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

Gallo V 1 , Vineis P 2 , Cancellieri M 1 , Chiodini P 3 , Barker RA 4 , Brayne C 4 Show all authors , Pearce N 5 , Vermeulen R 6 , Panico S 7 , Bueno-de-Mesquita B 2 , Vanacore N 8 , Forsgren L 9 , Ramat S 10 , Ardanaz E 11 , Arriola L 12 , Peterson J 13 , Hansson O 14 , Gavrila D 12 , Sacerdote C 15 , Sieri S 16 , Kühn T 17 , Katzke VA 17 , van der Schouw YT 6 , Kyrozis A 18 , Masala G 19 , Mattiello A 7 , Perneczky R 2 , Middleton L 2 , Saracci R 20 , Riboli E 2

Affiliations 

  • 1 Centre for Primary Care and Public Health, Blizard Institute, Queen Mary University of London, London, UK
  • 2 School of Public Health, Imperial College London, London, UK
  • 3 Medical Statistics Unit, University of Campania 'Luigi Vanvitelli', Naples, Italy
  • 4 Institute of Public Health, University of Cambridge, Cambridge, UK
  • 5 Epidemiology and Medical Statistics Unit, London School of Hygiene and Tropical Medicine, London, UK
  • 6 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
  • 7 Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy
  • 8 National Centre for Disease Prevention and Health Promotion, Italian National Institute of Health, Rome, Italy
  • 9 Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden
  • 10 Department of Neuroscience, Psychology, Drug Research, and Child Health, University of Florence, Careggi Hospital-University, Florence, Italy
  • 11 Navarra Public Health Institute, IdiSNA, Pamplona, Spain
  • 12 CIBER Epidemiology and Public Health, CIBERESP, Madrid, Spain
  • 13 Department of Neurology, Lund University, Lund, Sweden
  • 14 Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, Lund, Sweden
  • 15 Unit of Cancer Epidemiology, Centre for Cancer Prevention (CPO-Piemonte), Turin, Italy
  • 16 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
  • 17 Division of Cancer Epidemiology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
  • 18 Hellenic Health Foundation, Athens, Greece
  • 19 Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research, Prevention, and Clinical Network (ISPRO), Florence, Italy
  • 20 International Agency for Research on Cancer (IARC), Lyon, France
Int J Epidemiol, 2019 Jun 01;48(3):912-925.
PMID: 30462234 DOI: 10.1093/ije/dyy230

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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