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 language | English (US) |
|---|---|
| Journal | Movement Disorders |
| DOIs | |
| State | Accepted/In press - 2022 |
Keywords
- HLA
- Parkinson's disease
- gene-environment interaction
- smoking
ASJC Scopus subject areas
- Neurology
- Clinical Neurology
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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.
In: Movement Disorders, 2022.Research output: Contribution to journal › Article › peer-review
TY - JOUR
T1 - The Interaction between HLA-DRB1 and Smoking in Parkinson's Disease Revisited
AU - Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease (Courage-PD) Consortium
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 - KraincMD, Dimitri
AU - Burbulla, Lena F.
N1 - Funding Information: We thank the GWAS and Sequencing Consortium of Alcohol and Nicotine consortium (GSCAN use) for providing summary statistics for this analysis. Additional Courage-PD investigators are: Sophia N. Pchelina (Saint Petersburg, Russia), Thomas Brücke (Wien, Austria), Marie-Anne Loriot (Paris, France), Claire Mulot (Paris, France), Yves Koudou (Villejuif, France), Alain Destée (Lille, France), Georgia Xiromerisiou (Larissa, Greece), Christos Koros (Athens, Greece), Matina Maniati (Athens, Greece), Maria Bozi (Athens, Greece), Micol Avenali (Pavia, Italy), Margherita Canesi (Milan, Italy), Giorgio Sacilotto (Milan, Italy), Michela Zini (Milan, Italy), Roberto Cilia (Milan, Italy), Francesca Del Sorbo (Milan, Italy), Nicoletta Meucci (Milan, Italy), Rosanna Asselta (Milan, Italy), Radha Procopio (Catanzaro, Italy), Clara Hellberg (Lund, Sweden), Manabu Funayama (Tokyo, Japan), Aya Ikeda (Tokyo, Japan), Takashi Matsushima (Tokyo, Japan), Yuanzhe Li (Tokyo, Japan), Hiroyo Yoshino (Tokyo, Japan), Zied Landoulsi (Luxembourg, Luxembourg), Rubén Fernández-Santiago (Barcelona, Spain), Nicholas Wood (London, UK), Huw R. Morris (London, United Kingdom). Funding Information: : This study used data from the Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson‘s Disease (Courage‐PD) consortium, conducted under a partnership agreement between 35 studies. The Courage‐PD consortium is supported by the EU JPND research ( https://www.neurodegenerationresearch.eu/initiatives/annual-calls-for-proposals/closed-calls/risk-factors-2012/risk-factor-call-results/courage-pd/ ). C.D. is the recipient of a doctoral grant from Université Paris‐Saclay, France. P.M. was funded by the FNR, Luxembourg as part of the National Centre of Excellence in Research on Parkinson's disease (NCER‐PD, FNR11264123), and the DFG Research Units FOR2715 (INTER/DFG/17/11583046) and FOR2488 (INTER/DFG/19/14429377). A.B.S., D.G.H., and C.E. are funded by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services, project ZO1 AG000949. E.R. is funded by the Canadian Consortium on Neurodegeneration in Aging. S.K. is funded by MSWA. P.T. is the recipient of an Estonian Research Council Grant PRG957. E.M.V. is funded by the Italian Ministry of Health (Ricerca Corrente 2021). S.B. and J.C. are supported by grants from the National Research Foundation of South Africa (106052); the South African Medical Research Council (Self‐Initiated Research Grant); and Stellenbosch University, South Africa; they also acknowledge the support of the NRF‐DST Centre of Excellence for Biomedical Tuberculosis Research; South African Medical Research Council Centre for Tuberculosis Research; Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town. P.P. and M.D.F. have received funding from the Spanish Ministry of Science and Innovation (SAF2013‐47939‐R). K.W. and N.L.P. are funded by the Swedish Research Council (K2002‐27X‐14,056‐02B, 521–2010‐2479, 521–2013‐2488, and 2017–02175). N.L.P. is funded by the National Institutes of Health (ES10758 and AG 08724). C.R. is funded by the Märta Lundkvist Foundation, Swedish Brain Foundation, Karolinska Institutet Research Fund. A.C.B. from the Swedish Brain Foundation, Swedish Research Council, and Karolinska Institutet Research Funds. M.T is funded by the Parkinson's UK. M.S. was supported by the grants from the German Research Council (DFG/SH 599/6–1), MSA Coalition, and The Michael J. Fox Foundation (USA Genetic Diversity in PD Program: GAP‐India Grant ID: 17473). P.G. GEN sample collection was funded by the MRC and UK Medical Research Council (CEC, KEM). The sponsors had no role in the study design, data collection, data analysis, data interpretation, the writing of the report, or the decision to submit the paper for publication. Funding agencies Funding Information: A.B.S. reports grants from Department of Defense, during the conduct of the study and grants from The Michael J. Fox Foundation, outside the submitted work. W.P. reports personal fees from Grünenthal, personal fees from AbbVie, personal fees from AOP Orphan, personal fees from Zambon, personal fees and other from Boehringer Ingelheim, personal fees from Stada, and personal fees from UCB Pharma, outside the submitted work. A.E.L. reports personal fees from AbbVie, personal fees from AFFiRis, personal fees from Janssen, personal fees from Biogen, personal fees from Merck, personal fees from Sun Pharma, personal fees from Corticobasal Solutions, personal fees from Sunovion, personal fees from Paladin, personal fees from Lilly, personal fees from Medtronic, personal fees from Theravance, personal fees from Lundbeck, personal fees from Retrophin, personal fees from Roche, and personal fees from PhotoPharmics, outside the submitted work. A.B. reports grants from France Parkinson + FRC, grants from Agence Nationale de Recherche (ANR)‐EPIG, grants from ANR‐Joint Programming for Neurodegenerative Diseases (JPND), grants from Roger de Spoelberch Foundation (RDS), grants from France Alzheimer, grants from Institut de France, grants from ANR‐EPIG, and grants from FMR (maladies rares), outside the submitted work. J.C.C. reports grants from The Michael J. Fox Foundation, Sanofi, and served in advisory boards for Air Liquide, Biogen, Denali, Ever Pharma, Idorsia, Prevail Therapeutic, Theranexus, and UCB, outside the submitted work. M.C.C.H. reports grants from France Parkinson, grants from ANR (MetDePaDi, Synapark), grant from ANR–JPND (TransNeuro), grants from Fondation de France, grants from The Michael J. Fox Foundation, outside the submitted work. K.B. reports grants from The Michael J. Fox Foundation, grants from BMBF; personal fees from Zambon, UCB, and Abbvie; and grants from University of Tuebingen, outside the submitted work. L.S. has received the following grants over the past year: PPMI2 (supported by The Michael J. Fox Foundation), IMPRIND‐IMI2 Number 116060 (EU, H2020), “Transferring autonomous and non‐autonomous cell degeneration 3D models between EU and USA for development of effective therapies for neurodegenerative diseases (ND)‐CROSS NEUROD” (H2020‐EU 1.3.3., 778003), “Chaperone‐Mediated Autophagy in Neurodegeneration” (Hellenic Foundation for Research and Innovation grant HFRI‐FM17‐3013), and “CMA as a Means to Counteract α‐Synuclein Pathology in Non‐Human Primates” grant by The Michael J. Fox Foundation (Collaborator). He is co‐head and PI at the NKUA of the General Secretariat of Research and Technology (GSRT)‐funded grant “National Network of Precision Medicine for Neurodegenerative Diseases.” He has served on an Advisory Board for AbbVie, ITF Hellas, and Biogen and has received honoraria from Abbvie and Sanofi. There are no specific disclosures related to the current work. E.M.V. serves as Associate Editor of Journal of Medical Genetics, Section Editor of Pediatric Research, Member of the Editorial Board of Movement Disorders Clinical Practice; grants from the Italian Ministry of Health, CARIPLO Foundation, Pierfranco and Luisa Mariani Foundation, and Telethon Foundation Italy, outside the submitted work. N.H. reports grants from Japan Agency for Medical Research and Development (AMED), Japan Society for the Promotion of Science (JSPS), and the Ministry of Education Culture, Sports, Science, and Technology Japan; grant‐in‐aid for Scientific Research on Innovative Areas; personal fees and other from Dai‐Nippon Sumitomo Pharma, Takeda Pharmaceutical, Kyowa Kirin, GSK K.K, Nippon Boehringer Ingelheim, FP Pharmaceutical Corporation, Eisai, Kissei Pharmaceutical Company, Nihon Medi‐physics, Novartis Pharma K.K, Biogen Idec Japan, and AbbVie, from Medtronic, other from Boston Scientific Japan, personal fees and other from Astellas Pharma, grants and other from Ono Pharmaceutical, other from Nihon Pharmaceutical, other from Asahi Kasei Medical, other from Mitsubishi Tanabe Pharma Corporation, personal fees and other from Daiichi Sankyo, other from OHARA Pharmaceutical, other from Meiji Seika Pharma, personal fees from Sanofi K.K., personal fees from Pfizer Japan, personal fees from Alexion Pharmaceuticals, personal fees from Mylan N.V, personal fees from MSD K.K, personal fees from Lund Beck Japan, and other from Hisamitsu Pharmaceutical, outside the submitted work. K.N. reports grants from Japan Society for the Promotion of Science (JSPS), outside the submitted work. P.K. reports other from Centre Hospitalier de Luxembourg; University of Luxembourg, grants from Fonds National de Recherche (FNR), and from null, outside the submitted work. B.P.C.W. reports grants from ZonMW, grants from Hersenstichting, grants from uniQure, other from uniQure, grants from Gossweiler Fund, and grants from Radboud university medical centre, outside the submitted work. B.R.B. reports grants from Netherlands Organization for Health Research and Development, grants from The Michael J. Fox Foundation, grants from Parkinson Vereniging, grants from Parkinson Foundation, grants from Gatsby Foundation, grants from Verily Life Sciences, grants from Horizon 2020, grants from Topsector Life sciences and Health, grants from Stichting Parkinson Fonds, grants from UCB, grants from AbbVie, during the conduct of the study; personal fees from Biogen, personal fees from AbbVie, personal fees from Walk with Path, personal fees from UCB, personal fees from AbbVie, personal fees from Zambon, personal fees from Bial, personal fees from Roche, outside the submitted work; and serves as editor‐in‐chief of the Journal of Parkinson's Disease and serves on the editorial board of Practical Neurology and Digital Biomarkers. M. Toft reports grants from Research Council of Norway, during the conduct of the study; grants from South‐Eastern Norway Regional Health Authority, and grants from The Michael J. Fox, outside the submitted work. L.P. reports grants from Norwegian Health Association, and grants from South‐Eastern Norway Regional Health Authority, outside the submitted work. J.J.F. reports grants from GlaxoSmithKline, Grunenthal, Fundação MSD (Portugal), TEVA, MSD, Allergan, Novartis, Medtronic, GlaxoSmithKline, Novartis, Lundbeck, Solvay, BIAL, Merck‐Serono, Merz, Ipsen, Biogen, Acadia, Abbvie, and Sunovion Pharmaceuticals, personal fees from Faculdade de Medicina de Lisboa, Campus Neurológico Sénior (CNS), BIAL, and Novartis outside the submitted work. E.T. received honoraria for consultancy from TEVA, Bial, Prevail Therapeutics, Boehringer Ingelheim, Roche, and BIOGEN and has received funding for research from Spanish Network for Research on Neurodegenerative Disorders (CIBERNED), Instituto Carlos III (ISCIII), and The Michael J. Fox Foundation for Parkinson's Research. K.W. reports grants from Swedish Research Council during the conduct of the study. N.L.P. reports grants from Swedish Research Council during the conduct of the study. A.P. reports grants from Parkinsonfonden (The Swedish Parkinson Foundation), grants from ALF (Swedish Government), grants from Region Skåne, Sweden, Skåne University Hospital, Hans‐Gabriel och Trolle Wachtmeister Stiftelse för Medicinsk Forskning, Sweden, and Multipark—a strategic research environment at Lund University, during the conduct of the study; and personal fees from Elsevier, outside the submitted work. E.Y.R. reports grants from ALF (Swedish Government), Hans‐Gabriel och Trolle Wachtmeister Stiftelse för Medicinsk Forskning, Sweden, and Demensfonden (all in Sweden). M. Tan reports grants from Parkinson's United Kingdom (UK), other from The Michael J. Fox Foundation and University College London, outside the submitted work. R.K. reports grants from FNR and the German Research Council (DFG), non‐financial support from AbbVie, Zambon, during the conduct of the study; personal fees from University of Luxembourg; Luxembourg Institute of Health; Centre Hospitalier de Luxembourg, grants from Fonds National de Recherche, Luxembourg (FNR), grants from FNR, grants from FNR, Luxembourg/DFG, grants from FNR, Luxembourg (FNR), personal fees from Desitin/Zambon, personal fees from AbbVie, and personal fees from Medtronic, outside the submitted work. T.G. reports personal fees from UCB Pharma, Novartis, Teva, and MedUpdate, grants from The Michael J. Fox Foundation for Parkinson's Research, Bundesministerium für Bildung und Forschung (BMBF), and DFG, other from JPND program, funded by the European Commission, outside the submitted work; in addition, T.G. has a patent patent number: EP1802749 (A2) () gene, its production and use for the detection and treatment of neurodegenerative disorders issued. A.E. reports grants from ANR, The Michael J. Fox foundation, Plan Ecophyto (French Ministry of Agriculture), and France Parkinson, outside the submitted work. Relevant conflicts of interest/financial disclosures: KASPP LRRK2 Publisher Copyright: © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PY - 2022
Y1 - 2022
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.
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.
KW - HLA
KW - Parkinson's disease
KW - gene-environment interaction
KW - smoking
UR - http://www.scopus.com/inward/record.url?scp=85133891525&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133891525&partnerID=8YFLogxK
U2 - 10.1002/mds.29133
DO - 10.1002/mds.29133
M3 - Article
C2 - 35810454
AN - SCOPUS:85133891525
SN - 0885-3185
JO - Movement Disorders
JF - Movement Disorders
ER -