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Meta-Analysis
. 2011 Sep;70(9):1556-61.
doi: 10.1136/ard.2010.148122. Epub 2011 May 25.

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis

Ana M Valdes  1 , Gert De Wilde, Sally A Doherty, Rik J Lories, Frances L Vaughn, Laura L Laslett, Rose A Maciewicz, Anushka Soni, Deborah J Hart, Weiya Zhang, Kenneth R Muir, Elaine M Dennison, Margaret Wheeler, Paul Leaverton, Cyrus Cooper, Tim D Spector, Flavia M Cicuttini, Victoria Chapman, Graeme Jones, Nigel K Arden, Michael Doherty
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Free PMC article
Meta-Analysis

The Ile585Val TRPV1 variant is involved in risk of painful knee osteoarthritis

Ana M Valdes et al. Ann Rheum Dis. 2011 Sep.
Free PMC article

Abstract

Objective: To assess if a coding variant in the gene encoding transient receptor potential cation channel, subfamily V, member 1 (TRPV1) is associated with genetic risk of painful knee osteoarthritis (OA).

Methods: The Ile585Val TRPV1 variant encoded by rs8065080 was genotyped in 3270 cases of symptomatic knee OA, 1098 cases of asymptomatic knee OA and 3852 controls from seven cohorts from the UK, the USA and Australia. The genetic association between the low-pain genotype Ile-Ile and risk of symptomatic and asymptomatic knee OA was assessed.

Results: The TRPV1 585 Ile-Ile genotype, reported to be associated with lower thermal pain sensitivity, was associated with a lower risk of symptomatic knee OA in a comparison of symptomatic cases with healthy controls, with an odds ratio (OR) of 0.75 (95% CI 0.64 to 0.88; p=0.00039 by meta-analysis) after adjustment for age, sex and body mass index. No difference was seen between asymptomatic OA cases and controls (OR=1.02, 95% CI 0.82 to 1.27 p=0.86) but the Ile-Ile genotype was associated with lower risk of symptomatic versus asymptomatic knee OA adjusting for covariates and radiographic severity (OR=0.73, 95% CI 0.57 to 0.94 p=0.0136). TRPV1 expression in articular cartilage was increased by inflammatory cytokines (tumour necrosis factor α and interleukin 1). However, there were no differences in TRPV1 expression in healthy and arthritic synovial tissue.

Conclusions: A genotype involved in lower peripheral pain sensitivity is significantly associated with a decreased risk of painful knee OA. This indicates a role for the pro-nociceptive gene TRPV1 in genetic susceptibility to symptomatic knee OA, which may also be influenced by a role for this molecule in cartilage function.

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Conflict of interest statement

Competing interest Dr. RA Maciewicz is employed by, owns stock and has patent applications for AstraZeneca. All other authors and organizations declare no conflict of interest.

Figures

Figure 1
Figure 1
Forest plot showing study specific estimates for the association between the Ile–Ile TRPV1 585 genotype and (A) knee osteoarthritis (OA; regardless of symptoms) versus controls; (B) symptomatic knee OA versus controls; (C) asymptomatic knee OA versus controls; (D) symptomatic versus asymptomatic knee OA. *OR estimates are adjusted for age sex and body mass index (BMI); †OR estimates are adjusted for age, sex, BMI and Kellgren–Lawrence grade; ‡OR estimates are adjusted for relatedness between twins. COS, Clearwater Osteoarthritis Study; GOAL, Genetics of Osteoarthritis and Lifestyle; HCS, Hertfordshire Cohort Study; TASOAC, Tasmanian Older Adult Cohort.
Figure 2
Figure 2
Gene expression of TRPV1 in joint tissues. (A) Cartilage explants from knee prosthesis surgery patients (n=4) were cultured in Dulbecco's modified Eagle's medium/10% fetal bovine serum for 10 days with or without tumour necrosis factor α (TNFα) and interleukin 1 (IL-1; 10 ng/ml) (triplicates). TRPV1 expression was determined by real-time quantitative PCR and analysed using the delta-delta Ct method standardised for independent biological replicates. Data are expressed as mean and 95% CIs. The difference between the control conditions and the cytokine cultured conditions yielded a p<0.0001 in a Mann–Whitney U test. (B) Synovial biopsy specimens were analysed for expression of TRPV1 by real-time qualitative PCR and data expressed as mean and 95% CIs using relative expression compared with housekeeping gene β-actin (n=3). The difference between the control conditions and the cytokine cultured conditions yielded a p<0.0.4 in a Mann–Whitney U test.
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