The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited

Cloé Domenighetti, Venceslas Douillard, Pierre Emmanuel Sugier, Ashwin Ashok Kumar Sreelatha, Claudia Schulte, Sandeep Grover, Patrick May, Dheeraj R. Bobbili, Milena Radivojkov-Blagojevic, Peter Lichtner, Andrew B. Singleton, Dena G. Hernandez, Connor Edsall, Pierre Antoine Gourraud, George D. Mellick, Alexander Zimprich, Walter Pirker, Ekaterina Rogaeva, Anthony E. Lang, Sulev KoksPille Taba, Suzanne Lesage, Alexis Brice, Jean Christophe Corvol, Marie Christine Chartier-Harlin, Eugénie Mutez, Kathrin Brockmann, Angela B. Deutschländer, Georges M. Hadjigeorgiou, Efthimos Dardiotis, Leonidas Stefanis, Athina Maria Simitsi, Enza Maria Valente, Simona Petrucci, Stefano Duga, Letizia Straniero, Anna Zecchinelli, Gianni Pezzoli, Laura Brighina, Carlo Ferrarese, Grazia Annesi, Andrea Quattrone, Monica Gagliardi, Hirotaka Matsuo, Akiyoshi Nakayama, Nobutaka Hattori, Kenya Nishioka, Sun Ju Chung, Yun Joong Kim, Rejko Krüger, Thomas Gasser, Manu Sharma, Nicolas Vince, Alexis Elbaz*, Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

Abstract

Background: Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions. Objective: To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction. Methods: We genotyped 182 single nucleotide polymorphism (SNPs) associated with smoking initiation in 12 424 cases and 9480 controls to perform a Mendelian randomization (MR) analysis in strata defined by HLA-DRB1. Results: At the amino acid level, a valine at position 11 (V11) in HLA-DRB1 displayed the strongest association with PD. MR showed an inverse association between genetically predicted smoking initiation and PD only in absence of V11 (odds ratio, 0.74, 95% confidence interval, 0.59–0.93, PInteraction = 0.028). In silico predictions of the influence of V11 and smoking-induced modifications of α-synuclein on binding affinity showed findings consistent with this interaction pattern. Conclusions: Despite being one of the most robust findings in PD research, the mechanisms underlying the inverse association between smoking and PD remain unknown. Our findings may help better understand this association.

Original languageEnglish
Pages (from-to)1929-1937
Number of pages9
JournalMovement disorders : official journal of the Movement Disorder Society
Volume37
Issue number9
Early online date10 Jul 2022
DOIs
Publication statusPublished - Sep 2022

Keywords

  • gene-environment interaction
  • HLA
  • Parkinson's disease
  • smoking

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