Genome-wide association scan of neuropathic pain symptoms post total joint replacement highlights a variant in the protein-kinase C gene

Abstract

Neuropathic pain-like joint symptoms (NP) are seen in a proportion of individuals diagnosed with osteoarthritis (OA) and post total joint replacement (TJR). In this study, we performed a genome-wide association study (GWAS) using NP as defined by the painDETECT questionnaire (score 412 indicating possible NP) in 613 post-TJR participants recruited from Nottinghamshire (UK). The prevalence of possible NP was 17.8%. The top four hits from the GWAS and two other biologically relevant singlenucleotide polymorphisms (SNPs) were replicated in individuals with OA and post TJR from an independent study in the same area (N = 908) and in individuals from the Rotterdam Study (N = 212). Three of these SNPs showed effect sizes in the same direction as in the GWAS results in both replication cohorts. The strongest association upon meta-analysis of a recessive model was for the variant allele in rs887797 mapping to the protein kinase C alpha (PRKCA) gene odds ratio (OR) possNP = 2.41 (95% CI 1.74-3.34, P = 1.29 × 10 − 7). This SNP has been found to be associated with multiple sclerosis and encodes a functional variant affecting splicing and expression of the PRKCA gene. The PRKCA gene has been associated with long-term potentiation, synaptic plasticity, chronic pain and memory in the literature, making this a biologically relevant finding.

The Rotterdam Study: 2018 update on objectives, design and main results

“…In addition, we identified a variant in the protein-kinase C gene to be associated with neuropathic pain symptoms after total joint replacement highlights [ 217 ].…”

Osteoarthritis year in review 2018: genetics and epigenetics

“…These included one hand OA study 1 , one hip OA study 2 , and two knee OA studies in Chinese cohorts 3,4 . One additional study examined variation associated with neuropathic pain following total joint replacement 5 (summarized in Table II).…”

Genetic studies of human neuropathic pain conditions: a review

“…Thus, the publication of 3 genome-wide association studies (GWAS) in neuropathic pain during the past 3 years is an exciting recent development, even if the top findings in these studies are just below the threshold of genome-wide significance. 95 , 96 , 150 Aside from these GWAS, studies done in patients genotyped or sequenced at targeted gene panels have been informative about loci that may modulate susceptibility to developing neuropathic pain after a traumatic event, physical injury, or the onset of another disease. Variants identified in this disease category are listed in Table 1 .…”

“…The first genome-wide scan in a postoperative pain cohort (individuals with knee and hip replacement surgery) was published this year. 150 The strongest associated variant, just shy of genome-wide significance (rs887797, P = 1.29 × 10e-7), lies in PRKCA , which encodes protein kinase C alpha, and the next best association is for a variant in MAT2B (rs7734804, P = 5.25 × 10e-6). Both of these associations were confirmed in one of their 2 replication joint-related neuropathic pain cohorts.…”