Exploring causality of the association between smoking and Parkinson's disease
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 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. ; Mortality data from the Netherlands are obtained from "Statistics Netherlands". In addition we would like to thank for their financial support: Europe Against cancer Program of the European Commission (SANCO); ISCIII, Red de Centros RCESP, C03/09; Spanish Ministry of Health (ISCIII RETICC RD06/0020); Deutsche Krebshilfe; Deutsches Krebsforschungszentrum; German Federal Ministry of Education and Research; Danish Cancer Society; Health Research Fund (FIS) of the Spanish Ministry of Health; Spanish Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra; Spanish Ministry of Health (ISCIII RETICC RD06/0020)Cancer Research U.K.; Medical Research Council, United Kingdom; Stroke Association, United Kingdom; National Institute of Health Research funding of a Biomedical Research Centre in Cambridge ; British Heart Foundation; Department of Health, United Kingdom; Food Standards Agency, United Kingdom; Wellcome Trust, United Kingdom Greek Ministry of Health; Greek Ministry of Education; Italian Association for Research on Cancer (AIRC); Italian National Research Council; Dutch Ministry of Public Health, Welfare and Sports (VWS); Netherlands Cancer Registry (NKR); LK Research Funds; Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland); World Cancer Research Fund (WCRF); Statistics Netherlands (The Netherlands); Swedish Cancer; Swedish Research Council; European Research Council, Regional Government of Skåne and Västerbotten, Sweden; Norwegian Cancer Society; Research Council of Norway; French League against cancer, Inserm, Mutuelle Generale l'Education National and IGR. Claudio Ruffmann received funding from 'Fondazione Grigioni per la lotta al Morbo di Parkinson