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

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]

After the introduction of statins, clinical emphasis first focussed on LDL cholesterol-lowering, then on the potential for raising HDL cholesterol, with less focus on lowering triglycerides. However, the understanding from genetic studies and negative results from randomised trials that low HDL cholesterol might not cause cardiovascular disease as originally thought has now generated renewed interest in raised concentrations of triglycerides. This renewed interest has also been driven by epidemiological and genetic evidence supporting raised triglycerides, remnant cholesterol, or triglyceride-rich lipoproteins as an additional cause of cardiovascular disease and all-cause mortality. Triglycerides can be measured in the non-fasting or fasting states, with concentrations of 2-10 mmol/L conferring increased risk of cardiovascular disease, and concentrations greater than 10 mmol/L conferring increased risk of acute pancreatitis and possibly cardiovascular disease. Although randomised trials showing cardiovascular benefit of triglyceride reduction are scarce, new triglyceride-lowering drugs are being developed, and large-scale trials have been initiated that will hopefully provide conclusive evidence as to whether lowering triglycerides reduces the risk of cardiovascular disease. [ABSTRACT FROM AUTHOR]

Abstract: Background: We determined the predictive power of tobacco smoking on aortic aneurysm as opposed to other risk factors in the general population. Methods: We recorded tobacco smoking and other risk factors at baseline, and assessed hospitalization and death from aortic aneurysm in 15,072 individuals from the Copenhagen City Heart Study followed for up to 34years and in 56,211 individuals from the Copenhagen General Population Study followed for up to 7years. Results: During follow-up, 335 and 169 individuals developed aortic aneurysm outcomes in the Copenhagen City Heart Study and Copenhagen General Population Study, respectively. According to the magnitude of the hazard ratios, tobacco consumption was the most important risk factor for hospitalization and death from aortic aneurysm, followed by male sex and hypertension in both cohorts. The population attributable risk of aortic aneurysm outcomes due to tobacco consumption was 64% and 47% in the Copenhagen City Heart Study and Copenhagen General Population Study, respectively, and ranked highest among population attributable risks of aortic aneurysm in both cohorts. The absolute 10-year risk for hospitalization or death from aortic aneurysm in males and females consuming above 20g tobacco daily was 3.5% and 1.3%, among those >60years with plasma cholesterol >5mmol/L and a systolic blood pressure >140mmHg. Conclusions: Tobacco smoking is the most important predictor of future aortic aneurysm outcomes in the general population, with population attributable risks at or above 47%. [Copyright &y& Elsevier]

Objectives: The aim of this study was to examine the effect of PCSK9 R46L on low-density lipoprotein cholesterol (LDL-C), risk of ischemic heart disease (IHD), and mortality. Background: The 46L allele has been associated with reductions in LDL-C and risk of IHD, but results vary between studies. Methods: We determined the association of R46L genotype with LDL-C, risk of IHD, myocardial infarction (MI), and mortality in the prospective CCHS (Copenhagen City Heart Study) (n = 10,032) and validated the results in: 1) the cross-sectional CGPS (Copenhagen General Population Study) (n = 26,013); and 2) the case-control CIHDS (Copenhagen Ischemic Heart Disease Study) (n = 9,654). We also performed meta-analyses of present and previous studies (n = 66,698). Results: In carriers (2.6%) versus noncarriers, the 46L allele was associated with reductions in LDL-C of 0.35 to 0.55 mmol/l (11% to 16%) from 20 to 80+ years in the general population (CCHS and CGPS; p values <0.0001). Observed risk reductions for IHD in 46L allele carriers were: 6% in the CCHS study (hazard ratio [HR]: 0.94; 95% confidence interval [CI]: 0.68 to 1.31), 46% in the CGPS study (odds ratio [OR]: 0.54; 95% CI: 0.39 to 0.77), 18% in the CIHDS study (OR: 0.82; 95% CI: 0.55 to 1.21), and 30% in the studies combined (OR: 0.70; 95% CI: 0.58 to 0.86). In the CCHS study, HR for mortality was 1.18 (95% CI: 0.93 to 1.50). In meta-analyses, 46L allele carriers had a 12% (0.43 mmol/l) reduction in LDL-C and a 28% reduction in risk of IHD (HR: 0.72; 95% CI: 0.62 to 0.84), similar to results in the CCHS, CGPS, and CIHDS studies combined. However, the observed 12% (0.43 mmol/l) reduction in LDL-C theoretically predicted an only 5% reduction in risk of IHD (HR: 0.95; 95% CI: 0.92 to 0.97). Conclusions: The PCSK9 46L allele was associated with reductions in LDL-C from 20 to 80+ years in the general population. The reduction in risk of IHD was larger than predicted by the observed reduction in LDL-C alone. This could be because genotype is a better predictor of lifelong exposure to LDL-C than LDL-C measured in adult life. [Copyright &y& Elsevier]

The article discusses the study on high levels of lipoprotein(a) and the risk of myocardial infarction (MI) and ischemic heart disease (IHD). It highlights the measurement of lipoprotein(a) levels right after sampling and corrected for regression dilution bias. It adds that results indicate a positive correlation between high levels of lipoproteins and the risk of IHD and excessively high levels of lipoproteins increases the risk of MI, with higher risk for the elderly.

Objective Gout is the most common form of inflammatory arthritis and is caused by hyperuricaemia. Some studies have found a reduction in plasma urate with vitamin C supplementation. We tested the hypothesis that high plasma vitamin C is causally associated with low plasma urate and low risk of hyperuricaemia, using a Mendelian randomization approach. Methods We measured plasma urate and genotyped for the SLC23A1 rs33972313 vitamin C variant in 106 147 individuals from the Copenhagen General Population Study, of which 24 099 had hyperuricaemia. We measured plasma vitamin C in 9234 individuals and genotyped for the SLC2A9 rs7442295 urate variant in 102 345 individuals. Results Each 10 µmol/l higher plasma vitamin C was associated with a −2.3(95%CI: −0.69 to −3.9) µmol/l lower plasma urate after multivariable adjustments. The SLC23A1 rs33972313 GG genotype was associated with a 9% (5.6%, 11.9%) higher plasma vitamin C compared with AA and AG combined but was not associated with plasma urate (P = 0.31). Likewise, for each 10 µmol/l higher plasma vitamin C the odds ratios for hyperuricaemia were 0.92 (0.86, 0.98) observationally after multivariable adjustments, but 1.01 (0.84, 1.23) genetically. Conclusion High plasma vitamin C was associated with low plasma urate and with low risk of hyperuricaemia. However, the SLC23A1 genetic variant causing lifelong high plasma vitamin C was not associated with plasma urate levels or with risk of hyperuricaemia. Thus, our data do not support a causal relationship between high plasma vitamin C and low plasma urate. [ABSTRACT FROM AUTHOR]

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS 269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS 269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635–0.677) in African and 0.844 (95% CI = 0.840–0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67–2.00) and 2.19 (95% CI = 2.14–2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659–0.700 and AUC = 0.845, 95% CI = 0.841–0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87–2.26 and OR = 2.21, 95% CI = 2.16–2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS 269 developed from multi-ancestry GWASs and fine-mapping. Our findings suggest that in men of African and European ancestry, genome-wide polygenic risk scores including >1 million variants are not more predictive of prostate cancer risk than a carefully constructed polygenic risk score limited to variants with statistical evidence of an association with prostate cancer risk. [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 extracellular superoxide dismutase (SOD3, EC-SOD) enzyme is a major extracellular scavenger of the superoxide anion, a free radical with the potential to cause oxidative damage. Previously, R213G heterozygosity has been associated with a decreased risk of chronic obstructive pulmonary disease (COPD) and an increased risk of ischemic heart disease (IHD). We questioned whether SOD3 R213G homozygosity (213GG) influences morbidity, mortality, and lung function. We found 14 R213G homozygotes (213GG) among 95,871 individuals (1/7000) from the Copenhagen General Population Study and the Copenhagen City Heart Study. The hazard ratiofor homozygotes versus noncarriers (NC) (213RR) was 2.8 (95% confidence interval: 1.2-6.8, p = 0.02) for IHD, 1.8 (0.7-4.8, p = 0.25) for any form of cancer, and 2.3 (0.9-6.2, p = 0.10) for all-cause mortality. R213G heterozygosity was not associated with morbidity or mortality. Among never-smokers, we found a 20% lower forced expiratory volume in 1 s (FEV1)% predicted ( p = 0.003), a 16% lower FVC% predicted ( p = 0.01), and a 7% lower FEV1/FVC ratio ( p = 0.02) in R213G homozygotes compared to NC. Our results lead to the hypotheses that the SOD3 enzyme plays a role in cardiovascular disease and in impairing and maintaining lung function in never-smokers. However, our findings should be retested in larger studies and in nonsmoking COPD patient cohorts. [ABSTRACT FROM AUTHOR]

Elevated concentrations of Lipoprotein (a) [Lp(a)] is an inherited, causal risk factor for atherosclerotic cardiovascular disease (ASCVD). This study aims to investigate the clinical utility for patients, and the economic benefit to healthcare systems and society of measuring Lp(a) concentrations more widely today. We conducted a structured literature review to identify the economic and health benefits and costs of measuring the Lp(a) concentration, potential barriers hindering the uptake of the measure, and potential solutions to address them. These findings were then discussed in an advisory board attended by experts and patient organisations. It was found that if Lp(a) concentration is measured more widely today, patients, healthcare system and society would experience clinical and economic benefits even before specific Lp(a) lowering pharmacological treatments become available. Furthermore , a wider uptake of the Lp(a) measurement would support the development of epidemiological data. For Lp(a) measurement to be more widely used, key barriers which are hindering its uptake need to be addressed. These include i) the perception that the measure may have limited clinical value, ii) lack of awareness on Lp(a), iii) lack of data on the CV benefit of reducing Lp(a), iv) technical and clinical guidelines barriers, and v) healthcare system barriers. Scientific communities and industry should collaborate to address technical challenges and deficiencies in clinical guidelines. However, policy intervention will be crucial for national ASCVD plans to acknowledge the importance of Lp(a). [Display omitted] [ABSTRACT FROM AUTHOR]

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]

Objectives: The purpose of this study was to determine whether elevated lipoprotein(a) levels and corresponding LPA risk genotypes (rs10455872, rs3798220, kringle IV type 2 repeat polymorphism) prospectively associate with increased risk of aortic valve stenosis (AVS). Background: The etiologic basis of AVS is unclear. Recent data implicate an LPA genetic variant (rs10455872), associated with Lp(a) levels, in calcific AVS. Methods: We combined data from 2 prospective general population studies, the Copenhagen City Heart Study (1991 to 2011; n = 10,803) and the Copenhagen General Population Study (2003 to 2011; n = 66,877), following up 77,680 Danish participants for as long as 20 years, during which time 454 were diagnosed with AVS. We conducted observational and genetic instrumental variable analyses in a Mendelian randomization study design. Results: Elevated Lp(a) levels were associated with multivariable adjusted hazard ratios for AVS of 1.2 (95% confidence interval [CI]: 0.8 to 1.7) for 22nd to 66th percentile levels (5 to 19 mg/dl), 1.6 (95% CI: 1.1 to 2.4) for 67th to 89th percentile levels (20 to 64 mg/dl), 2.0 (95% CI: 1.2 to 3.4) for 90th to 95th percentile levels (65 to 90 mg/dl), and 2.9 (95% CI: 1.8 to 4.9) for levels greater than 95th percentile (>90 mg/dl), versus levels less than the 22nd percentile (<5 mg/dl; trend, p < 0.001). Lp(a) levels were elevated among carriers of rs10455872 and rs3798220 minor alleles, and of low number of KIV-2 repeats (trend, all p < 0.001). Combining all genotypes, instrumental variable analysis yielded a genetic relative risk for AVS of 1.6 (95% CI: 1.2 to 2.1) for a 10-fold Lp(a) increase, comparable to the observational hazard ratio of 1.4 (95% CI: 1.2 to 1.7) for a 10-fold increase in Lp(a) plasma levels. Conclusions: Elevated Lp(a) levels and corresponding genotypes were associated with increased risk of AVS in the general population, with levels >90 mg/dl predicting a threefold increased risk. [Copyright &y& Elsevier]

Background: Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.Methods: We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-LRx, referred to here as APO(a)-LRx (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).Results: The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-LRx dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.Conclusions: APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.). [ABSTRACT FROM AUTHOR]

Introduction: Observational studies have found lower concentrations of plasma bilirubin in current smokers compared with former and never smokers. However, whether there is a causal relationship between smoking and bilirubin is unknown. In a Mendelian randomization analysis, we tested the hypothesis that higher tobacco consumption is causally associated with lower concentrations of plasma bilirubin.Methods: We genotyped 103 557 individuals aged 20-100 years from the Copenhagen General Population Study for the CHRNA3 rs1051730 genotype, known to be associated with higher tobacco consumption. Tobacco consumption was defined as daily and cumulative tobacco consumption.Results: In observational multivariable-adjusted analyses, a 10 g/day higher daily tobacco consumption was associated with a 0.28 µmol/L (95% confidence interval = 0.20 to 0.35) lower concentration of plasma bilirubin in current smokers, and a 10 pack-year higher cumulative tobacco consumption was associated with a 0.19 µmol/L (0.17 to 0.21) lower concentration of plasma bilirubin in former and current smokers. Using the CHRNA3 rs1051730 genotype as a proxy for daily and cumulative tobacco consumption, the difference in plasma bilirubin per T-allele was -0.12 µmol/L (-0.23 to -0.002) in current smokers and -0.09 µmol/L (-0.15 to -0.01) in current and former smokers combined. Furthermore, observationally bilirubin concentrations increased with time from smoking cessation in former smokers.Conclusion: Higher daily and cumulative tobacco consumption were associated with lower concentrations of plasma bilirubin in observational and genetic analyses, suggesting that the association is causal.Implications: Our results are compatible with two possible interpretations of previous observational studies, either that bilirubin is a mediator of smoking-induced respiratory disease or that the association between plasma bilirubin and respiratory disease stems from residual confounding because of smoking. Future studies should examine whether bilirubin is a causal risk factor for respiratory disease, or merely a marker of smoking status. [ABSTRACT FROM AUTHOR]

Background 25-hydroxyvitamin D (25(OH)D) may be associated with lung function through modulation of pulmonary protease-antiprotease imbalance, airway inflammation, lung remodelling and oxidative stress. We examined the association of plasma 25(OH)D levels with lung function, lung function decline and risk of chronic obstructive pulmonary disease (COPD). Methods Plasma 25(OH)D was measured in 10 116 participants in the Copenhagen City Heart Study and in 8391 participants in the Copenhagen General Population Study. In the former study, up to three measurements of lung function spanning 20 years allowed analyses of lung function decline. Results In both cohorts, forced vital capacity in % of predicted was 7% lower and forced expiratory volume in 1 s in % of predicted was 7-10% lower for lowest versus highest decile of 25(OH)D (ptrend≤1×10-28). In prospective analyses, participants in the lower versus higher 25(OH)D quintiles had a faster decline in forced expiratory volume in 1 s % predicted (pinteraction=1×10-7) and forced vital capacity % predicted (pinteraction=8×10-8). In cross-sectional analyses, multivariable adjusted ORs for COPD were 2.30 (95% CI 1.55 to 3.41) and 3.06 (1.97 to 4.76) for lowest versus highest quintile in the Copenhagen City Heart Study using Global Initiative for Chronic Obstructive Lung Disease (GOLD) and lower limit of normal criteria. The corresponding ORs were 1.82 (1.13 to 2.92) and 2.23 (1.35 to 3.69) in the Copenhagen General Population Study. In prospective analyses, corresponding multivariable adjusted HRs for developing COPD were 1.58 (1.05 to 2.40) and 2.00 (1.19 to 3.36). Conclusions We observed a novel association of lower plasma 25(OH)D levels with faster decline in lung function and with a higher risk of COPD in prospective analyses. [ABSTRACT FROM AUTHOR]

OBJECTIVE-Alterations of pancreatic β-cell cholesterol content may contribute to β-cell dysfunction. Two important determinants of intracellular cholesterol content are the ATPbinding cassette (ABC) transporters A1 (ABCA1) and -G1 (ABCG1).Whether genetic variation in ABCA1 and ABCG1 predicts risk of type 2 diabetes in the general population is unknown. RESEARCH DESIGN AND METHOD-We tested whether genetic variation in the promoter and coding regions of ABCA1 and ABCG1 predicted risk of type 2 diabetes in the general population. Twenty-seven variants, identified by previous resequencing of both genes, were genotyped in the Copenhagen City Heart Study (CCHS) (n = 10,185). Two loss-of-function mutations (ABCA1 N1800H and ABCG1 g.-376C>T) (n = 322) and a common variant (ABCG1 g.-530A>G) were further genotyped in the Copenhagen General Population Study (CGPS) (n = 30,415). RESULT-Only one of the variants examined, ABCG1 g.-530A>G, predicted a decreased risk of type 2 diabetes in the CCHS (P for trend = 0.05). Furthermore, when validated in the CGPS or in the CCHS and CGPS combined (n = 40,600), neither the two loss-of-function mutations (ABCA1 N1800H, ABCG1 g.-376C>T) nor ABCG1 g.-530A>G were associated with type 2 diabetes (P values >0.57 and >0.30, respectively). CONCLUSION-Genetic variations in ABCA1 and ABCG1 were not associated with increased risk of type 2 diabetes in the general population. These data were obtained in general population samples harboring the largest number of heterozygotes for loss-of-function mutations in ABCA1 and ABCG1 [ABSTRACT FROM AUTHOR]

The article discusses a study which investigated the association between high density lipoprotein (HDL)-cholesterol and the occurrence of cardiovascular events after treatment with potent statin therapy. The study involved adults who were not suffering from diabetes or previous cardiovascular disease. The authors of the study found that rosuvastatin 20 milligrams (mg) per day reduced the incidence of the primary endpoint by 44 percent. It was concluded that HDL-cholesterol concentrations were not predictive of residual vascular risk.

Simple Summary: It is well-recognised the strong contribution of genetic factors to prostate cancer (PrCa) susceptibility, thus genetic screening is critical for presymptomatic diagnosis and identification of individuals at high-risk. In this context, recurrent founder variants in cancer predisposing genes, by providing specific targets for early identification of carriers at risk of developing the disease, may be leveraged to implement cost-efficient targeted genetic screening strategies. The goal of this study was to investigate whether CHEK2 c.349A>G, the only recurrent "likely pathogenic" variant in CHEK2 gene reported in the Portuguese population, plays an important role in PrCa development, and the possibility of a founder effect behind its origin. Our results clearly demonstrate that c.349A>G in the CHEK2 tumour-suppressor gene is a founder variant significantly associated with an increased risk of PrCa, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. The identification of recurrent founder variants in cancer predisposing genes may have important implications for implementing cost-effective targeted genetic screening strategies. In this study, we evaluated the prevalence and relative risk of the CHEK2 recurrent variant c.349A>G in a series of 462 Portuguese patients with early-onset and/or familial/hereditary prostate cancer (PrCa), as well as in the large multicentre PRACTICAL case–control study comprising 55,162 prostate cancer cases and 36,147 controls. Additionally, we investigated the potential shared ancestry of the carriers by performing identity-by-descent, haplotype and age estimation analyses using high-density SNP data from 70 variant carriers belonging to 11 different populations included in the PRACTICAL consortium. The CHEK2 missense variant c.349A>G was found significantly associated with an increased risk for PrCa (OR 1.9; 95% CI: 1.1–3.2). A shared haplotype flanking the variant in all carriers was identified, strongly suggesting a common founder of European origin. Additionally, using two independent statistical algorithms, implemented by DMLE+2.3 and ESTIAGE, we were able to estimate the age of the variant between 2300 and 3125 years. By extending the haplotype analysis to 14 additional carrier families, a shared core haplotype was revealed among all carriers matching the conserved region previously identified in the high-density SNP analysis. These findings are consistent with CHEK2 c.349A>G being a founder variant associated with increased PrCa risk, suggesting its potential usefulness for cost-effective targeted genetic screening in PrCa families. [ABSTRACT FROM AUTHOR]