Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance

the Michael J. Fox Foundation LRRK2 Cohort Consortium

doi:10.1002/mds.28189

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance

the Michael J. Fox Foundation LRRK2 Cohort Consortium

Vagelos College of Physicians and Surgeons

Producción científica › revisión exhaustiva

64 Citas (Scopus)

Resumen

Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21–0.57) and in both pathogenic and risk variant carriers (OR_Pathogenic, 0.38; 95% CI, 0.21–0.67 and OR_RiskVariant, 0.19; 95% CI, 0.04–0.99). Similar associations were observed for ibuprofen and aspirin separately (OR_Ibuprofen, 0.19; 95% CI, 0.07–0.50 and OR_Aspirin, 0.51; 95% CI, 0.28–0.91). Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.

Idioma original	English
Páginas (desde-hasta)	1755-1764
Número de páginas	10
Publicación	Movement Disorders
Volumen	35
N.º	10
DOI	https://doi.org/10.1002/mds.28189
Estado	Published - oct. 1 2020

Financiación

M.S. has received grant support from The Smart Family Foundation and NIH/NINDS K23NS0099441‐O1A. She has served as a consultant for Boston Scientific and has received honoraria for participating as a Scientific Review Committee member from the Parkinson Study Group. C.M.T. has received grant support from the Michael J. Fox Foundation, Parkinson's Foundation, Department of Defense, BioElectron Technology Corp, Roche/Genentech, Biogen Idec, National Institutes of Health; honorarium and data monitoring committee service from Cadent Therapeutics, Intec Pharma, Northwestern University, consulting services from Neurocrine Biosciences, Adamas Therapeutics, Gray Matter Technologies, CNS Ratings, Lundbeck Pharmaceuticals and Acorda Pharmaceuticals. C. Meng has nothing to disclose. C. Marras has received grant support from the Michael J. Fox Foundation, the Canadian Institutes of Health Research (CIHR), the Parkinson’s Foundation (US), the International Parkinson and Movement Disorders Society. She has served as a consultant for Acorda Therapeutics and has received honoraria for teaching from EMD Serono and for participating as a Steering Committee member from the Michael J. Fox Foundation. She has served on the advisory board for Denali Therapeutics. S.M.G. has received grant support from the Michael J. Fox Foundation, US Department of Defense, Biogen, ATSDR and OSHA. A.E.L. has served as an advisor for Abbvie, Acorda, AFFiRis, Biogen, Denali, Janssen, Intracellular, Kallyope, Lundbeck, Paladin, Retrophin, Roche, Sun Pharma, Theravance, Jazz Pharma, PhotoPharmics, Sunovion, and Corticobasal Degeneration Solutions; received honoraria from Sun Pharma, AbbVie and Sunovion; received grants from Brain Canada, Canadian Institutes of Health Research, Edmond J Safra Philanthropic Foundation, Michael J. Fox Foundation, the Ontario Brain Institute, Parkinson Foundation, Parkinson Society Canada, and W. Garfield Weston Foundation; received publishing royalties from Saunders, Wiley‐Blackwell, Johns Hopkins Press, and Cambridge University Press. E.T. received honoraria for consultancy from TEVA, Bial, Prevail, 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 (MJFF). B.S. has received research grant support from The Michael J. Fox Foundation and the Amici Foundation. J.W.L. has received research support from the Farmer Family Foundation. A.B. has nothing to disclose. J.C.C. received honoraria for advisory boards outside the current work in the past year from UCB, Prevaile Therapeutics, Idorsia, Sanofi and Biogen. S.G. has nothing to disclose. C.K. has received honorarium from Centogene and Biogen. S. Brockman has nothing to disclose. D.B. has received consulting honoraria/advisory board from Biogen, BIAL, Lundbeck and UCB Pharma, received honoraria from Abbvie, Zambon, Desitin, GE, and has received research grant support from Janssen Pharmaceutica, German Parkinson's Disease Association, BMWi, BMBF, Parkinson's Fonds Deutschland gGmbH, UCB Pharma, the European Union, Novartis, Lundbeck Pharmaceutical and the Damp Foundation. K.B. has received research grant support from The Michael J. Fox Foundation. J.J.F. has received research grant support from GlaxoSmithKline, Grunenthal, Fundacao MSD (Portugal), TEVA, MSD, Allergan, Novartis and Medtronic. He has received consulting fees from GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Merck‐Serono, BIAL, Merz, Ipsen, Biogen, Acadia, Allergan, Abbvie, Sunovion Pharmaceuticals. He has participated in advisory boards for BIAL and expert testimony for Novartis. M.T. has nothing to disclose. G.D.M. has received research grant support from NHMRC Australia, AEGIUM Foundation, and from philanthropic donations. C.M.S. has nothing to disclose. K.H. has nothing to disclose. E.K.T. has received research grant support from the Singapore Ministry of Health’s National Medical Research Council, and from the NMRC Open Fund Large Collaborative Grant (MOH‐OFLCG18May‐0002) and Singapore Translational Research (STaR) Investigator Award (NMRC/STaR/0030/2018). S. Bressman has received research grant from The Michael J. Fox Foundation, and has received consulting honoraria from Denali Therapeutics and Athena. R.S.P. has received research grant support from The Michael J. Fox Foundation, the Bigglesworth Family Foundation and the National Institutes of Health. This study was supported by the Michael J Fox Foundation (C.T., C.M., C.L.M., S.G., B.S.), the Smart Family Foundation (M.S.) and National Institutes of Health/National Institute of Neurological Disorders and Stroke K23NS0099441-O1A (M.S.L.). The LRRK2 Cohort Consortium is coordinated and funded by the Michael J. Fox Foundation for Parkinson's Research. C.K. is supported by the German Research Foundation (DFG, FOR2488). We thank Aaron Viser for his assistance in reviewing and preparing the article and tables for publication. This study was supported by the Michael J Fox Foundation (C.T., C.M., C.L.M., S.G., B.S.), the Smart Family Foundation (M.S.) and National Institutes of Health/National Institute of Neurological Disorders and Stroke K23NS0099441‐O1A (M.S.L.). The LRRK2 Cohort Consortium is coordinated and funded by the Michael J. Fox Foundation for Parkinson's Research. C.K. is supported by the German Research Foundation (DFG, FOR2488). We thank Aaron Viser for his assistance in reviewing and preparing the article and tables for publication. : Study supported by the Michael J. Fox Foundation (C.T., C.M., C.L.M., S.G., B.S.), the Smart Family Foundation (M.L.S.) and National Institutes of Health/National Institute of Neurological Disorders and Stroke K23NS0099441‐O1A (M.S.). The LRRK2 Cohort Consortium is coordinated and funded by the Michael J. Fox Foundation for Parkinson's Research. C.K. is supported by the German Research Foundation (DFG, FOR2488). Funding agencies

Financiadores	Número del financiador
AFFiRis
Adamas Therapeutics
Amici Foundation
Bigglesworth Family Foundation
Fundacao MSD
NHMRC Australia
National Institute of Neurological Disorders and Stroke K23NS0099441-O1A
National Institute of Neurological Disorders and Stroke K23NS0099441‐O1A
OSHA
Parkinson's Fonds Deutschland gGmbH
Parkinson’s Foundation
Singapore Translational Research	NMRC/STaR/0030/2018
Spanish Network for Research on Neurodegenerative Disorders
National Institutes of Health
U.S. Department of Defense
National Institute of Neurological Disorders and Stroke	K23NS099441, K23NS0099441‐O1A
Michael J. Fox Foundation for Parkinson's Research
Boehringer Ingelheim
GlaxoSmithKline
Novartis
Roche
Medtronic
California Department of Fish and Game
Agency for Toxic Substances and Disease Registry
Biogen
Teva Pharmaceutical Industries
AbbVie
Meso Scale Diagnostics
Allergan
International Parkinson and Movement Disorder Society
Janssen Pharmaceuticals
Ontario Brain Institute
Fondation Brain Canada
Smart Family Foundation
Aegis Foundation
Parkinson's Foundation
Neurocrine Biosciences
UCB Pharma
European Parkinson’s Disease Association
Farmer Family Foundation
Johns Hopkins University Press
Canadian Institutes of Health Research
W. Garfield Weston Foundation
Parkinson Society Canada
National Medical Research Council	MOH‐OFLCG18May‐0002
Ministry of Health -Singapore
Deutsche Forschungsgemeinschaft	FOR2488
Bundesministerium für Bildung und Forschung
Edmond J. Safra Philanthropic Foundation
Instituto de Salud Carlos III
Bundesministerium für Wirtschaft und Energie
Damp Stiftung
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas

ASJC Scopus Subject Areas

Neurology
Clinical Neurology

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10.1002/mds.28189

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@article{307071674dda42a9a5705dc2a5ae3707,

title = "Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance",

abstract = "Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Methods: Symptomatic ({"}LRRK2-PD{"}) and asymptomatic ({"}LRRK2-non-PD{"}) participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21–0.57) and in both pathogenic and risk variant carriers (ORPathogenic, 0.38; 95% CI, 0.21–0.67 and ORRiskVariant, 0.19; 95% CI, 0.04–0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen, 0.19; 95% CI, 0.07–0.50 and ORAspirin, 0.51; 95% CI, 0.28–0.91). Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.",

author = "{the Michael J. Fox Foundation LRRK2 Cohort Consortium} and {San Luciano}, Marta and Tanner, {Caroline M.} and Cheryl Meng and Connie Marras and Goldman, {Samuel M.} and Lang, {Anthony E.} and Eduardo Tolosa and Birgitt Sch{\"u}le and Langston, {J. William} and Alexis Brice and Corvol, {Jean Christophe} and Stefano Goldwurm and Christine Klein and Simone Brockman and Daniela Berg and Kathrin Brockmann and Ferreira, {Joachim J.} and Meriem Tazir and Mellick, {George D.} and Sue, {Carolyn M.} and Kazuko Hasegawa and Tan, {Eng King} and Susan Bressman and Rachel Saunders-Pullman and Rachel Saunders-Pullman and Deborah Raymond and Andres Deik and Barrett, {Matthew James} and Jose Cabassa and Mark Groves and Hunt, {Ann L.} and Naomi Lubarr and Joan Miravite and Christina Palmese and Rivka Sachdev and Harini Sarva and Lawrence Severt and Vicki Shanker and Swan, {Matthew Carrington} and Jeannie Soto-Valencia and Brooke Johannes and Robert Ortega and Laurie Ozelius and Susan Bressman and Alcalay, {Roy N.} and Tang, {Ming X.} and Santana, {Helen Mejia} and Ernest Roos and Martha Orbe-Reilly and Marder, {Karen S.}",

note = "Publisher Copyright: {\textcopyright} 2020 International Parkinson and Movement Disorder Society",

year = "2020",

month = oct,

day = "1",

doi = "10.1002/mds.28189",

language = "English",

volume = "35",

pages = "1755--1764",

journal = "Movement Disorders",

issn = "0885-3185",

publisher = "John Wiley and Sons Inc.",

number = "10",

}

TY - JOUR

T1 - Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance

AU - the Michael J. Fox Foundation LRRK2 Cohort Consortium

AU - San Luciano, Marta

AU - Tanner, Caroline M.

AU - Meng, Cheryl

AU - Marras, Connie

AU - Goldman, Samuel M.

AU - Lang, Anthony E.

AU - Tolosa, Eduardo

AU - Schüle, Birgitt

AU - Langston, J. William

AU - Brice, Alexis

AU - Corvol, Jean Christophe

AU - Goldwurm, Stefano

AU - Klein, Christine

AU - Brockman, Simone

AU - Berg, Daniela

AU - Brockmann, Kathrin

AU - Ferreira, Joachim J.

AU - Tazir, Meriem

AU - Mellick, George D.

AU - Sue, Carolyn M.

AU - Hasegawa, Kazuko

AU - Tan, Eng King

AU - Bressman, Susan

AU - Saunders-Pullman, Rachel

AU - Raymond, Deborah

AU - Deik, Andres

AU - Barrett, Matthew James

AU - Cabassa, Jose

AU - Groves, Mark

AU - Hunt, Ann L.

AU - Lubarr, Naomi

AU - Miravite, Joan

AU - Palmese, Christina

AU - Sachdev, Rivka

AU - Sarva, Harini

AU - Severt, Lawrence

AU - Shanker, Vicki

AU - Swan, Matthew Carrington

AU - Soto-Valencia, Jeannie

AU - Johannes, Brooke

AU - Ortega, Robert

AU - Ozelius, Laurie

AU - Bressman, Susan

AU - Alcalay, Roy N.

AU - Tang, Ming X.

AU - Santana, Helen Mejia

AU - Roos, Ernest

AU - Orbe-Reilly, Martha

AU - Marder, Karen S.

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21–0.57) and in both pathogenic and risk variant carriers (ORPathogenic, 0.38; 95% CI, 0.21–0.67 and ORRiskVariant, 0.19; 95% CI, 0.04–0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen, 0.19; 95% CI, 0.07–0.50 and ORAspirin, 0.51; 95% CI, 0.28–0.91). Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.

AB - Background: The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. Objectives: The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Methods: Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. Results: A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21–0.57) and in both pathogenic and risk variant carriers (ORPathogenic, 0.38; 95% CI, 0.21–0.67 and ORRiskVariant, 0.19; 95% CI, 0.04–0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen, 0.19; 95% CI, 0.07–0.50 and ORAspirin, 0.51; 95% CI, 0.28–0.91). Conclusions: Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association.

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U2 - 10.1002/mds.28189

DO - 10.1002/mds.28189

M3 - Article

C2 - 32662532

AN - SCOPUS:85087894893

SN - 0885-3185

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EP - 1764

JO - Movement Disorders

JF - Movement Disorders

IS - 10

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Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance

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