Warner, Sophie Catriona
(2016)
The genetics and epidemiology of neuropathic pain-like symptoms in people with osteoarthritis and post-total joint replacement.
PhD thesis, University of Nottingham.
Abstract
Background: Osteoarthritis (OA) is the most common form of arthritis and one of the leading causes of pain and disability worldwide. The only long-term treatment for severe, end-stage OA is removal of the damaged tissues by a total joint replacement (TJR). However for some individuals, pain continues to be a concern post-TJR. As well as this, a proportion of individuals with OA and post-TJR suffer with neuropathic pain-like symptoms (NP). NP is caused by changes or damage to the nervous system, which can occur as a result of nerve injury or chronic pain. NP differs from nociceptive pain in that symptoms can occur in response to a non-harmful stimulus, or in the absence of a stimulus. It is also hard to treat NP effectively. The molecular mechanisms underlying pain and NP in OA are still not well understood and therefore require further study. The high prevalence of OA means research in this field has the potential to impact many individuals.
Objectives: The aims of this thesis were a) to describe the effects of NP on post-TJR satisfaction, b) to investigate the genetic contribution to NP in people post-TJR using a genome-wide approach and c) to analyse two candidate genes for an association with pain in people with symptomatic OA or asymptomatic OA.
Methods: Individuals from three independent Nottinghamshire-based cohorts were analysed: 1) the Genetics of OA and Lifestyle (GOAL) study, 2) the Nottingham Genetics of OA Study (NGOAS) and 3) individuals recruited from Nottinghamshire who formed part of the Arthritis Research Council OA Genetics (arcOGEN) Consortium. Participants from all three studies were X-rayed at the time of recruitment and the Kellgren-Lawrence (K/L) grading system was used to classify radiographic severity of OA at the joints of interest. All participants answered questionnaires containing validated assessment tools. NP was assessed using the painDETECT questionnaire.
Logistic regression analysis was used to identify factors associated with NP in people with OA and post-TJR. A modified LASSO variable reduction method was used to identify the contribution of these factors to post-TJR satisfaction. A genome-wide association scan (GWAS) was used to assess the genetic contribution to NP post-TJR. Candidate gene analysis allowed variants in two genes to be investigated for an association with pain and NP in people with OA and post-TJR.
Results: NP was found to be a very strong predictor of post-TJR satisfaction: AUC=0.79 (0.75-0.82). Other contributing factors were the site of the TJR (knee or hip replacement), history of revision surgery and other measures of pain. The use of opioid medications was also significant associated with a lower likelihood of satisfaction post-TJR: OR=0.54 95% CI 0.36-0.80, p=0.002 after adjustment for covariates and pain intensity. Overall, possible NP affected 17.3% of post-TJR patients (10.2% of those satisfied, 41.9% of those partially or not satisfied).
A reproducible genetic effect was found between a single nucleotide polymorphism (SNP) in the protein kinase C alpha (PRKCA) gene and the risk of possible NP in people with knee pain, knee OA, hip OA and post-TJR: OR= OR=2.41 95% CI 1.74-3.34, p=1.29x10-7 after meta-analysis in three cohorts.
Candidate gene analysis found a consistent genetic effect in the substance P receptor gene (TACR1). The G allele at rs11688000 was associated with lower risk of symptomatic OA (OR=0.84 95% CI 0.70-1.00, p=0.047). This variant was also associated in four independent cohorts, yielding an overall OR=0.80 95% 0.70-0.91, p=8.66x10-4 after meta-analysis in five cohorts (total symptomatic OA n=1,566, total asymptomatic OA n=894).
A SNP in the interleukin-15 receptor alpha (IL15RA) gene was found to be significantly associated with the risk of symptomatic OA versus asymptomatic OA: OR=1.56 95% 1.18-2.07, p=0.002. This remained significant (OR=1.43 95% CI 1.04-1.99, p=0.029) after adjustment for covariates (age, sex and body mass index) and tibiofemoral K/L knee OA radiographic grade. Another variant in the IL15RA gene was significantly associated with NP post-TJR: OR=0.76 95% 0.63-0.92, p=0.005 after meta-analysis in two cohorts.
Conclusion: The significant contribution of NP to post-TJR satisfaction highlights the importance of identifying cases of NP in people with OA. The PDQ used here to measure NP is a validated tool which could easily be introduced more widely into clinical practice post-TJR. These results also highlight the prevalence of NP symptoms post-TJR. My work also has identified a biologically relevant genetic effect for the risk of NP post-TJR. The SNPs identified in this GWAS provide the first results from a GWAS on NP in OA and could inform future replication studies in additional cohorts. The association of variants in the TACR1 and IL15RA genes with pain in people with OA and, the case of IL15RA, with NP pain post-TJR suggests potential treatment targets for future studies into therapies to treat pain and NP in people with OA.
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