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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: Results regarding telomere length and cancer risk are conflicting. We tested the hypothesis that long telomeres are associated with increased risk of any cancer and specific cancer types in genetic and observational analyses.Methods: Individuals (N = 95 568) from the Copenhagen City Heart Study and the Copenhagen General Population Study had the telomere length-associated genotypes rs7726159 (TERT), rs1317082 (TERC), and rs2487999 (OBFC1) determined, and 65 176 had telomere length measured. A total of 10 895 individuals had had a cancer diagnosis. Endpoints were any cancer and 25 specific cancer types. We conducted Cox regression analyses and logistic regression analyses. The three genotypes were combined as an allele sum.Results: Telomere length increased 67 base-pairs [95% confidence interval (CI) 61-74] per allele. In logistic regression models, the per-allele odds ratio (OR) for cancer was 1.05 (95% CI 1.03-1.07) for the allele sum, 1.05 (1.02-1.09) for rs7726159, 1.05 (1.02-1.08) for rs1317082 and 1.07 (1.02-1.12) for rs2487999. In contrast, the hazard ratio for any cancer was 1.01 (1.00-1.01) per 200-base-pair increase in telomere length in multivariable adjusted observational analysis. In genetic analyses according to specific cancer types, the per-allele odds ratio was 1.19 (1.12-1.27) for melanoma and 1.14 (1.06-1.22) for lung cancer.Conclusions: Genetic determinants of long telomeres are associated with increased cancer risk, particularly melanoma and lung cancer. This genetic predisposition to enhanced telomere maintenance may represent a survival advantage for pre-cancerous cells, allowing for multiple cell divisions leading to cancer development. [ABSTRACT FROM AUTHOR]

Background: In the clinic, the combination of obesity and chronic obstructive pulmonary disease (COPD) has been increasing. However, whether high body mass index (BMI) affects the risk of exacerbations and pneumonias in individuals with COPD is presently unknown. Genetics can be used to assess the causal role of high BMI in exacerbations and pneumonias in individuals with COPD. We tested the hypothesis that high BMI is associated with an increased risk of exacerbations and pneumonias in individuals with COPD, both observationally and genetically.Methods: We genotyped 93 894 individuals of Danish descent, aged 20-100 years, from the Copenhagen General Population Study, for FTO (rs9939609), MC4R (rs17782313) and TMEM18 (rs6548238), and created an allele score. A total of 10 883 individuals had spirometric COPD with forced expiratory volume in 1 s (FEV1) / forced vital capacity (FVC) < lower limit of normal (LLN). In these individuals, we observed 1453 exacerbations and 3390 pneumonias during 4.7 years of follow-up.Results: For each increase in allele score, BMI was 0.28 kg/m2 [95% confidence interval (CI): 0.25-0.30) higher. Age- and sex-adjusted genetic hazard ratios (HRs) per one allele score increase in individuals with COPD were 1.13 (1.01-1.27) for exacerbations, 1.10 (1.03-1.19) for pneumonias and 1.12 (1.04-1.21) for exacerbations and/or pneumonias. Corresponding multivariable adjusted observational HRs per unit (kg/m2) BMI increase were 0.98 (0.95-1.01), 0.99 (0.96-1.03) and 0.99 (0.96-1.01), respectively.Conclusions: Genetically determined high BMI was associated with an increased risk of recurrent exacerbations and pneumonias in individuals with COPD, whereas this was not the case for observationally determined high BMI. The genetic data are compatible with the notion that high BMI leads to increased risk of exacerbations and pneumonias in individuals with COPD. [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]