The interaction between HLA-DRB1 and smoking in Parkinson's disease revisited

Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium

doi:10.1002/mds.29133

The interaction between HLA-DRB1 and smoking in Parkinson's disease revisited

Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium

School of Medicine, Dentistry and Biomedical Sciences

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

41 Downloads (Pure)

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

Original language	English
Pages (from-to)	1929-1937
Number of pages	9
Journal	Movement Disorders
Volume	37
Issue number	9
Early online date	10 Jul 2022
DOIs	https://doi.org/10.1002/mds.29133
Publication status	Published - Sept 2022

Keywords

Parkinson's disease
HLA
gene-environment interaction
smoking

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The interaction between HLA-DRB1 and smoking in Parkinson's disease revisited
Copyright 2022 the authors. This is an open access Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits use, distribution and reproduction for non-commercial purposes, provided the author and source are cited.
Final published version, 797 KBLicence: CC BY-NC

Cite this

@article{d6acc14f61334ac1abf0f5314000b945,

title = "The interaction between HLA-DRB1 and smoking in Parkinson's disease revisited",

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. {\textcopyright} 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society",

keywords = "Parkinson's disease, HLA, gene-environment interaction, smoking",

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

year = "2022",

month = sep,

doi = "10.1002/mds.29133",

language = "English",

volume = "37",

pages = " 1929--1937",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley \& Sons Inc.",

number = "9",

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TY - JOUR

T1 - The interaction between HLA-DRB1 and smoking in Parkinson's disease revisited

AU - Domenighetti, Cloé

AU - Douillard, Venceslas

AU - Sugier, Pierre-Emmanuel

AU - Sreelatha, Ashwin Ashok Kumar

AU - Schulte, Claudia

AU - Grover, Sandeep

AU - May, Patrick

AU - Bobbili, Dheeraj R

AU - Radivojkov-Blagojevic, Milena

AU - Lichtner, Peter

AU - Singleton, Andrew B

AU - Hernandez, Dena G

AU - Edsall, Connor

AU - Gourraud, Pierre-Antoine

AU - Mellick, George D

AU - Zimprich, Alexander

AU - Pirker, Walter

AU - Rogaeva, Ekaterina

AU - Lang, Anthony E

AU - Koks, Sulev

AU - Taba, Pille

AU - Lesage, Suzanne

AU - Brice, Alexis

AU - Corvol, Jean-Christophe

AU - Chartier-Harlin, Marie-Christine

AU - Mutez, Eugénie

AU - Brockmann, Kathrin

AU - Deutschländer, Angela B

AU - Hadjigeorgiou, Georges M

AU - Dardiotis, Efthimos

AU - Stefanis, Leonidas

AU - Simitsi, Athina Maria

AU - Valente, Enza Maria

AU - Petrucci, Simona

AU - Duga, Stefano

AU - Straniero, Letizia

AU - Zecchinelli, Anna

AU - Pezzoli, Gianni

AU - Brighina, Laura

AU - Ferrarese, Carlo

AU - Annesi, Grazia

AU - Quattrone, Andrea

AU - Gagliardi, Monica

AU - Matsuo, Hirotaka

AU - Nakayama, Akiyoshi

AU - Hattori, Nobutaka

AU - Nishioka, Kenya

AU - Chung, Sun Ju

AU - Kim, Yun Joong

AU - Morrison, Karen E

AU - Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium

PY - 2022/9

Y1 - 2022/9

N2 - 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

AB - 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

KW - Parkinson's disease

KW - HLA

KW - gene-environment interaction

KW - smoking

U2 - 10.1002/mds.29133

DO - 10.1002/mds.29133

M3 - Article

C2 - 35810454

SN - 0885-3185

VL - 37

SP - 1929

EP - 1937

JO - Movement Disorders

JF - Movement Disorders

IS - 9

ER -

The interaction between HLA-DRB1 and smoking in Parkinson's disease revisited

Abstract

Keywords

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