Search

Background: Smoking is strongly associated with higher risk of psoriasis in several observational studies; however, whether this association is causal or can be explained by confounding or reverse causation is not fully understood. Randomized controlled trials are the gold standard when examining causality; however, when this method is not feasible, the Mendelian randomization design is an alternative. Herein genetic variants can be used as robust proxies for modifiable exposures and thereby avoiding confounding and reverse causation.In this study, we hypothesized that smoking is an independent and causal risk factor for psoriasis and tested this using a Mendelian randomization design., Methods: We used data from the Copenhagen General Population Study including 105,912 individuals with full information on lifestyle factors, biochemistry, and genotype data. In total, 1,240 cases of moderate to severe psoriasis were included to investigate the association between smoking and psoriasis. To assess causality of the association, we used the genetic variant CHRNA3 rs1051730, where the T-allele is strongly associated with high lifelong cumulative smoking, as a proxy for smoking., Results: In observational analyses, the multivariable adjusted hazard ratio of developing moderate to severe psoriasis was 1.64 (95% confidence interval: 1.35-2.00) in ever smokers with ≤ 20 pack-years and 2.23 (1.82-2.73) in ever smokers with > 20 pack-years compared to never smokers. In genetic analyses, the odds ratio of developing moderate to severe psoriasis was 1.05 (0.95-1.16) per CHRNA3 rs10511730 T-allele in ever smokers., Conclusion: Smoking was an independent risk factor for moderate to severe psoriasis in observational analyses. However, using a genetic variant as a robust proxy for smoking, we did not find this association to be causal., Competing Interests: CN-K has served as an investigator for Galderma, Abbvie, LEO Pharma, and CSL Behring. LS has served as an investigator for AbbVie, Pfizer, Sanofi, Janssen Cilag, Boehringer Ingelheim, AstraZeneca, Eli Lilly, Novartis, Regeneron, Galderma and LEO Pharma. LS has received research funding from Novartis, Bristol-Myers Squibb, AbbVie, Janssen Pharmaceuticals, the Danish National Psoriasis Foundation, the LEO Foundation, and the Kgl Hofbundtmager Aage Bang Foundation, and honoraria as consultant and/or speaker for AbbVie, Eli Lilly, Novartis, Pfizer, and LEO Pharma, Janssen Cilag, UCB, Almirall, Bristol-Myers Squibb, and Sanofi. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Näslund-Koch, Vedel-Krogh, Bojesen and Skov.)

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., (© The Author(s) 2018. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)