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. 2019 Jun 1;48(3):912-925.
doi: 10.1093/ije/dyy230.

Exploring causality of the association between smoking and Parkinson's disease

Valentina Gallo  1   2   3 , Paolo Vineis  2 , Mariagrazia Cancellieri  1   4   5 , Paolo Chiodini  6 , Roger A Barker  7 , Carol Brayne  7 , Neil Pearce  3 , Roel Vermeulen  8   9 , Salvatore Panico  10 , Bas Bueno-de-Mesquita  2   11   12   13 , Nicola Vanacore  14 , Lars Forsgren  15 , Silvia Ramat  16 , Eva Ardanaz  17   18 , Larraitz Arriola  18   19   20 , Jesper Peterson  21 , Oskar Hansson  22 , Diana Gavrila  18   23 , Carlotta Sacerdote  24   25 , Sabina Sieri  26 , Tilman Kühn  27 , Verena A Katzke  27 , Yvonne T van der Schouw  8 , Andreas Kyrozis  28   29 , Giovanna Masala  30 , Amalia Mattiello  10 , Robert Perneczky  2   31   32   33 , Lefkos Middleton  2 , Rodolfo Saracci  34 , Elio Riboli  2
Affiliations

Exploring causality of the association between smoking and Parkinson's disease

Valentina Gallo et al. Int J Epidemiol. .

Abstract

Background: The aim of this paper is to investigate the causality of the inverse association between cigarette smoking and Parkinson's disease (PD). The main suggested alternatives include a delaying effect of smoking, reverse causality or an unmeasured confounding related to a low-risk-taking personality trait.

Methods: A total of 715 incident PD cases were ascertained in a cohort of 220 494 individuals from NeuroEPIC4PD, a prospective European population-based cohort study including 13 centres in eight countries. Smoking habits were recorded at recruitment. We analysed smoking status, duration, and intensity and exposure to passive smoking in relation to PD onset.

Results: Former smokers had a 20% decreased risk and current smokers a halved risk of developing PD compared with never smokers. Strong dose-response relationships with smoking intensity and duration were found. Hazard ratios (HRs) for smoking <20 years were 0.84 [95% confidence interval (CI) 0.67-1.07], 20-29 years 0.73 (95% CI 0.56-0.96) and >30 years 0.54 (95% CI 0.43-0.36) compared with never smokers. The proportional hazard assumption was verified, showing no change of risk over time, arguing against a delaying effect. Reverse causality was disproved by the consistency of dose-response relationships among former and current smokers. The inverse association between passive smoking and PD, HR 0.70 (95% CI 0.49-0.99) ruled out the effect of unmeasured confounding.

Conclusions: These results are highly suggestive of a true causal link between smoking and PD, although it is not clear which is the chemical compound in cigarette smoking responsible for the biological effect.

Keywords: EPIC; NeuroEPIC4PD; Parkinson’s disease; causal inference; cohort study; passive smoking; smoking; smoking patterns.

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Figures

Figure 1.
Figure 1.
Direct Acyclic Graphs (DAGs) showing the hypotheses on the observed association between cigarette smoking and Parkinson’s disease. (A) Smoking protects against PD (causal effect); (B) smoking delays PD onset; (C) subjects with a specific personality trait are both less likely to smoke and more susceptible to PD (confounding effect); (D) subtle dopaminergic changes before disease onset make quitting smoking easier (reverse causality).
Figure 2.
Figure 2.
Analysis of the residuals of Schoenfeld residuals to assess the proportionality assumption comparing former smokers (A) and current smokers (B) with never smokers. Figures represent plots of beta-coefficient estimates (log hazard ratios) for former smokers (A) and current smokers (B) against follow-up (time) in years. The darker (blue) line represents a smoothed curve of scaled Shoenfeld residuals with 95% confidence intervals (darker (blue) dotted lines), whereas the lighter (red) line represents a beta-coefficient estimate from a Cox-regression model.
Figure 3.
Figure 3.
HRs and relative 95% CIs for smoking duration (A) and intensity (B) among former (continuous line) and current (dashed line) smokers at recruitment in the EPIC study.
See this image and copyright information in PMC

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