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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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
SUBMITTER: Domenighetti C
PROVIDER: S-EPMC9597672 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
Domenighetti Cloé C Douillard Venceslas V Sugier Pierre-Emmanuel PE Sreelatha Ashwin Ashok Kumar AAK Schulte Claudia C Grover Sandeep S May Patrick P Bobbili Dheeraj R DR Radivojkov-Blagojevic Milena M Lichtner Peter P Singleton Andrew B AB Hernandez Dena G DG Edsall Connor C Gourraud Pierre-Antoine PA Mellick George D GD Zimprich Alexander A Pirker Walter W Rogaeva Ekaterina E Lang Anthony E AE Koks Sulev S Taba Pille P Lesage Suzanne S Brice Alexis A Corvol Jean-Christophe JC Chartier-Harlin Marie-Christine MC Mutez Eugénie E Brockmann Kathrin K Deutschländer Angela B AB Hadjigeorgiou Georges M GM Dardiotis Efthimos E Stefanis Leonidas L Simitsi Athina Maria AM Valente Enza Maria EM Petrucci Simona S Duga Stefano S Straniero Letizia L Zecchinelli Anna A Pezzoli Gianni G Brighina Laura L Ferrarese Carlo C Annesi Grazia G Quattrone Andrea A Gagliardi Monica M Matsuo Hirotaka H Nakayama Akiyoshi A Hattori Nobutaka N Nishioka Kenya K Chung Sun Ju SJ Kim Yun Joong YJ Kolber Pierre P van de Warrenburg Bart P C BPC Bloem Bastiaan R BR Aasly Jan J Toft Mathias M Pihlstrøm Lasse L Correia Guedes Leonor L Ferreira Joaquim J JJ Bardien Soraya S Carr Jonathan J Tolosa Eduardo E Ezquerra Mario M Pastor Pau P Diez-Fairen Monica M Wirdefeldt Karin K Pedersen Nancy L NL Ran Caroline C Belin Andrea C AC Puschmann Andreas A Ygland Rödström Emil E Clarke Carl E CE Morrison Karen E KE Tan Manuela M Krainc Dimitri D Burbulla Lena F LF Farrer Matt J MJ Krüger Rejko R Gasser Thomas T Sharma Manu M Vince Nicolas N Elbaz Alexis A
Movement disorders : official journal of the Movement Disorder Society 20220710 9
<h4>Background</h4>Two studies that examined the interaction between HLA-DRB1 and smoking in Parkinson's disease (PD) yielded findings in opposite directions.<h4>Objective</h4>To perform a large-scale independent replication of the HLA-DRB1 × smoking interaction.<h4>Methods</h4>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.<h4>Results</h4> ...[more]