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Effect modification of the association between total cigarette smoking and ALS risk by intensity, duration and time-since-quitting: Euro-MOTOR
  1. Susan Peters1,2,
  2. Anne E Visser2,
  3. Fabrizio D'Ovidio3,
  4. Jelle Vlaanderen1,
  5. Lützen Portengen1,
  6. Ettore Beghi4,
  7. Adriano Chio3,
  8. Giancarlo Logroscino5,6,
  9. Orla Hardiman7,
  10. Elisabetta Pupillo4,
  11. Jan H Veldink2,
  12. Roel Vermeulen1,8,
  13. Leonard H van den Berg2
  14. Euro-MOTOR consortium
    1. 1 Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
    2. 2 Department of Neurology, University Medical Centre Utrecht, Utrecht, The Netherlands
    3. 3 “Rita Levi Montalcini” Department of Neuroscience, University of Turin, Torino, Italy
    4. 4 Department of Neuroscience, Istituto Mario Negri, Milan, Italy
    5. 5 Unit of Neurodegenerative Diseases, Department of Clinical Research in Neurology, University of Bari "Aldo Moro", Pia Fondazione Cardinale G. Panico, Tricase, Lecce, Italy
    6. 6 Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro", Bari, Italy
    7. 7 Academic Unit of Neurology, Trinity Biomedical Sciences Institute, Trinity College, Dublin, Ireland
    8. 8 University Medical Centre Utrecht, Julius Centre for Public Health Sciences and Primary Care, Utrecht, The Netherlands
    1. Correspondence to Dr Susan Peters, Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3584 CM, The Netherlands; s.peters{at}


    Background We investigated the association between cigarette smoking and risk of amyotrophic lateral sclerosis (ALS) in a pooled analysis of population-based case–control studies and explored the independent effects of intensity, duration and time-since-quitting.

    Methods ALS cases and controls, matched by age, sex and region, were recruited in the Netherlands, Italy and Ireland (*Euro-MOTOR project). Demographics and detailed lifetime smoking histories were collected through questionnaires. Effects of smoking status, intensity (cigarettes/day), duration (years), pack-years and time-since-quitting (years) on ALS risk were estimated using logistic regression models, adjusting for age, sex, alcohol, education and centre. We further investigated effect modification of the linear effects of pack-years by intensity, duration and time-since-quitting using excess OR (eOR) models.

    Results Analyses were performed on 1410 cases and 2616 controls. Pack-years were positively associated with ALS risk; OR=1.26 (95% CI: 1.03 to 1.54) for the highest quartile compared with never smokers. This association appeared to be predominantly driven by smoking duration (ptrend=0.001) rather than intensity (ptrend=0.86), although the trend for duration disappeared after adjustment for time-since-quitting. Time-since-quitting was inversely related to ALS (ptrend<0.0001). The eOR decreased with time-since-quitting smoking, until about 10 years prior to disease onset. High intensity smoking with shorter duration appeared more deleterious than lower intensity for a longer duration.

    Conclusions Our findings provide further support for the association between smoking and ALS. Pack-years alone may be insufficient to capture effects of different smoking patterns. Time-since-quitting appeared to be an important factor, suggesting that smoking may be an early disease trigger.

    • amyotrophic lateral sclerosis
    • case–control study
    • pooled analysis
    • tobacco

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    • RV and LHvdB contributed equally.

    • Collaborators Euro-MOTOR consortium: Anneke J van der Kooi; Joost Raaphorst; Andrea Calvo; Cristina Moglia; Federico Casale; Giuseppe Fuda; Antonio Canosa; Umberto Manera; Alessandro Bombaci; Maurizio Grassano; Rosario Vasta; Paolina Salamone; Giuseppe Marrali; Barbara Iazzolino; Letizia Mazzini; James Rooney; Mark Heverin; Alice Vajda; Giancarlo Comi; Nilo Riva; Christian Lunetta; Francesca Gerardi; Massimiliano Filosto; Maria Sofia Cotelli; Fabrizio Rinaldi; Luca Chiveri; Maria Cristina Guaita; Patrizia Perrone; Ceroni Mauro; Luca Diamanti; Carlo Ferrarese; Lucio Tremolizzo; Maria Luisa Delodovici; Giorgio Bono; Rosanna Tortelli; Chiara Zecca.

    • Contributors SP, AEV, FD, EB, AC, GL, OH, EP, JHV, RV and LvdB contributed to the study concept and design and participated in data collection and processing. SP performed the statistical analyses. SP, JV, LP and RV contributed to the analyses and interpretation of data. SP wrote the manuscript. AEV, FD, JV, LP, EB, AC, GL, OH, EP, JHV, RV and LvdB revised the manuscript for intellectual content. EB, AC, GL, OH, JHV, RV and LvdB provided study supervision. EB, AC, GL, OH, JHV and LvdB obtained funding.

    • Funding This work was supported by funding from the European Community's Health Seventh Framework Programme (FP7/2007-2013, grant number 259867); and the Netherlands ALS Foundation.

    • Competing interests EB reports grants from UCB-PHARMA, personal fees from MA-Provider, grants from American ALS Association, grants from EISAI, grants from Shire. AC reports personal fees from Biogen, grants from Italfarmaco, personal fees from Roche, personal fees from Cytokinetics, personal fees from Mitsubishi Tanabe. OH has received speaking honoraria from Novartis, Biogen Idec, Sanofi Aventis and Merck-Serono; and has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics and Sanofi Aventis. LvdB serves on scientific advisory boards for the Prinses Beatrix Spierfonds, Thierry Latran Foundation, Biogen, Cytokinetics, Orion and Sarepta. SP, AEV, FD, JV, LP, GL, EP, JHV and RV report no potential conflicts of interest.

    • Patient consent for publication Not required.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data availability statement No data are available.