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Aims Whether high body mass index (BMI) causally influences development and prognosis of heart failure has implications for clinical practice. We tested the hypotheses that high BMI causally influences heart failure incidence and mortality. Methods and results Using observational and Mendelian randomization causal, genetic analyses, we studied 106 121 individuals from the Copenhagen General Population Study, 18 407 from the Copenhagen City Heart Study, and 977 323 from publicly available databases. In observational analyses in the Copenhagen studies with 10 years of median follow-up, multivariable adjusted hazard ratios per 1 kg/m2 increment of BMI were 1.06 (95% confidence interval: 1.05–1.07; P < 0.001; n = 124 528; events = 6589) for heart failure incidence, 1.04 (1.03–1.06; P < 0.001; n = 124 528; events = 1237) for heart failure mortality, and 1.01 (1.00–1.01; P < 0.001; n = 124 528; events = 24 144) for all-cause mortality. In genetic analyses in the Copenhagen studies, the age and sex adjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.19 (1.05–1.36; P = 0.008; n = 118 200; events = 6541) for heart failure incidence, 1.27 (0.82–1.98; P = 0.28; n = 118 200; events = 889) for heart failure mortality, and 1.11 (1.02–1.22; P = 0.022; n = 118 200; events = 16 814) for all-cause mortality. Finally, combining genetic data from the Copenhagen studies, the Genetic Investigation of ANthropometric Traits, the Heart Failure Molecular Epidemiology for Therapeutic Targets, and the UK Biobank, the unadjusted causal risk ratios per 1 kg/m2 increment of BMI were 1.39 (1.27–1.52; P < 0.001; n = 1 095 523; events = 53 850) for heart failure incidence, 1.18 (1.00–1.38; P = 0.05; n = 576 853; events = 2373) for heart failure mortality, and 1.02 (1.00–1.04; P = 0.03; n = 576 853; events = 44 734) for all-cause mortality. Conclusion High BMI causally increases the risk of both heart failure incidence and mortality. [ABSTRACT FROM AUTHOR]

Background: A deteriorating effect of severe alpha(1)-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain.Objective: To test the hypothesis that MZ intermediate alpha(1)-antitrypsin deficiency affects pulmonary function and disease.Design: Population-based cohort study with 21-year follow-up.Setting: Copenhagen, Denmark.Participants: 9187 adults randomly selected from the Danish general population.Measurements: Plasma alpha(1)-antitrypsin levels, annual decrease in FEV(1), airway obstruction, and hospitalization and mortality from chronic obstructive pulmonary disease (COPD).Results: 451 participants (4.9%) carried the MZ genotype. Plasma alpha(1)-antitrypsin levels were 31% lower in MZ heterozygotes than in persons with the MM genotype (Student t -test, P < 0.001). Annual decrease in FEV(1) was 25 mL in MZ heterozygotes and 21 mL in persons with the MM genotype (t -test, P = 0.048). Airway obstruction was found in 19% of MZ heterozygotes compared with 15% of MM carriers (chi-square test, P = 0.023); in a logistic regression analysis adjusted for age, sex, and tobacco consumption, the corresponding odds ratio was 1.3 (CI, 1.0 to 1.7). The incidence of hospitalization and mortality from COPD was 32 cases per 10 000 person-years in persons with the MZ genotype and 22 cases per 10 000 person-years in those with the MM genotype (log-rank test, P = 0.063). In a Cox regression model adjusted for age, sex, tobacco use, and FEV(1) at study entry, relative risk for COPD outcomes in persons with the MZ genotype versus persons with the MM genotype was 1.5 (CI, 1.0 to 2.3). All these results were independent of the S and E alleles in this gene and were not affected by cystic fibrosis Delta F508 heterozygosity.Conclusions: MZ heterozygotes had a slightly greater rate of decrease in FEV(1) and were modestly over-represented among persons with airway obstruction and COPD. In the population at large, MZ heterozygosity may account for a fraction of COPD cases---on the order of 2%, similar to the percentage of persons with COPD who have the severe but rare ZZ genotype. [ABSTRACT FROM AUTHOR]

Background Recent meta-analyses have suggested that short telomere length was associated with increased risk of cancer. We therefore tested the hypotheses that short telomere length was associated with increased risk of cancer and with increased risk of early death after cancer. Methods We measured leukocyte telomere length in a prospective study of 47 102 Danish general population participants from the Copenhagen City Heart Study and the Copenhagen General Population Study. Participants were followed for up to 20 years for cancer diagnosis and death. Follow-up was 100% complete. All statistical tests were two-sided. Results Telomere length decreased linearly with increasing age (P <.001). During follow-up, we observed 3142 first cancers and, among these individuals, 1730 deaths. Decreasing quartiles of telomere length were associated with decreasing survival after cancer (log-rank P <.001). Multivariable-adjusted hazard ratios of early death were 1.31 (95% confidence interval [CI] = 1.14 to 1.52) in individuals in the quartile and 1.43 (95% CI = 1.13 to 1.80) in individuals in the decile with the shortest telomeres vs the longest. Unadjusted hazard ratios of cancer risk were 1.74 (95% CI = 1.58 to 1.93) and 2.00 (95% CI = 1.70 to 2.35) in individuals in the quartile and decile with the shortest vs longest telomeres; however, multivariable adjustment changed these hazard ratios to 0.98 (95% CI = 0.88 to 1.08) and 0.95 (95% CI = 0.80 to 1.11), mainly because of age adjustment. Conclusions Short telomere length is associated with reduced survival after cancer but not with cancer risk. The latter contrasts with findings from recent meta-analyses. [ABSTRACT FROM AUTHOR]

Background: Adiposity, assessed as elevated body mass index (BMI), is associated with increased risk of ischemic heart disease (IHD); however, whether this is causal is unknown. We tested the hypothesis that positive observational associations between BMI and IHD are causal. Methods and Findings: In 75,627 individuals taken from two population-based and one case-control study in Copenhagen, we measured BMI, ascertained 11,056 IHD events, and genotyped FTO(rs9939609), MC4R(rs17782313), and TMEM18(rs6548238). Using genotypes as a combined allele score in instrumental variable analyses, the causal odds ratio (OR) between BMI and IHD was estimated and compared with observational estimates. The allele score-BMI and the allele score-IHD associations used to estimate the causal OR were also calculated individually. In observational analyses the OR for IHD was 1.26 (95% CI 1.19-1.34) for every 4 kg/m² increase in BMI. A one-unit allele score increase associated with a 0.28 kg/m² (95 CI% 0.20-0.36) increase in BMI and an OR for IHD of 1.03 (95% CI 1.01-1.05) (corresponding to an average 1.68 kg/m² BMI increase and 18% increase in the odds of IHD for those carrying all six BMI increasing alleles). In instrumental variable analysis using the same allele score the causal IHD OR for a 4 kg/m² increase in BMI was 1.52 (95% CI 1.12-2.05). Conclusions: For every 4 kg/m² increase in BMI, observational estimates suggested a 26% increase in odds for IHD while causal estimates suggested a 52% increase. These data add evidence to support a causal link between increased BMI and IHD risk, though the mechanism may ultimately be through intermediate factors like hypertension, dyslipidemia, and type 2 diabetes. This work has important policy implications for public health, given the continuous nature of the BMI-IHD association and the modifiable nature of BMI. This analysis demonstrates the value of observational studies and their ability to provide unbiased results through inclusion of genetic data avoiding confounding, reverse causation, and bias. [ABSTRACT FROM AUTHOR]

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

Background: The M235T and T174M angiotensinogen mutations have been linked to increased risk for ischemic heart and cerebrovascular disease.Objective: To determine whether angiotensinogen mutations are associated with ischemic heart disease, myocardial infarction, and ischemic cerebrovascular disease.Design: Six case-control studies from the Copenhagen City Heart Study.Setting: Copenhagen, Denmark.Participants: Participants in the Copenhagen City Heart Study and patients from the same hospital with ischemic heart disease (n = 866 and n = 943, respectively), myocardial infarction (n = 519 and n = 493, respectively), or ischemic cerebrovascular disease (n = 489 and n = 434, respectively) and 7975 controls without these conditions.Measurements: Genotypes for the M235T and T174M angiotensinogen mutations were compared between controls and Copenhagen City Heart Study participants with ischemic heart disease, myocardial infarction, and cerebrovascular disease (studies 1a, 1b, and 1c) and patients from Copenhagen University Hospital with the same conditions (studies 2a, 2b, and 2c).Results: Relative allele frequencies of 235T and 174M in the general population were 0.41 and 0.12, respectively. Genotype was not associated with increased risk for ischemic heart or ischemic cerebrovascular disease in studies of either mutation alone or combined in women or men. Among compound heterozygotes (235MT /174TM ), women in case-control study 2a had decreased risk for ischemic heart disease in age-adjusted analysis; however, this decreased risk was not seen in multifactorial-adjusted or matched analyses, in men, or in case-control study 1a. Among double homozygotes (235TT /174MM ), women in case-control study 2b had increased risk for myocardial infarction in matched analysis; however, this increased risk was not seen in age- or multifactorial-adjusted analyses, in men, or in case-control study 1b. Among single homozygotes (235TT /174TT ), men in case-control study 2b had increased risk for myocardial infarction in multifactorial-adjusted and matched analyses. This risk was not present in age-adjusted analysis, in women, or in case-control study 1b. In addition, male single homozygotes had decreased risk for ischemic cerebrovascular disease in case-control study 2c in age- and multifactorial-adjusted analyses, but this finding was not seen in matched analysis, in women, or in case-control study 1c.Conclusions: In six large case-control studies, the M235T and T174M angiotensinogen mutations were not consistently associated with increased (or decreased) risk for ischemic heart disease, myocardial infarction, or ischemic cerebrovascular disease. Statistically significant associations may represent chance findings rather than real phenomena. [ABSTRACT FROM AUTHOR]

Background: Low-density lipoprotein cholesterol (LDL-C) is causally associated with a high risk of coronary artery disease. Whether this also holds for a spectrum of peripheral vascular diseases is unknown.Objectives: The purpose of this study was to determine whether high LDL-C causally relates to risk of retinopathy, neuropathy, chronic kidney disease (CKD), and peripheral arterial disease (PAD) in the general population.Methods: One-sample Mendelian randomization (MR) of 116,419 Danish individuals, 2-sample MR on summary-level data from the Global Lipid Genetics Consortium (GLGC) (n = 94,595) and the UK Biobank (n = 408,455), and meta-analysis of randomized statin trials (n = 64,134) were performed.Results: Observationally, high LDL-C did not associate with high risk of retinopathy or neuropathy. There were stepwise increases in risk of CKD and PAD with higher LDL-C (both p for trend <0.001), with hazard ratios of 1.05 (95% confidence interval [CI]: 0.97 to 1.13) for CKD, and 1.41 (95% CI: 1.23 to 1.62) for PAD in individuals with LDL-C above the 95th percentile versus below the 50th percentile. In genetic, causal analyses in the Copenhagen studies, the risk ratio of disease for a 1 mmol/l higher LDL-C was 1.06 (95% CI: 0.24 to 4.58) for retinopathy, 1.05 (95% CI: 0.64 to 1.72) for neuropathy, 3.83 (95% CI: 2.00 to 7.34) for CKD, and 2.09 (95% CI: 1.30 to 2.38) for PAD. Summary-level data from the GLGC and the UK Biobank for retinopathy, neuropathy, and PAD gave similar results. For CKD, a 1-mmol/l lower LDL-C conferred a higher eGFR of 1.95 ml/min/1.73 m2 (95% CI: 1.88 to 2.02 ml/min/1.73 m2) observationally, 5.92 ml/min/1.73 m2 (95% CI: 4.97 to 6.86 ml/min/1.73 m2) genetically, and 2.69 ml/min/1.73 m2 (95% CI: 1.48 to 3.94 ml/min/1.73 m2) through statin therapy.Conclusions: High LDL-C was not causally associated with risk of retinopathy and neuropathy; however, high LDL-C was observationally and genetically associated with high risks of PAD and CKD, suggesting that LDL-C is causally involved in the pathogenesis of these diseases. [ABSTRACT FROM AUTHOR]