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Ann Neurol. 2017 Nov;82(5):655-664. doi: 10.1002/ana.25065. Epub 2017 Oct 26.

Pooled analysis of the HLA-DRB1 by smoking interaction in Parkinson disease.

Author information

Department of Epidemiology, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA.
Department of Health Care Management, College of Health Technology, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
Universite Paris-Saclay, Univ. Paris-Sud, UVSQ, CESP, INSERM, Villejuif, France.
INSERM UMR-S 1147, CRB EPIGENETEC, Univ. Paris Descartes, Sorbonne Paris Cite, 75006 Paris, France.
Assistance Publique-Hopitaux de Paris, Hopital Europeen Georges Pompidou, Biochimie, Pharmacogenetique et Oncologie Moleculaire, 75015 Paris, France.
Danish Cancer Society Research Center, Danish Cancer Society, Copenhagen, Denmark.
Genetic and Molecular Epidemiology Group, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Department of Neurology, School of Medicine, University of California, Los Angeles, Los Angeles, CA.
Department of Environmental Health Sciences, Fielding School of Public Health, University of California, Los Angeles, Los Angeles, CA.



Inflammatory response plays an important role in Parkinson disease (PD). Previous studies have reported an association between human leukocyte antigen (HLA)-DRB1 and the risk of PD. There has also been growing interest in investigating whether inflammation-related genes interact with environmental factors such as smoking to influence PD risk. We performed a pooled analysis of the interaction between HLA-DRB1 and smoking in PD in 3 population-based case-control studies from Denmark and France.


We included 2,056 cases and 2,723 controls from 3 PD studies (Denmark, France) that obtained information on smoking through interviews. Genotyping of the rs660895 polymorphism in the HLA-DRB1 region was based on saliva or blood DNA samples. To assess interactions, we used logistic regression with product terms between rs660895 and smoking. We performed random-effects meta-analysis of marginal associations and interactions.


Both carrying rs660895-G (AG vs AA: odds ratio [OR] = 0.81; GG vs AA: OR = 0.56; p-trend = 0.003) and ever smoking (OR = 0.56, p < 0.001) were inversely associated with PD. A multiplicative interaction was observed between rs660895 and smoking using codominant, additive (interaction parameter = 1.37, p = 0.005), and dominant (interaction parameter = 1.54, p = 0.001) genetic models without any heterogeneity (I² = 0.0%); the inverse association of rs660895-(AG+GG) with PD seen in never smokers (OR = 0.64, p < 0.001) disappeared among ever smokers (OR = 1.00, p = 0.99). Similar interactions were observed when we investigated light and heavy smokers separately.


Our study provides the first evidence that smoking modifies the previously reported inverse association of rs660895-G with PD, and suggests that smoking and HLA-DRB1 are involved in common pathways, possibly related to neuroinflammation. Ann Neurol 2017;82:655-664.

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