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Biobank research may lead to an improved understanding of disease etiology and advance personalized medicine. Denmark (population ~5.9 million) provides a unique setting for population-based health research. The country is a rich source of biobanks and the universal, tax-funded healthcare system delivers routinely collected data to numerous registries and databases. By virtue of the civil registration number (assigned uniquely to all Danish citizens), biological specimens stored in biobanks can be combined with clinical and demographic data from these population-based health registries and databases. In this review, we aim to provide an understanding of advantages and possibilities of biobank research in Denmark. As knowledge about the Danish setting is needed to grasp the full potential, we first introduce the Danish healthcare system, the Civil Registration System, the population-based registries, and the interface with biobanks. We then describe the biobank infrastructures, comprising the Danish National Biobank Initiative, the Bio- and Genome Bank Denmark, and the Danish National Genome Center. Further, we briefly provide an overview of fourteen selected biobanks, including: The Danish Newborn Screening Biobank; The Danish National Birth Cohort; The Danish Twin Registry Biobank; Diet, Cancer and Health; Diet, Cancer and Health – Next generations; Danish Centre for Strategic Research in Type 2 Diabetes; Vejle Diabetes Biobank; The Copenhagen Hospital Biobank; The Copenhagen City Heart Study; The Copenhagen General Population Study; The Danish Cancer Biobank; The Danish Rheumatological Biobank; The Danish Blood Donor Study; and The Danish Pathology Databank. Last, we inform on practical aspects, such as data access, and discuss future implications. [ABSTRACT FROM AUTHOR]

Background: Obese individuals may be at higher risk of chronic cough. We investigated the risk and impact of chronic cough in obese individuals from the general population.Methods: We recorded chronic cough, body mass index (BMI) and other related clinical conditions in 44 554 adults from the Copenhagen General Population Study. Individuals with asthma and/or chronic obstructive pulmonary disease were excluded (n=10 977). BMI was divided into: underweight (BMI <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obese (30.0-34.9 kg/m2) and severely obese (≥35.0 kg/m2).Results: Among 33 577 adults from the general population, 27 829 (83%) were non-obese and 5748 (17%) were obese. Compared with individuals with normal weight, multivariable adjusted ORs for chronic cough risk were 1.4 (95% CI 1.2 to 1.6) in overweight, 1.9 (95% CI 1.7 to 2.2) in obese and 2.6 (95% CI 2.1 to 3.2) in severely obese individuals. Mediation analyses showed that chronic cough due to obesity was up to 23% mediated by gastro-oesophageal reflux disease (GERD). Other mediators included low vegetable intake with 10% and occupational exposure with 8%. Among obese individuals, those with versus without chronic cough had worse accompanying respiratory symptoms, more often comorbidities including GERD and diabetes, greater healthcare utilisations, lower lung function and higher blood inflammation (all p<0.05).Conclusion: There is dose-response relationship between BMI and chronic cough, and chronic cough risk is twofold to threefold higher in obese individuals from the general population. This increased risk was partly mediated by GERD, low vegetable intake and occupational exposure, supporting that there may be benefit to gain by ameliorating some of these factors in obese individuals with chronic cough. [ABSTRACT FROM AUTHOR]

We tested the hypothesis that low plasma adiponectin is associated observationally and causally with increased risk of type 2 diabetes. Observational analyses are prone to confounding and reverse causation, while genetic Mendelian randomization (MR) analyses are much less influenced by these biases. We examined 30,045 individuals from the Copenhagen General Population Study observationally (plasma adiponectin [1,751 individuals with type 2 diabetes]), 96,903 Copenhagen individuals using one-sample MR (5 genetic variants [5,012 individuals with type 2 diabetes]), and 659,316 Europeans (ADIPOGen, GERA, DIAGRAM, UK Biobank) using two-sample MR (10 genetic variants [62,892 individuals type 2 diabetes]). Observationally, and in comparisons with individuals with median plasma adiponectin of 28.9 μg/mL (4th quartile), multivariable adjusted hazard ratios (HRs) for type 2 diabetes were 1.42 (95% CI 1.18-1.72) for 19.2 μg/mL (3rd quartile), 2.21 (1.84-2.66) for 13.9 μg/mL (2nd quartile), and 4.05 (3.38-4.86) for 9.2 μg/mL (1st quartile). Corresponding cumulative incidence for type 2 diabetes at age 70 years was 3%, 7%, 11%, and 20%, respectively. A 1 μg/mL lower plasma adiponectin conferred an HR for type 2 diabetes of 1.07 (1.06-1.09), while genetic, causal risk ratio per 1 unit log-transformed lower plasma adiponectin was 1.13 (95% CI 0.83-1.53) in one-sample MR and 1.26 (1.01-1.57) in two-sample MR. In conclusion, low plasma adiponectin is associated with increased risk of type 2 diabetes, an association that could represent a causal relationship. [ABSTRACT FROM AUTHOR]

Rationale: Individuals who will develop chronic obstructive pulmonary disease (COPD) could be identified at an early age before clinical manifestations appear. Objectives: We investigated risk of clinical COPD 10 years later in young adults from the general population with and without early COPD with a focus on smoking exposure. Methods: We included 14,870 individuals aged 20-100 years from the Copenhagen General Population Study with spirometry 10 years apart. Early COPD was defined as baseline FEV1/FVC less than the lower limit of normal in individuals aged <50 years. Outcomes included clinical COPD at final examination 10 years later (chronic respiratory symptoms with FEV1/FVC <0.70 and FEV1 <80% predicted) and acute exacerbation hospitalizations during follow-up. Measurements and Main Results: Among 5,497 individuals aged <50 years at baseline with FEV1/FVC ≥0.70, 104 (3%) developed clinical COPD 10 years later; 4% of smokers with ≥10 pack-years had early COPD; 3% of smokers with <10 pack-years had early COPD; and 2% of never-smokers had early COPD. Among smokers with ≥10 pack-years, 24% developed clinical COPD in those with early COPD versus 4% in those without early COPD. Corresponding numbers were 10% and 1% in smokers with <10 pack-years and 3% and <1% in never-smokers, respectively. Among individuals with early COPD, odds ratios for clinical COPD 10 years later were 7.77 (95% confidence interval [CI], 4.10-14.7) in smokers with ≥10 pack-years and 8.56 (95% CI, 4.92-14.9) in all smokers, whereas hazard ratios for acute exacerbation hospitalizations were 4.16 (95% CI, 1.66-10.5) and 4.33 (95% CI, 1.89-9.93), respectively. Results were validated in the Copenhagen City Heart Study. Conclusions: Depending on amount of smoking exposure, <24% of young adults in the general population with early COPD develop clinical COPD 10 years later. A smoking exposure threshold for early COPD should be reconsidered, as younger individuals are less represented in those with high smoking exposure. [ABSTRACT FROM AUTHOR]

Background: Vitamin D may regulate the innate immune system, and randomised controlled trials suggest a beneficial effect of vitamin D supplementation against acute respiratory tract infections. By using a Mendelian randomisation approach, we tested the hypothesis that low 25-hydroxyvitamin D is associated with increased risk of bacterial pneumonia in observational and genetic analyses.Methods: We genotyped 116 335 randomly chosen white Danes aged 20 to 100 from the Copenhagen City Heart Study and Copenhagen General Population Study for plasma 25-hydroxyvitamin D decreasing genetic variants around CYP2R1 (rs117913124, rs12794714 and rs10741657), DHCR7 (rs7944926 and rs11234027), GEMIN2 (rs2277458) and HAL (rs3819817). Information on plasma 25-hydroxyvitamin D was available on 35 833 individuals. Individuals were followed from 1981 through 2018 for hospital diagnoses of bacterial pneumonias.Results: During up to 38 years follow-up, we observed 6342 bacterial pneumonias in observational analyses and 13 916 in genetic analyses. In observational analyses, multivariable adjusted HR for bacterial pneumonias was 1.27 (95% CI: 1.16 to 1.40) for individuals with 25-hydroxyvitamin D<25 nmol/L compared with those with ≥25 nmol/L. In genetic analyses, the OR for bacterial pneumonia per 10 nmol/L lower plasma 25-hydroxyvitamin D was 1.12 (95% CI: 1.02 to 1.23) in Wald's ratio, 1.12 (95% CI: 1.04 to 1.20) in inverse-variance weighted, 1.63 (95% CI: 0.96 to 2.78) in MR-Egger and 1.15 (95% CI: 1.05 to 1.26) in weighted median instrumental variable analysis. This association was strongest for genetic variants around CYP2R1. There was no observational or genetic evidence to support that 25-hydroxyvitamin D is associated with risk of urinary tract infections, skin infections, sepsis or gastroenteritis, which were used as negative control outcomes.Conclusions: Low vitamin D is associated observationally and genetically with increased risk of bacterial pneumonias. [ABSTRACT FROM AUTHOR]

Background: Different airflow limitation criteria are often used to diagnose COPD. We investigated head-to-head whether Global Initiative for Chronic Obstructive Lung Disease (GOLD) (FEV1/FVC <0.70) and four lower limit of normal (LLN) (FEV1/FVC Methods: 108 246 individuals aged 20-100 years randomly selected from the general population were followed from 2003 through 2018 to determine risk of COPD exacerbations, respiratory mortality and all-cause mortality. LLN criteria used equations from Global Lung Initiative (GLI), National Health and Nutrition Examination Survey (NHANES), European Community for Steel and Coal (ECSC) and Copenhagen City Heart Study (CCHS)/Copenhagen General Population Study (CGPS).Results: Prevalence of airflow limitation was 17% for GOLD, 8.6% for GLI, 10% for NHANES, 8.2% for ECSC and 14% for CCHS/CGPS. During 14.4 years follow-up, we observed 2745 COPD exacerbations, 762 respiratory deaths and 10 338 all-cause deaths. Comparing individuals with versus without airflow limitation, HRs for COPD exacerbations were 17 (95% CI 14 to 20) for GOLD, 21 (18 to 24) for GLI, 20 (17 to 23) for NHANES, 21 (18 to 24) for ECSC and 18 (16 to 21) for CCHS/CGPS. Corresponding HRs for respiratory mortality were 3.7 (3.1 to 4.3), 6.4 (5.6 to 7.5), 5.7 (4.9 to 6.6), 6.2 (5.3 to 7.2) and 4.5 (3.9 to 5.2), and for all-cause mortality 1.5 (1.4 to 1.5), 1.9 (1.8 to 2.0), 1.8 (1.7 to 1.9), 1.9 (1.8 to 2.0) and 1.7 (1.6 to 1.7), respectively. Differences in Harrell's C were minute for these outcomes; nonetheless, Harrell's C was slightly higher for LLN criteria compared with GOLD for mortality outcomes.Conclusions: The prevalence of airflow limitation ranged from 8% to 17% using GOLD and four different LLN criteria; however, identified individuals with the five different criteria had similar risk of COPD exacerbations and mortality. [ABSTRACT FROM AUTHOR]

Background: People with human immunodeficiency virus (PWH) may be at risk of nonalcoholic fatty liver disease. We compared the prevalence of moderate-to-severe hepatic steatosis (M-HS) in PWH with human immunodeficiency virus (HIV)-uninfected controls and determined risk factors for M-HS in PWH.Methods: The Copenhagen Co-Morbidity in HIV Infection study included 453 participants, and the Copenhagen General Population Study included 765 participants. None had prior or current viral hepatitis or excessive alcohol intake. Moderate-to-severe hepatic steatosis was assessed by unenhanced computed tomography liver scan defined by liver attenuation ≤48 Hounsfield units. Adjusted odds ratios (aORs) were computed by adjusted logistic regression.Results: The prevalence of M-HS was lower in PWH compared with uninfected controls (8.6% vs 14.2%, P < .01). In multivariable analyses, HIV (aOR, 0.44; P < .01), female sex (aOR, 0.08; P = .03), physical activity level (aOR, 0.09; very active vs inactive; P < .01), and alcohol (aOR, 0.89 per unit/week; P = .02) were protective factors, whereas body mass index (BMI) (aOR, 1.58 per 1 kg/m2; P < .01), alanine transaminase (ALT) (aOR, 1.76 per 10 U/L; P < .01), and exposure to integrase inhibitors (aOR, 1.28 per year; P = .02) were associated with higher odds of M-HS.Conclusions: Moderate-to-severe hepatic steatosis is less common in PWH compared with demographically comparable uninfected controls. Besides BMI and ALT, integrase inhibitor exposure was associated with higher prevalence of steatosis in PWH. [ABSTRACT FROM AUTHOR]

Background: Increased pericardial adipose tissue is associated with higher risk of cardiovascular disease. We aimed to determine whether human immunodeficiency virus (HIV) status was independently associated with larger pericardial adipose tissue volume and to explore possible HIV-specific risk factors.Methods: Persons with HIV (PWH) were recruited from the Copenhagen Comorbidity in HIV Infection (COCOMO) Study and matched 1:1 on age and sex to uninfected controls. Pericardial adipose tissue volume was measured using cardiac computed tomography.Results: A total of 587 PWH and 587 controls were included. Median age was 52 years, and 88% were male. Human immunodeficiency virus status was independently associated with 17 mL (95% confidence interval [CI], 10-23; P < .001) larger pericardial adipose tissue volume. Larger pericardial adipose tissue volume was associated with low CD4+ nadir and prior use of stavudine, didanosine, and indinavir. Among PWH without thymidine analogue or didanosine exposure, time since initiating combination antiretroviral treatment (per 5-year use) was associated with l6 mL (95% CI, -6 to -25; P = .002) lower pericardial adipose tissue volume.Conclusions: Human immunodeficiency virus status was independently associated with larger pericardial adipose tissue volume. Severe immunodeficiency, stavudine, didanosine, and indinavir were associated with larger pericardial adipose tissue volume. Persons with HIV with prior exposure to these drugs may constitute a distinct cardiovascular risk population. [ABSTRACT FROM AUTHOR]

Background: The role and impact of chronic cough in individuals with COPD have not been described in the general population. This study hypothesized that comorbid chronic cough is a marker of disease severity in individuals with COPD.Methods: This study identified individuals with COPD and chronic cough, and recorded respiratory symptoms, health-care utilizations, lung function, and inflammatory biomarkers in blood in a nested cohort of 43,271 adults from the Copenhagen General Population Study (CGPS).Results: Among 43,271 individuals from the general population, 8,181 (19%) experienced COPD, of whom 796 (10%) had chronic cough. Individuals with COPD and chronic cough had a Leicester Cough Questionnaire median (25th-75th percentiles) total score of 17.7 (16.0-18.9), corresponding to 5.9 (5.3-6.3) for the physical domain, 5.6 (4.9-6.3) for the psychological domain, and 6.3 (5.8-6.8) for the social domain. Among individuals with COPD, those with chronic cough vs those without chronic cough more often experienced sputum production (60% vs 8%), wheezing (46% vs 14%), dyspnea (66% vs 38%), chest pain/tightness (9% vs 4%), nighttime dyspnea (8% vs 3%), episodes of acute bronchitis/pneumonias in the last 10 years (45% vs 25%), and ≥ 3 general practitioner visits in the past 12 months (53% vs 37%). Furthermore, these individuals had lower FEV1 % predicted (81% vs 89%) and FEV1/FVC (0.64 vs 0.66), as well as higher levels of high-sensitivity C-reactive protein, fibrinogen, leukocytes, neutrophils, eosinophils, and IgE in blood.Conclusions: Comorbid chronic cough in individuals with COPD is associated with a more severe disease in terms of more respiratory symptoms and health-care utilizations, lower lung function, and increased inflammation in blood. [ABSTRACT FROM AUTHOR]

Rationale: Identification of younger adults at high risk of developing chronic obstructive pulmonary disease (COPD) could lead to implementation of preventive measures before disease onset and halt progression.Objectives: To investigate the prevalence, characteristics, and prognosis of individuals with early COPD in the general population.Methods: We investigated 105,630 randomly chosen adults from a Danish contemporary population-based cohort. Early COPD was defined as FEV1/FVC less than the lower limit of normal in individuals under 50 years of age with 10 pack-years or greater of tobacco consumption.Measurements and Main Results: Among 8,064 individuals under 50 years of age with 10 pack-years or greater of tobacco consumption, 1,175 (15%) had early COPD, of whom 58% were current smokers. Individuals with early COPD more often had chronic respiratory symptoms, severe lung function impairment, asthma, and a history with bronchitis/pneumonia. During the 14.4-year follow-up, we observed 117 acute hospitalizations with obstructive lung disease, 227 acute hospitalizations with pneumonia, and 185 deaths among the 8,064 younger adults. Compared with individuals without COPD, those with early COPD had multivariable adjusted hazard ratios of 6.42 (95% confidence interval, 3.39-12.2) for acute obstructive lung disease hospitalizations, 2.03 (1.43-2.88) for acute pneumonia hospitalizations, and 1.79 (1.28-2.52) for all-cause mortality.Conclusions: Among individuals under 50 years of age and 10 pack-years or greater of tobacco consumption from the general population, 15% fulfill criteria of early COPD. Individuals with early COPD more often have chronic respiratory symptoms and severe lung function impairment, and an increased risk of acute respiratory hospitalizations and early death. [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: Coronary artery calcification (CAC) is commonly assessed with Agatston score (AS). A higher sensitivity and precision for the detection of CAC has been demonstrated with calibrated mass score (cMS). We hypothesized that cMS would detect low-level CAC not detectable with AS in a large asymptomatic background population.Methods: Participants (N = 2985) from the Copenhagen General Population Study were evaluated for CAC using both conventional AS and cMS. The population was grouped according to number of traditional risk factors and heart score was used to assess the risk of event for those with no CAC, those with only cMS > 0 and those with both AS and cMS > 0.Results: In participants with an AS = 0, 11% had cMS > 0. The risk profile of this cMS-only group was between that of the CAC-negative participants and those with AS > 0 and cMS > 0. Overall, 6% of the population belonged to the cMS-only group independent of the number of risk factors.Conclusion: In individuals with AS = 0, a fraction was found to have cMS > 0. Based on traditional risk factors, this group has a higher 10-year risk than individuals with both AS = 0 and cMS = 0; cMS might offer very early cardiovascular risk assessment in asymptomatic individuals.Key Points: • In individuals with AS=0, a fraction has CAC with highly sensitive cMS. • This fraction has a higher 10-year risk of cardiovascular disease. • Regardless of risk factors, 6% has CAC detectable only with cMS. • cMS might offer very early cardiovascular risk assessment in asymptomatic individuals. [ABSTRACT FROM AUTHOR]

Background: Urate is a strong antioxidant in plasma and may protect against lung function impairment. We tested the hypothesis that high plasma urate is causally associated with better lung function and low risk of respiratory symptoms and COPD.Methods: We measured lung function and plasma urate in 114 979 individuals from the Copenhagen City Heart Study and the Copenhagen General Population Study and genotyped for SLC2A9 rs7442295 and ABCG2 rs2231142 variants, previously associated with high plasma urate, in 110 152 individuals.Results: In the two studies combined, multivariable-adjusted 100 µmol/L higher plasma urate was associated with -1.54% (95% CI -1.67 to -1.40) lower FEV1 % predicted and -1.57% (95% CI -1.69 to -1.44) lower FVC % predicted observationally; the corresponding estimates for genetically determined 100 µmol/L higher plasma urate were -0.46% (95% CI -1.17 to 0.25) and -0.40% (95% CI -1.03 to 0.23). High plasma urate was also associated with higher risk of respiratory symptoms; however, genetically determined high plasma urate was not associated with respiratory symptoms. Finally, we identified 14 151 individuals with COPD and found ORs of 1.08 (95% CI 1.06 to 1.11) for COPD observationally and 1.01 (95% CI 0.88 to 1.15) genetically per 100 µmol/L higher plasma urate.Conclusion: High plasma urate was associated with worse lung function and higher risk of respiratory symptoms and COPD in observational analyses; however, genetically high plasma urate was not associated with any of these outcomes. Thus, our data do not support a direct causal relationship. [ABSTRACT FROM AUTHOR]

Introduction: Whether HIV influences pulmonary function remains controversial. We assessed dynamic pulmonary function in people living with HIV (PLWHIV) and uninfected controls.Methods: A total of 1098 PLWHIV from the Copenhagen Co-morbidity in HIV infection study and 12 161 age-matched and sex-matched controls from the Copenhagen General Population Study were included. Lung function was assessed using FEV1 and FVC, while airflow limitation was defined by the lower limit of normal (LLN) of FEV1/FVC and by FEV1/FVC<0.7 with FEV1predicted <80% (fixed). Logistic and linear regression models were used to determine the association between HIV and pulmonary function adjusting for potential confounders (including smoking and socioeconomic status).Results: In predominantly white men with mean (SD) age of 50.6 (11.1) the prevalence of airflow limitation (LLN) was 10.6% (95% CI 8.9% to 12.6%) in PLWHIV and 10.6% (95% CI 10.0 to 11.1) in uninfected controls. The multivariable adjusted OR for airflow limitation defined by LLN for HIV was 0.97 (0.77-1.21, P<0.78) and 1.71 (1.34-2.16, P<0.0001) when defined by the fixed criteria. We found no evidence of interaction between HIV and cumulative smoking in these models (P interaction: 0.25 and 0.17 for LLN and fixed criteria, respectively). HIV was independently associated with 197 mL (152-242, P<0.0001) lower FEV1 and 395 mL (344-447, P<0.0001) lower FVC, and 100 cells/mm3 lower CD4 nadir was associated with 30 mL (7-52, P<0.01) lower FEV1 and 51 mL (24-78, P<0.001) lower FVC.Conclusion: HIV is a risk factor for concurrently decreased FEV1 and FVC. This excess risk is not explained by smoking or socioeconomic status and may be mediated by prior immunodeficiency.Trial Registration Number: NCT02382822. [ABSTRACT FROM AUTHOR]

Background: Epidemiological studies have observed a positive association between an earlier age at sexual development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in adolescent boys in a Mendelian randomization (MR) approach.Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the PRACTICAL consortium (n = 43,737) as a replication sample.Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR) of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64-0.89). In an instrumental variable estimation of the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between pubertal boys of the same age) was associated with a 77 % (95 % CI, 43-91 %) reduced odds of high Gleason prostate cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs. localized cancer, per tertile: 0.95; 95 % CI, 0.91-1.00) and prostate cancer-specific mortality (hazard ratio amongst cases, per tertile: 0.94; 95 % CI, 0.90-0.98), but not with disease grade.Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially aggressive disease. [ABSTRACT FROM AUTHOR]

Background: Observational studies suggest that obesity is associated with increased risk of asthma. However, it is unknown whether this could be explained by wheezing. We tested the hypothesis that high body mass index (BMI) observationally and genetically is associated with high risk of wheezing and asthma, and that the association between high BMI and asthma is explained by wheezing.Methods: We genotyped 85,437 individuals aged 20-100 years from the Copenhagen General Population Study for FTO (rs9939609), MC4R (rs17782313), TMEM18 (rs6548238) GNPDA2 (rs10938397) and BDNF (rs10767664); 14,500 individuals experienced wheezing and 5406 had asthma. Wheezing was self-reported, and asthma was ascertained through self-report, hospital contacts with asthma, and/or receiving medication for asthma. BMI was calculated as measured weight divided by measured height squared (kg/m2).Results: In observational analyses versus BMI of 18.5-22.4 kg/m2, ORs for wheezing were 1.23 (95% CI 1.00 to 1.52) for BMI <18.5 kg/m2, 1.17 (1.10 to 1.25) for 22.5-24.9 kg/m2, 1.44 (1.35 to 1.54) for 25-27.4 kg/m2, 1.86 (1.73 to 1.99) for 27.5-29.9 kg/m2, 2.48 (2.31 to 2.66) for 30-34.9 kg/m(2), 3.86 (3.48 to 4.28) for 35-39.9 kg/m2 and 6.05 (5.12 to 7.14) for BMI ≥40 kg/m2. Corresponding ORs for asthma were 1.28 (0.95 to 1.74), 1.07 (0.97 to 1.17), 1.14 (1.04 to 1.25), 1.32 (1.20 to 1.46), 1.39 (1.25 to 1.54), 1.54 (1.31 to 1.81) and 1.99 (1.55 to 2.56), respectively. Compared with BMI allele score 0-4, scores 5, 6 and 7-10 were associated with 0.22, 0.51 and 0.76 kg/m2 higher BMI, respectively. Genetically determined ORs per unit higher BMI were 1.22 (1.15 to 1.31) for wheezing, 1.18 (1.10 to 1.27) for wheezing without asthma, 1.08 (0.98 to 1.19) for asthma, and 0.85 (0.73 to 0.99) for asthma without wheezing. Corresponding observational ORs were 1.09 (1.09 to 1.10), 1.09 (1.08 to 1.09), 1.03 (1.03 to 1.04) and 0.99 (0.98 to 1.00), respectively.Conclusions: High BMI was associated with high risk of wheezing without asthma, but not with high risk of asthma without wheezing. [ABSTRACT FROM AUTHOR]

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]

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: Guidelines recommend initiating primary prevention for atherosclerotic cardiovascular disease (ASCVD) with statins based on absolute ASCVD risk assessment. Recently, alternative trial-based and hybrid approaches were suggested for statin treatment eligibility.Objectives: This study compared these approaches in a direct head-to-head fashion in a contemporary population.Methods: The study used the CGPS (Copenhagen General Population Study) with 37,892 subjects aged 40 to 75 years recruited in 2003 to 2008, all free of ASCVD, diabetes, and statin use at baseline.Results: Among the population studied, 42% were eligible for statin therapy according to the 2013 American College of Cardiology/American Heart Association (ACC/AHA) risk assessment and cholesterol treatment guidelines approach, versus 56% with the trial-based approach and 21% with the hybrid approach. Among these statin-eligible subjects, the ASCVD event rate per 1,000 person-years was 9.8, 6.8, and 11.2, respectively. The ACC/AHA-recommended absolute risk score was well calibrated around the 7.5% 10-year ASCVD risk treatment threshold and discriminated better than the trial-based or hybrid approaches. Compared with the ACC/AHA risk-based approach, the net reclassification index for eligibility for statin therapy among 40- to 75-year-old subjects from the CGPS was -0.21 for the trial-based approach and -0.13 for the hybrid approach.Conclusions: The clinical performance of the ACC/AHA risk-based approach for primary prevention of ASCVD with statins was superior to the trial-based and hybrid approaches. Our results indicate that the ACC/AHA guidelines will prevent more ASCVD events than the trial-based and hybrid approaches, while treating fewer people compared with the trial-based approach. [ABSTRACT FROM AUTHOR]

Background: Increased levels of the inflammatory biomarker high-sensitivity C-reactive protein predict cardiovascular events. Since statins lower levels of high-sensitivity C-reactive protein as well as cholesterol, we hypothesized that people with elevated high-sensitivity C-reactive protein levels but without hyperlipidemia might benefit from statin treatment.Methods: We randomly assigned 17,802 apparently healthy men and women with low-density lipoprotein (LDL) cholesterol levels of less than 130 mg per deciliter (3.4 mmol per liter) and high-sensitivity C-reactive protein levels of 2.0 mg per liter or higher to rosuvastatin, 20 mg daily, or placebo and followed them for the occurrence of the combined primary end point of myocardial infarction, stroke, arterial revascularization, hospitalization for unstable angina, or death from cardiovascular causes.Results: The trial was stopped after a median follow-up of 1.9 years (maximum, 5.0). Rosuvastatin reduced LDL cholesterol levels by 50% and high-sensitivity C-reactive protein levels by 37%. The rates of the primary end point were 0.77 and 1.36 per 100 person-years of follow-up in the rosuvastatin and placebo groups, respectively (hazard ratio for rosuvastatin, 0.56; 95% confidence interval [CI], 0.46 to 0.69; P<0.00001), with corresponding rates of 0.17 and 0.37 for myocardial infarction (hazard ratio, 0.46; 95% CI, 0.30 to 0.70; P=0.0002), 0.18 and 0.34 for stroke (hazard ratio, 0.52; 95% CI, 0.34 to 0.79; P=0.002), 0.41 and 0.77 for revascularization or unstable angina (hazard ratio, 0.53; 95% CI, 0.40 to 0.70; P<0.00001), 0.45 and 0.85 for the combined end point of myocardial infarction, stroke, or death from cardiovascular causes (hazard ratio, 0.53; 95% CI, 0.40 to 0.69; P<0.00001), and 1.00 and 1.25 for death from any cause (hazard ratio, 0.80; 95% CI, 0.67 to 0.97; P=0.02). Consistent effects were observed in all subgroups evaluated. The rosuvastatin group did not have a significant increase in myopathy or cancer but did have a higher incidence of physician-reported diabetes.Conclusions: In this trial of apparently healthy persons without hyperlipidemia but with elevated high-sensitivity C-reactive protein levels, rosuvastatin significantly reduced the incidence of major cardiovascular events. (ClinicalTrials.gov number, NCT00239681.) [ABSTRACT FROM AUTHOR]

Background: The high-density lipoprotein hypothesis of atherosclerosis has been challenged by clinical trials of cholesteryl ester transfer protein (CETP) inhibitors, which failed to show significant reductions in cardiovascular events. Plasma levels of high-density lipoprotein cholesterol (HDL-C) decline drastically during sepsis, and this phenomenon is explained, in part, by the activity of CETP, a major determinant of plasma HDL-C levels. We tested the hypothesis that genetic or pharmacological inhibition of CETP would preserve high-density lipoprotein levels and decrease mortality in clinical cohorts and animal models of sepsis.Methods: We examined the effect of a gain-of-function variant in CETP (rs1800777, p.Arg468Gln) and a genetic score for decreased CETP function on 28-day sepsis survival using Cox proportional hazard models adjusted for age and sex in the UK Biobank (n=5949), iSPAAR (Identification of SNPs Predisposing to Altered Acute Lung Injury Risk; n=882), Copenhagen General Population Study (n=2068), Copenhagen City Heart Study (n=493), Early Infection (n=200), St Paul's Intensive Care Unit 2 (n=203), and Vasopressin Versus Norepinephrine Infusion in Patients With Septic Shock studies (n=632). We then studied the effect of the CETP inhibitor, anacetrapib, in adult female APOE*3-Leiden mice with or without human CETP expression using the cecal-ligation and puncture model of sepsis.Results: A fixed-effect meta-analysis of all 7 cohorts found that the CETP gain-of-function variant was significantly associated with increased risk of acute sepsis mortality (hazard ratio, 1.44 [95% CI, 1.22-1.70]; P<0.0001). In addition, a genetic score for decreased CETP function was associated with significantly decreased sepsis mortality in the UK Biobank (hazard ratio, 0.77 [95% CI, 0.59-1.00] per 1 mmol/L increase in HDL-C) and iSPAAR cohorts (hazard ratio, 0.60 [95% CI, 0.37-0.98] per 1 mmol/L increase in HDL-C). APOE*3-Leiden.CETP mice treated with anacetrapib had preserved levels of HDL-C and apolipoprotein-AI and increased survival relative to placebo treatment (70.6% versus 35.3%, Log-rank P=0.03), whereas there was no effect of anacetrapib on the survival of APOE*3-Leiden mice that did not express CETP (50.0% versus 42.9%, Log-rank P=0.87).Conclusions: Clinical genetics and humanized mouse models suggest that inhibiting CETP may preserve high-density lipoprotein levels and improve outcomes for individuals with sepsis. [ABSTRACT FROM AUTHOR]

Background: Plasma apolipoprotein B (apoB) is a composite measure of all apoB-containing lipoproteins causing atherosclerotic cardiovascular disease; however, it is unclear which fraction of risk is explained by cholesterol and triglycerides, respectively, in very low-density lipoproteins (VLDLs).Objectives: The authors tested the hypothesis that VLDL cholesterol and triglycerides each explain part of the myocardial infarction risk from apoB-containing lipoproteins.Methods: Nested within 109,751 individuals from the Copenhagen General Population Study, the authors examined 25,480 subjects free of lipid-lowering therapy and myocardial infarction at study entry. All had measurements of plasma apoB (quantitating number of apoB-containing lipoproteins) and cholesterol and triglyceride content of VLDL, intermediate-density lipoproteins (IDLs), and low-density lipoproteins (LDLs).Results: During a median 11 years of follow-up, 1,816 were diagnosed with myocardial infarction. Per 1-mmol/l higher levels, multivariable-adjusted hazard ratios for myocardial infarction were 2.07 (95% confidence interval [CI]: 1.81 to 2.36) for VLDL cholesterol, 1.19 (95% CI: 1.14 to 1.25) for VLDL triglycerides, 5.38 (95% CI: 3.73 to 7.75) for IDL cholesterol, and 1.86 (95% CI: 1.62 to 2.14) for LDL cholesterol. Per 1-g/l higher plasma apoB, the corresponding value was 2.21 (95% CI: 1.90 to 2.58). In a step-up Cox regression, risk factors for myocardial infarction entered by importance as VLDL cholesterol, systolic blood pressure, smoking, and IDL + LDL cholesterol, whereas VLDL triglycerides did not enter the model. VLDL cholesterol explained 50% and IDL + LDL cholesterol 29% of the risk of myocardial infarction from apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk.Conclusions: VLDL cholesterol explained one-half of the myocardial infarction risk from elevated apoB-containing lipoproteins, whereas VLDL triglycerides did not explain risk. [ABSTRACT FROM AUTHOR]

Background: Despite the greater prevalence of familial hypercholesterolemia (FH) in subjects with ischemic heart disease (IHD), premature IHD, and severe hypercholesterolemia (low-density lipoprotein ≥190 mg/dl), overall prevalence estimates are not available.Objectives: The aim of this study was to provide worldwide estimates of FH prevalence in subjects with IHD, premature IHD, and severe hypercholesterolemia compared with those in the general population.Methods: In this systematic review and meta-analyses, Embase, PubMed, and the Web of Science were searched until June 3, 2019, for peer-reviewed papers and conference abstracts reporting heterozygous FH prevalence in nonfounder populations, revealing 104 studies eligible for inclusion.Results: Estimates of FH prevalence were pooled using random-effects meta-analyses and were 0.32% (95% confidence interval [CI]: 0.26% to 0.39% [corresponding to 1:313]) among 10,921,310 unique subjects in the general population (33,036 patients with FH) on the basis of 44 studies, 3.2% (95% CI: 2.2% to 4.3% [1:31]) among 84,479 unique subjects with IHD (2,103 patients with FH) on the basis of 28 studies, 6.7% (95% CI: 4.9% to 8.7% [1:15]) among 31,316 unique subjects with premature IHD (1,471 patients with FH) on the basis of 32 studies, and 7.2% (95% CI: 4.6% to 10.8% [1:14]) among 17,728 unique subjects with severe hypercholesterolemia (920 patients with FH) on the basis of 7 studies. FH prevalence in the general population was similar using genetic versus clinical diagnoses. Seventeen of 195 countries (9%) in the world have reported FH prevalence for the general population, leaving 178 (91%) countries in the world with unknown prevalence.Conclusions: Compared with 1:313 among subjects in the general population, FH prevalence is 10-fold higher among those with IHD, 20-fold higher among those with premature IHD, and 23-fold higher among those with severe hypercholesterolemia. The prevalence of FH is unknown in 90% of countries in the world. [ABSTRACT FROM AUTHOR]

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]

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]