before clinical implementation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02036450. [ABSTRACT FROM AUTHOR]

Background mRNA-based COVID-19 vaccines have short- and long-term efficacy in healthy individuals, but their efficacy in patients with psoriasis receiving immunomodulatory therapy is less studied. Objectives To investigate long-term immunity after COVID-19 vaccination in patients with psoriasis receiving immunomodulatory therapy. Methods A prospective cohort study including patients (n = 123) with psoriasis receiving methotrexate (MTX) or biologics and controls (n = 226). Only mRNA-based COVID-19 vaccines administered with standard intervals between doses were investigated. Markers of immunity included SARS-CoV-2 spike glycoprotein-specific IgG and IgA, neutralizing capacity, and interferon-γ release from T cells stimulated with peptides of the SARS-CoV-2 spike glycoprotein. Results The proportion of IgG responders was lower 6 months after vaccination in patients receiving anti-tumour necrosis factor (TNF) treatment compared with controls. Anti-TNF treatment was associated with lower IgG levels (β = −0.82, 95% confidence interval −1.38 to −0.25; P = 0.001). The median neutralizing index was lower in the anti-TNF group [50% inhibition (interquartile range [IQR] 37–89)] compared with controls [98% inhibition (IQR 96–99)]; P < 0.001. Cellular responses were numerically lowest in the anti-TNF group. Conclusions Treatment with anti-TNF has an impact on the immunity elicited by mRNA-based COVID-19 vaccination in patients with psoriasis, resulting in a faster waning of humoral and cellular markers of immunity; however, the clinical implications are unknown. [ABSTRACT FROM AUTHOR]

Background: Results from randomized controlled trials (RCTs) have raised concern that the cholesterol-lowering drug ezetimibe might increase the risk of cancer. We tested the hypothesis that genetic variation in NPC1L1, mimicking treatment with ezetimibe, was associated with an increased risk of cancer.Methods: We included 67 257 individuals from the general population. Of these, 8333 developed cancer and 2057 died of cancer from 1968 to 2011. To mimic the effect of ezetimibe, we calculated weighted allele scores based on the low-density lipoprotein (LDL) cholesterol-lowering(= NPC1L1-inhibitory) effect of each variant. We tested the associations of the NPC1L1 allele scores with LDL cholesterol and with risk of any cancer, death from any cancer and 27 site-specific cancers. As a positive control, we tested the association of the NPC1L1 allele scores with risk of ischaemic vascular disease (IVD).Results: The NPC1L1 allele scores did not associate with risk of any cancer, death from any cancer or with any of 27 site-specific cancers. Hazard ratios (HRs) for a 1-unit increase in internally weighted allele scores were 1.00 (95% confidence interval: 0.98-1.02) for any cancer, and 1.02 (0.98-1.06) for cancer death. The corresponding HR for IVD was 0.97 (0.94-0.99). Results were similar for an externally weighted allele score and for a simple allele count. Finally, the null association with cancer was robust in sensitivity analyses.Conclusions: Lifelong, genetic inhibition of NPC1L1, mimicking treatment with ezetimibe, does not associate with risk of cancer. These results suggest that long-term treatment with ezetimibe is unlikely to increase the risk of cancer, in agreement with the overall evidence from ezetimibe RCTs. [ABSTRACT FROM AUTHOR]

Red blood cell parameters are frequently used biomarkers when assessing clinical status in newborns and in early childhood. Cell counts, amounts, and concentrations of these parameters change through gestation and after birth. Robust age-specific reference intervals are needed to optimize clinical decision making. The Copenhagen Baby Heart Study (CBHS) and the COMPARE study are prospective cohort studies including red blood cell parameters from 7,938 umbilical cord blood samples and 295 parallel venous blood samples from newborns with follow-up at two and at 14–16 months after birth. For venous blood at birth, reference intervals for hemoglobin, erythrocytes, and hematocrit were 145–224 g/L, 4.1–6.4 × 1012/L, and 0.44–0.64, respectively. Hemoglobin, erythrocytes, and hematocrit were lower at birth in children delivered by prelabor cesarean section compared to vaginal delivery. Conversion algorithms based on term newborns were: venous hemoglobin=(umbilical cord hemoglobin˗86.4)/0.39; venous erythrocytes=(umbilical cord erythrocytes-2.20)/0.44; and venous hematocrit=(umbilical cord hematocrit-0.24)/0.45. This study presents new reference intervals for red blood cell parameters in early childhood, describes the impact of delivery mode, and provide exact functions for converting umbilical cord to venous blood measurements for term newborns. These findings may improve clinical decision making within neonatology and infancy and enhance our clinical understanding of red blood cell parameters for health and diseases in early life. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Up to 40% of all dementia cases may be preventable, primarily by treating or acting on well-established cardiovascular risk factors such as diabetes, hypertension, smoking, and physical inactivity. Whether physical inactivity is associated with risk of non-Alzheimer's dementia – a disease influenced by cardiovascular risk factors – and whether a given association differs for physical activity in leisure time and at work remains unknown. We conducted a prospective cohort study including 117,616 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study with up to 43 years of follow-up. Multifactorially adjusted hazard ratios for low versus high physical activity at leisure time was 1.60 (95% confidence interval 1.40–1.83) for non-Alzheimer's dementia and 0.94 (0.80–1.11) for Alzheimer's disease. Corresponding values for non-Alzheimer's dementia after additional adjustment for physical activity at work or apolipoprotein E (APOE) genotype were 1.60 (1.40–1.83) and 1.82 (1.34–2.15). Multifactorially and APOE adjusted hazard ratios for high versus low physical activity at work were 1.50 (1.10–2.05) for non-Alzheimer's dementia and 1.62 (1.14–2.31) for Alzheimer's disease. When combining the two types of physical activity, physical activity in leisure time had the strongest relationship with risk of non-Alzheimer's dementia. Physical inactivity in leisure time was associated with increased risk of non-Alzheimer's dementia, independent of modifiable risk factors and physical activity at work. The present study thus provides evidence for public health advice on physical activity in leisure time for the vascular part of dementia. [Display omitted] • Prospective study including 117,616 individuals from the general Danish population. • Up to 43 years of follow-up with no losses to follow-up. • Low leisure physical activity associates with high risk of non-Alzheimer's dementia. • Leisure versus work physical activity is superior in predicting risk. • Public health advice on physical activity may prevent non-Alzheimer's dementia. [ABSTRACT FROM AUTHOR]

The article discusses a study which examines the association of arcus corneae and xanthelasmata on the determination of individuals' risk of ischaemic vascular disease and death. Findings reveal that xanthelasmata can predict risk of myocardial infarction, ischaemic vascular disease and death. However, it indicates that arcus corneae is not an effective risk indicator for cardiovascular diseases.

Aims The association of plasma high-density lipoprotein (HDL) cholesterol with risk of dementia is unclear. We, therefore, tested the hypothesis that high levels of plasma HDL cholesterol are associated with increased risk of dementia and whether a potential association is of a causal nature. Methods and results In two prospective population-based studies, the Copenhagen General Population Study and the Copenhagen City Heart Study (N  = 111 984 individuals), we first tested whether high plasma HDL cholesterol is associated with increased risk of any dementia and its subtypes. These analyses in men and women separately were adjusted multifactorially for other risk factors including apolipoprotein E (APOE) genotype. Second, taking advantage of two-sample Mendelian randomization, we tested whether genetically elevated HDL cholesterol was causally associated with Alzheimer's disease using publicly available consortia data on 643 836 individuals. Observationally, multifactorially adjusted Cox regression restricted cubic spline models showed that both men and women with extreme high HDL cholesterol concentrations had increased risk of any dementia and of Alzheimer's disease. Men in the 96th–99th and 100th vs. the 41st–60th percentiles of HDL cholesterol had multifactorially including APOE genotype adjusted hazard ratios of 1.66 (95% confidence interval 1.30–2.11) and 2.00 (1.35–2.98) for any dementia and 1.59 (1.16–2.20) and 1.87 (1.11–3.16) for Alzheimer's disease. Corresponding estimates for women were 0.94 (0.74–1.18) and 1.45 (1.03–2.05) for any dementia and 0.94 (0.70–1.26) and 1.69 (1.13–2.53) for Alzheimer's disease. Genetically, the two-sample Mendelian randomization odds ratio for Alzheimer's disease per 1 SD increase in HDL cholesterol was 0.92 (0.74–1.10) in the IGAP2019 consortium and 0.98 (0.95–1.00) in the ADSP/IGAP/PGC-ALZ/UKB consortium. Similar estimates were observed in sex stratified analyses. Conclusion High plasma HDL cholesterol was observationally associated with increased risk of any dementia and Alzheimer's disease, suggesting that HDL cholesterol can be used as an easily accessible plasma biomarker for individual risk assessment. [ABSTRACT FROM AUTHOR]

Background: Among children with moderate acute malnutrition (MAM) the level of serum cobalamin (SC) and effect of food supplements are unknown. We aimed to assess prevalence and correlates of low SC in children with MAM, associations with hemoglobin and development, and effects of food supplements on SC.Methods and Findings: A randomized 2 × 2 × 3 factorial trial was conducted in Burkina Faso. Children aged 6 to 23 months with MAM received 500 kcal/d as lipid-based nutrient supplement (LNS) or corn-soy blend (CSB), containing dehulled soy (DS) or soy isolate (SI) and 0%, 20%, or 50% of total protein from milk for 3 months. Randomization resulted in baseline equivalence between intervention groups. Data on hemoglobin and development were available at baseline. SC was available at baseline and after 3 and 6 months. SC was available from 1,192 (74.1%) of 1,609 children at baseline. The mean (±SD) age was 12.6 (±5.0) months, and 54% were females. Low mid-upper arm circumference (MUAC; <125 mm) was found in 80.4% (958) of the children and low weight-for-length z-score (WLZ; <-2) in 70.6% (841). Stunting was seen in 38.2% (456). Only 5.9% were not breastfed. Median (IQR) SC was 188 (137; 259) pmol/L. Two-thirds had SC ≤222 pmol/L, which was associated with lower hemoglobin. After age and sex adjustments, very low SC (<112 pmol/L) was associated with 0.21 (95% CI: 0.01; 0.41, p = 0.04) and 0.24 (95% CI: 0.06; 0.42, p = 0.01) z-score lower fine and gross motor development, respectively. SC data were available from 1,330 (85.9%) of 1,548 children followed up after 3 months and 398 (26.5%) of the 1,503 children after 6 months. Based on tobit regression, accounting for left censored data, and adjustments for correlates of missing data, the mean (95% CI) increments in SC from baseline to the 3- and 6-month follow-up were 72 (65; 79, p < 0.001) and 26 (16; 37, p < 0.001) pmol/L, respectively. The changes were similar among the 310 children with SC data at all 3 time points. Yet, the increase was 39 (20; 57, p < 0.001) pmol/L larger in children given LNS compared to CSB if based on SI (interaction, p < 0.001). No effect of milk was found. Four children died, and no child developed an allergic reaction to supplements. The main limitation of this study was that only SC was available as a marker of status and was missing from a quarter of the children.Conclusions: Low SC is prevalent among children with MAM and may contribute to impaired erythropoiesis and child development. The SC increase during supplementation was inadequate. The bioavailability and adequacy of cobalamin in food supplements should be reconsidered.Trial Registration: ISRCTN Registry ISRCTN42569496. [ABSTRACT FROM AUTHOR]

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] [ABSTRACT FROM AUTHOR]

The coagulation system is not fully developed at birth and matures during the first months of infancy, complicating clinical decision making within hemostasis. This study evaluates coagulation parameters at birth and two months after birth, and tests whether cord blood can be used as a proxy for neonatal venous blood measurements. The Copenhagen Baby Heart Study (CBHS) and the COMPARE study comprise 13,237 cord blood samples and 444 parallel neonatal venous blood samples, with a two month follow-up in 362 children. Because coagulation parameters differed according to gestational age (GA), all analyses were stratified by GA. For neonatal venous blood, reference intervals for activated partial thromboplastin time (APTT) and prothrombin time (PT) were 28–43 s and 33–61% for GA 37–39 and 24–38 s and 30–65% for GA 40–42. Reference intervals for international normalized ratio (INR) and thrombocyte count were 1.1–1.7 and 194–409 × 109/L for GA 37–39 and 1.2–1.8 and 188–433 × 109/L for GA 40–42. Correlation coefficients between umbilical cord and neonatal venous blood for APTT, PT, INR, and thrombocyte count were 0.68, 0.72, 0.69, and 0.77 respectively, and the distributions of the parameters did not differ between the two types of blood (all p-values>0.05). This study describes new GA dependent reference intervals for common coagulation parameters in newborns and suggests that cord blood may serve as a proxy for neonatal venous blood for these traits. Such data will likely improve clinical decision making within hemostasis among newborn and infant children. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]