The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited
Authors
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 Koks ; Pille 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 ; Pierre Kolber ; Bart P C van de Warrenburg ; Bastiaan R Bloem ; Jan Aasly ; Mathias Toft ; Lasse Pihlstrøm ; Leonor Correia Guedes ; Joaquim J Ferreira ; Soraya Bardien ; Jonathan Carr ; Eduardo Tolosa ; Mario Ezquerra ; Pau Pastor ; Monica Diez-Fairen ; Karin Wirdefeldt ; Nancy L Pedersen ; Caroline Ran ; Andrea C Belin ; Andreas Puschmann ; Emil Ygland Rödström ; Carl E Clarke ; Karen E Morrison ; Manuela Tan ; Dimitri Krainc ; Lena F Burbulla ; Matt J Farrer ; Rejko Krüger ; Thomas Gasser ; Manu Sharma ; Nicolas Vince ; Alexis Elbaz
Citation
MOVEMENT DISORDERS, Vol.37(9) : 1929-1937, 2022-09
Genetic Predisposition to Disease OR HLA-DRB1 Chains / genetics OR Humans OR Parkinson Disease* / genetics OR Polymorphism, Single Nucleotide / genetics OR Smoking / genetics
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.