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Lipoprotein(a) [Lp(a)] is a well-recognized, independent risk factor for atherosclerotic cardiovascular disease, with elevated levels estimated to be prevalent in 20% of the population. Observational and genetic evidence strongly support a causal relationship between high plasma concentrations of Lp(a) and increased risk of atherosclerotic cardiovascular disease–related events, such as myocardial infarction and stroke, and valvular aortic stenosis. In this scientific statement, we review an array of evidence-based considerations for testing of Lp(a) in clinical practice and the utilization of Lp(a) levels to inform treatment strategies in primary and secondary prevention. [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: High lipoprotein(a) is associated with increased risk of myocardial infarction and aortic valve stenosis. Previous studies have examined the association of lipoprotein(a) and risk of stroke; however, the results are conflicting.Objectives: The purpose of this study was to test if high lipoprotein(a) is associated with high risk of ischemic stroke observationally and causally from human genetics.Methods: The study included 49,699 individuals from the Copenhagen General Population Study and 10,813 individuals from the Copenhagen City Heart Study with measurements of plasma lipoprotein(a), LPA kringle-IV type 2 number of repeats, and LPA rs10455872. The endpoint of ischemic stroke was ascertained from Danish national health registries and validated by medical doctors.Results: Compared with individuals with lipoprotein(a) levels <10 mg/dl (<18 nmol/l: first to 50th percentile), the multivariable-adjusted hazard ratio for ischemic stroke was 1.60 (95% confidence interval [CI]:1.24 to 2.05) for individuals with lipoprotein(a) levels >93mg/dl (>199 nmol/L: 96th to 100th percentile). In observational analyses for a 50 mg/dl (105 nmol/l) higher lipoprotein(a) level the age- and sex-adjusted hazard ratio for ischemic stroke was 1.20 (95% CI: 1.13 to 1.28), while the corresponding age- and sex-adjusted genetic causal risk ratio for KIV-2 number of repeats was 1.20 (95% CI: 1.02 to 1.43) and for rs10455872 was 1.27 (95% CI: 1.06 to 1.51). The highest absolute 10-year risk of ischemic stroke was 17% in active smoking individuals >70 years of age with hypertension and lipoprotein(a) levels >93 mg/dl (>199 nmol/l: 96th to 100th percentile). In the Copenhagen City Heart Study, risk estimates for high levels of lipoprotein(a) were in the same direction but did not reach statistical significance.Conclusions: In a large contemporary general population study, high plasma levels of lipoprotein(a) were associated with increased risk of ischemic stroke both observationally and causally from human genetics. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to test whether the association of C-reactive protein (CRP) with increased risk of atrial fibrillation is a robust and perhaps even causal association. Background: Elevated levels of CRP previously have been associated with increased risk of atrial fibrillation. Methods: We studied 10,276 individuals from the prospective Copenhagen City Heart Study, including 771 individuals who had atrial fibrillation during follow-up, and another 36,600 persons from the cross-sectional Copenhagen General Population Study, including 1,340 cases with atrial fibrillation. Individuals were genotyped for 4 CRP gene polymorphisms and had high-sensitivity CRP levels measured. Results: A CRP level in the upper versus lower quintile associated with a 2.19-fold (95% confidence interval [CI]: 1.54- to 3.10-fold) increased risk of atrial fibrillation. Risk estimates attenuated slightly after multifactorial adjustment to 1.77 (95% CI: 1.22 to 2.55), and after additional adjustment for heart failure and plasma fibrinogen level to 1.47 (95% CI: 1.02 to 2.13) and 1.63 (95% CI: 1.21 to 2.20), respectively. Genotype combinations of the 4 CRP polymorphisms associated with up to a 63% increase in plasma CRP levels (p < 0.001), but not with increased risk of atrial fibrillation. The estimated causal odds ratio for atrial fibrillation by instrumental variable analysis for a doubling in genetically elevated CRP levels was lower than the odds ratio for atrial fibrillation observed for a doubling in plasma CRP on logistic regression (0.94 [95% CI: 0.70 to 1.27] vs. 1.36 [95% CI: 1.30 to 1.44]; p < 0.001). Conclusions: Elevated plasma CRP robustly associated with increased risk of atrial fibrillation; however, genetically elevated CRP levels did not. This suggests that elevated plasma CRP per se does not increase atrial fibrillation risk. [ABSTRACT FROM AUTHOR]

Summary: Dominant mutations in the surfactant protein-C(SFTPC) gene have been linked with interstitial lung disease. The frequency of lung disease due to SFTPC mutations in the general population is unknown. The aim of this study was to identify novel SFTPC mutations that are associated with lung function or disease in the general population. We resequenced the SFTPC gene in 760 individuals and identified 18 genetic variants, of which 5 were novel. Of the five novel mutations, two were situated in highly conserved areas of the SFTPC gene: A53T and Y106X. We genotyped the Copenhagen City Heart Study(n =10,604) and the Copenhagen General Population Study(n =37,337) to assess the clinical relevance of these mutations. Genotyping identified 36 individuals heterozygous for A53T and 3 individuals heterozygous for Y106X. A53T heterozygotes and Y106X heterozygotes did not differ from non-carriers in FEV1% predicted, FVC% predicted or FEV1/FVC. A53T heterozygotes had a two-fold increased risk for asthma in the Copenhagen City Heart Study and Copenhagen General Population Study combined (adjusted odds ratio 2.2(1.0–4.9)). A53T heterozygotes did not differ consistently from non-carriers in risk of chronic obstructive pulmonary disease or interstitial lung disease. No Y106X heterozygotes suffered from asthma, chronic obstructive pulmonary disease (COPD), or interstitial lung disease. We identified two novel mutations in highly conserved areas of the SFTPC gene, and show that heterozygotes for the mutations have normal lung function and are unaffected by COPD and interstitial lung disease. A53T heterozygotes had increased asthma risk, but further research is required to conclusively determine whether this mutation is associated with asthma. [Copyright &y& Elsevier]

The apolipoprotein E(APOE) ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism, vascular disease and dementia. The impact of the full range of structural genetic variation in APOE for lipids, lipoproteins and apolipoproteins and for vascular disease in the general population is not known. We systematically sequenced APOE in 10,296 individuals from the Copenhagen City Heart Study and genotyped nine rare variants (frequency≥2/10,296) in 95,227 individuals from the Copenhagen General Population Study. The UK Biobank was used for validation of common APOE variants. Rare mutations in APOE , predicted to be deleterious, are present in 1 in 257 individuals in the general population. In the meta-analysis, multifactorially adjusted hazard ratios (95% confidence intervals) for ϵ44 and ϵ22 versus ϵ33 were 1.15 (1.04–1.26) and 1.02 (0.83–1.24) for ischemic cerebrovascular disease (ICVD), 1.11 (1.04–1.19) and 0.94 (0.83–1.08) for ischemic heart disease (IHD) and 1.03 (0.89–1.17) and 1.49 (1.20–1.87) for peripheral arterial disease (PAD). A multifactorially and ϵ2/ϵ3/ϵ4 adjusted weighted allele score on the continuous scale including all common and rare structural variants showed that for individuals with genetically predicted high plasma apoE and remnant cholesterol the risk for PAD was increased. APOE variants with high apoE, triglycerides, and remnant cholesterol are associated with PAD, whereas common APOE variants with high LDL cholesterol, triglycerides and remnant cholesterol are associated with IHD. APOE variants with low apoE are associated with increased risk of ICVD. These findings highlight that both rare and common structural variations in APOE play a role in vascular disease. [Display omitted] • The APOE ϵ2/ϵ3/ϵ4 polymorphism plays a central role in lipid metabolism. • We sequenced APOE in 10,296 and genotyped rare variants in 95,227 individuals. • ϵ2-like variants are associated with peripheral arterial disease. • Variants with low apoE are associated with ischemic cerebrovascular disease. • Structural variations in APOE beyond the ϵ2 and ϵ4 alleles play a role. [ABSTRACT FROM AUTHOR]

Background: Reduced low-density lipoprotein (LDL) cholesterol due to inhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) reduces cardiovascular events and may therefore also reduce cardiovascular and all-cause mortality.Objectives: This study tested the hypothesis that genetically low LDL cholesterol due to PCSK9 variation is causally associated with low cardiovascular and all-cause mortality in the general population.Methods: A total of 109,566 individuals from the Copenhagen General Population Study and the Copenhagen City Heart Study were genotyped for PCSK9 R46L (rs11591147), R237W (rs148195424), I474V (rs562556), and E670G (rs505151). During a median follow-up of 10 years (range 0 to 42 years) and 1,247,225 person-years, there were 3,828 cardiovascular deaths and 16,373 deaths from any cause. Results were validated using data on 431,043 individuals from the UK Biobank.Results: An increasing number of weighted PCSK9 alleles were associated with stepwise lower LDL cholesterol of up to 0.61 mmol/l (24 mg/dl; 18.2%; p for trend <0.001) and with lower cardiovascular mortality (p = 0.001), but not with lower all-cause mortality (p = 0.11). In causal, genetic analyses, a 0.5-mmol/l (19.4-mg/dl) lower LDL cholesterol was associated with risk ratios for cardiovascular and all-cause mortality of 0.79 (95% confidence interval [CI]: 0.63 to 0.99; p = 0.04) and 1.02 (95% CI: 0.94 to 1.12; p = 0.63) in the Copenhagen studies, 0.79 (95% CI: 0.58 to 1.08; p = 0.14) and 0.98 (95% CI: 0.87 to 1.10; p = 0.75) in the UK Biobank, and of 0.79 (95% CI: 0.65 to 0.95; p = 0.01) and 1.01 (95% CI: 0.94 to 1.08; p = 0.85), respectively, in studies combined.Conclusions: Genetically low LDL cholesterol due to PCSK9 variation was causally associated with low risk of cardiovascular mortality, but not with low all-cause mortality in the general population. [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 and aims Triglyceride-rich lipoproteins are causally associated with high risk of ischemic heart disease (IHD), and apolipoprotein E (apoE) has a central role in their plasma clearance. While both quantitative and qualitative changes of apoE are established causes of rare dyslipidemia syndromes, it remains unclear whether plasma levels of apoE are associated with risk of IHD in the general population. Methods We tested whether plasma levels of apoE at enrollment were associated with future risk of IHD and myocardial infarction (MI) in 91,695 individuals from the general population. Results Multifactorially adjusted hazard ratios (HRs) for highest versus lowest apoE tertile were 1.15 (1.04–1.27) for IHD and 1.16 (1.00–1.36) for MI in men, and 0.94 (0.84–1.05) and 1.04 (0.85–1.26) in women. These associations were attenuated by adjustments for triglyceride levels. Corresponding HRs for highest versus lowest apoE tertile in ε33 carriers were 1.18 (1.03–1.36) for IHD and 1.21 (0.98–1.49) for MI in men, and 0.91 (0.78–1.06) and 0.93 (0.71–1.21) in women. Thus, the present associations were independent of APOE genotype. Conclusion These findings suggest that high plasma levels of apoE are associated with IHD in men but not in women. Triglyceride-rich lipoproteins may partly explain these associations. [ABSTRACT FROM AUTHOR]

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]

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]

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]