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Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR 1) gene

Warner, S.C.; Walsh, David A.; Laslett, L.L.; Maciewicz, R.A.; Soni, A.; Hart, D.J.; Zhang, Weiya; Muir, K.R.; Dennison, E.M.; Leaverton, P.; Rampersaud, E.; Cooper, C.; Spector, T.D.; Cicuttini, F.M.; Arden, N.K.; Jones, G.; Doherty, M.; Valdes, Ana M.


S.C. Warner

Professor of Rheumatology

L.L. Laslett

R.A. Maciewicz

A. Soni

D.J. Hart

K.R. Muir

E.M. Dennison

P. Leaverton

E. Rampersaud

C. Cooper

T.D. Spector

F.M. Cicuttini

N.K. Arden

G. Jones

M. Doherty


Background: Substance P (SP) is a pain- and inflammation-related neuropeptide which preferentially binds to the neurokinin receptor 1 (NK1). SP and NK1 receptors have been implicated in joint pain, inflammation and damage in animal models and human studies of osteoarthritis (OA). The aim of this study was to test if genetic variation at the neurokinin 1 receptor gene (TACR1) is associated with pain in individuals with radiographic knee OA.
Methods: Participants from the Genetics of OA and Lifestyle study were used for the discovery group (n = 1615). Genotype data for six SNPs selected to cover most variation in the TACR1 gene were used to test for an association with symptomatic OA. Replication analysis was performed using data from the Chingford 1000 Women Study, Hertfordshire Cohort Study, Tasmanian Older Adult Cohort Study and the Clearwater OA Study. In total, n = 1715 symptomatic OA and n = 735 asymptomatic OA individuals were analysed.
Results: Out of six SNPs tested in the TACR1 gene, one (rs11688000) showed a nominally significant association with a decreased risk of symptomatic OA in the discovery cohort. This was then replicated in four additional cohorts. After adjusting for age, gender, body mass index and radiographic severity, the G (minor) allele at rs11688000 was associated with a decreased risk of symptomatic OA compared to asymptomatic OA cases (p = 9.90 × 10−4, OR = 0.79 95% 0.68–0.90 after meta-analysis).
Conclusions: This study supports a contribution from the TACR1 gene in human OA pain, supporting further investigation of this gene's function in OA.
Significance: This study contributes to the knowledge of the genetics of painful osteoarthritis, a condition which affects millions of individuals worldwide. Specifically, a contribution from the TACR1 gene to modulating pain sensitivity in osteoarthritis is suggested


Warner, S., Walsh, D. A., Laslett, L., Maciewicz, R., Soni, A., Hart, D., …Valdes, A. M. (2017). Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR 1) gene. European Journal of Pain, 21(7), 1277-1284.

Journal Article Type Article
Acceptance Date Jan 21, 2017
Online Publication Date May 11, 2017
Publication Date 2017-08
Deposit Date May 12, 2017
Publicly Available Date May 12, 2017
Journal European Journal of Pain
Print ISSN 1090-3801
Electronic ISSN 1532-2149
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 21
Issue 7
Pages 1277-1284
Public URL
Publisher URL
Additional Information This is the peer reviewed version of the following article: Pain in knee osteoarthritis is associated with variation in the neurokinin 1/substance P receptor (TACR1) gene / S.C. Warner, D.A. Walsh, L.L. Laslett, R.A. Maciewicz, A. Soni, D.J. Hart, W. Zhang, K.R. Muir, E.M. Dennison, P. Leaverton, E. Rampersaud, C. Cooper, T.D. Spector, F.M. Cicuttini, N.K. Arden, G. Jones, M. Doherty, A.M. Valdes, which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.