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Aims It is unclear whether higher triglyceride metabolism per se contributes to mortality separate from elevated triglyceride-rich lipoproteins and body mass index. This study tested the hypotheses that higher triglyceride metabolism, measured as higher plasma glycerol and β-hydroxybutyrate, is associated with increased all-cause, cardiovascular, cancer, and other mortality. Methods and results This study included 30 000 individuals nested within 109 751 individuals from the Copenhagen General Population Study. During a median follow-up of 10.7 years, 9897 individuals died (2204 from cardiovascular, 3366 from cancer, and 2745 from other causes), while none were lost to follow-up. In individuals with glycerol >80 µ mol/L (highest fourth) vs. individuals with glycerol <52 µ mol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.31 (95% confidence interval 1.22–1.40). In individuals with β-hydroxybutyrate >154 µ mol/L (highest fourth) vs. individuals with β-hydroxybutyrate <91 µ mol/L (lowest fourth), the multivariable adjusted hazard ratio for all-cause mortality was 1.18 (1.11–1.26). Corresponding values for higher plasma glycerol and β-hydroxybutyrate were 1.37 (1.18–1.59) and 1.18 (1.03–1.35) for cardiovascular mortality, 1.24 (1.11–1.39) and 1.16 (1.05–1.29) for cancer mortality, and 1.45 (1.28–1.66) and 1.23 (1.09–1.39) for other mortality, respectively. Results were robust to exclusion of first years of follow-up, to stratification for covariates including plasma triglycerides and body mass index, and to further adjustments. Conclusion This study observed an increased risk of all-cause, cardiovascular, cancer, and other mortality with higher triglyceride metabolism. This was not explained by higher plasma triglycerides and body mass index. The hypothesis studied in the present paper should be further validated by isotope flux studies. [ABSTRACT FROM AUTHOR]

Aims Recent evidence suggest that the lipoprotein(a)-associated risk of atherosclerotic cardiovascular disease (ASCVD) may be observed only in individuals with low-grade systemic inflammation. It was hypothesized that high lipoprotein(a) is a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis irrespective of C-reactive protein levels. Methods and results A total of 68 090 individuals from the Copenhagen General Population Study, a prospective cohort study, were included. During a median follow-up of 8.1 years, 5104 individuals developed ASCVD, 2432 myocardial infarction, and 1220 aortic valve stenosis. The risk of ASCVD, myocardial infarction, and aortic valve stenosis increased with higher values of both lipoprotein(a) and C-reactive protein. For individuals with lipoprotein(a) in the 91st–100th percentiles (≥70 mg/dl, ≥147 nmol/l) vs. the 1st–33rd percentiles (≤6 mg/dl, ≤9 nmol/l), the multivariable-adjusted hazard ratio for ASCVD was 1.61 (95% confidence interval 1.43–1.81) for those with C-reactive protein <2 mg/l and 1.57 (1.36–1.82) for those with C-reactive protein ≥2 mg/l (P for interaction = 0.87). The corresponding values were 2.08 (1.76–2.45) and 1.65 (1.34–2.04) for myocardial infarction, and 2.01 (1.59–2.55) and 1.73 (1.31–2.27) for aortic valve stenosis, respectively (P for interaction = 0.15 and = 0.18). The highest absolute 10-year risks were found in men aged 70–79 years with lipoprotein(a) levels in the 91st–100th percentiles and C-reactive protein ≥2 mg/l, with 34% for ASCVD, 19% for myocardial infarction, and 13% for aortic valve stenosis. The corresponding values in women were 20%, 10%, and 8%, respectively. Conclusion High lipoprotein(a) was a main driver for the risk of ASCVD, myocardial infarction, and aortic valve stenosis independent of C-reactive protein levels. [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]