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

Abstract

ObjectiveTo 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).MethodsThe 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.ResultsThe 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.ConclusionsA 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.

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…In mice, genetic deletion of TRPV1 reduced (but did not eliminate) tissue damage and mechanical hyperalgesia in the complete Freund's adjuvant (CFA) model of chronic arthritis (Szabó et al, 2005). TRPV1 is increased in synovial samples taken from patients with OA (Engler et al, 2007;Kelly et al, 2013), and the loss-of-function TRPV1 variant I585V has been linked to a decreased risk for painful OA (Valdes et al, 2011). Taken together, these findings identify TRPV1 as a promising target to relieve OA pain.…”

“…Chronic neuropathic pain is an even better example. Although the loss-of-function TRPV1 variant I585V was reported to confer decreased risk for painful OA (Valdes et al, 2011), neither the selective TRPV1 antagonist AMG9810, nor the TRPA1 blocker HC-030031, ameliorated ongoing spontaneous pain in a model of advanced OA (Okun et al, 2012). Moreover, the TRPV1 antagonist ABT-116 failed to provide pain relief in client-owned dogs with hip OA (Malek et al, 2012), and a clinical trial with AZD1386 involving 241 patients with OA in seven different countries had to be terminated prematurely for lack of efficacy (Svensson et al, 2010;Miller et al, 2014).…”

“…An I585V variant of TRPV1 (that shows decreased channel activity) reportedly might confer decreased genetic risk for painful knee osteoarthritis (OA) (Valdes et al, 2011). The same genetic variant of TRPV1, I585V, is also protective against childhood asthma (CanteroRecasens et al, 2010).…”

<b><i>TRPV1</i></b> Gene Polymorphisms Are Associated with Type 2 Diabetes by Their Interaction with Fat Consumption in the Korean Genome Epidemiology Study

“…The TRPV1 rs8065080 T allele (Ile) is reported to be associated with lower thermal pain sensitivity [30,31]. It significantly contributes to the somatosensory abnormalities in neuropathic pain patients [32].…”

Knee Pain in Adults & Adolescents, Diagnosis and Treatment

“…It is also likely that individuals differ in perception of pain. Valdes et al 2011 [27] has reported an amino acid variant in the TRPV1 gene is associated with lower pain thresholds in radiographic OA.…”