Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
The FAAH Gene Is Involved in Risk of Symptomatic Osteoarthritis of the Knee and in Pain in Osteoarthritis.
Valdes1, Ana M., Malfait3, Anne-Marie, Doherty5, Sally, Das4, Rosalina, Wheeler5, Margaret, Hart2, Deborah, Spector2, Tim D.
King's College London, London, United Kingdom
King's College London
Rush University Medical Center, Chicago, IL
Rush University Medical Center
University of Nottingham, United Kingdom
University of Southampton - University of Oxford, United Kingdom
Osteoarthritis (OA) is the most common large joint (hip or knee) pathology in older people and the main cause for large joint pain and disability in this age-group. FAAH (fatty acid amide hydrolase) is an enzyme that degrades the endocannabinoid anandamide. In animal models genetic or pharmacological inactivation of FAAH produces analgesic, anti-inflammatory, anxiolytic, and antidepressant phenotypes and human genetic variants have been associated with increased cold perception. Our aim was to assess if a genetic variant in the FAAH gene previously implicated in peripheral pain sensitivity is involved in risk for large joint OA.
Methods and Subjects:
The rs4141964 SNP in the FAAH gene was typed in 1847 knee OA cases, 1199 hip OA cases and 2036 controls from three independent UK cohorts (Nottingham, Chingford and Hertfordshire). Expression of the faah gene was tested in the dorsal root ganglia (DRG) of naive and medial meniscus destabilized (DMM) C57BL/6 mice. DMM operated mice were tested for mechanical allodynia at 4, 8, and 16 weeks after surgery, using von Frey fibers. At each of these time points, the DRG L2-L5 were harvested and mRNA was extracted for RT-PCR analysis.
The minor allele (A) at rs4141964 previously implicated in higher pain sensitivity - was found to be consistently increased among OA cases compared to controls in all three cohorts. A fixed effects meta-analysis for knee OA yielded OR= 1.17 95% CI 1.05 1.29; p=0.003 (Figure 1) and OR= 1.15 95% CI 1.01 1.30; p=0.034 for hip OA. No significant between-study heterogeneity was observed (I2=0%).
Figure 1. Genetic association between the FAAH polymorphism rs4141964 and knee OA in three UK cohorts. Forest plot showing the study specific estimates and the fixed effects meta-analysis estimate.
In the Hertfordshire cohort study the AA genotype was increased among OA patients with knee pain compared with those with asymptomatic OA (p<0.06). In the murine DMM model, progressive mechanical allodynia was apparent in the operated hind limb, 48 weeks post surgery, and then resolved 816 weeks after surgery. FAAH mRNA levels in the innervating DRG correlated with the mechanical allodynia, and FAAH mRNA was over-expressed relative to naive mice at 8 weeks, but not at 4 or 16 weeks post-surgery.
The FAAH gene appears to be implicated in large joint OA and OA pain.
Supported by the EU FP7 large collaborative project TREAT-OA (grant 200800), the MRC UK, Arthritis Research UK and the Oxford NIHR Musculoskeletal Biomedical Research Unit
To cite this abstract, please use the following information:
Valdes, Ana M., Malfait, Anne-Marie, Doherty, Sally, Das, Rosalina, Wheeler, Margaret, Hart, Deborah, et al; The FAAH Gene Is Involved in Risk of Symptomatic Osteoarthritis of the Knee and in Pain in Osteoarthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :841