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, 159 (6), 1064-1073

Genetic Variation in P2RX7 and Pain Tolerance

Affiliations

Genetic Variation in P2RX7 and Pain Tolerance

Oleg Kambur et al. Pain.

Abstract

P2X7 is a nonselective cation channel activated by extracellular ATP. P2X7 activation contributes to the proinflammatory response to injury or bacterial invasion and mediates apoptosis. Recently, P2X7 function has been linked to chronic inflammatory and neuropathic pain. P2X7 may contribute to pain modulation both by effects on peripheral tissue injury underlying clinical pain states, and through alterations in central nervous system processing, as suggested by animal models. To further test its role in pain sensitivity, we examined whether variation within the P2RX7 gene, which encodes the P2X7 receptor, was associated with experimentally induced pain in human patients. Experimental pain was assessed in Tromsø 6, a longitudinal and cross-sectional population-based study (N = 3016), and the BrePainGen cohort, consisting of patients who underwent breast cancer surgery (N = 831). For both cohorts, experimental pain intensity and tolerance were assessed with the cold-pressor test. In addition, multisite chronic pain was assessed in Tromsø 6 and pain intensity 1 week after surgery was assessed in BrePainGen. We tested whether the single-nucleotide polymorphism rs7958311, previously implicated in clinical pain, was associated with experimental and clinical pain phenotypes. In addition, we examined effects of single-nucleotide polymorphisms rs208294 and rs208296, for which previous results have been equivocal. Rs7958311 was associated with experimental pain intensity in the meta-analysis of both cohorts. Significant associations were also found for multisite pain and postoperative pain. Our results strengthen the existing evidence and suggest that P2X7 and genetic variation in the P2RX7-gene may be involved in the modulation of human pain sensitivity.

Conflict of interest statement

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Figures

Figure 1.
Figure 1.
Pain intensity and tolerance in the cold-pressor task in the Tromsø 6 and BrePainGen cohorts. Upper left panel shows the time vs cold pain intensity (CPI) curve during the cold-pressor task. Cold pain intensity (±SEM) is plotted on the y-axis and time on the x-axis. Area under the time-CPI curve (CPI AUC% + SEM) is shown on the upper right panel. Cold withdrawal times (CWTs) are shown in the lower panel as a Kaplan–Meier plot with the cumulative proportion of cold withdrawal plotted on y-axis and time on x-axis. BR, BrePainGen; f, female; m, male; NRS, numerical rating scale; TR6, Tromsø 6.
Figure 2.
Figure 2.
Human P2RX7 variants and cold-pressor pain in the Tromsø and BrePainGen data sets: SNP rs7958311. Experimental pain was assessed using the cold-pressor task. Cold pain intensity (CPI) was assessed using the numeric rating scale (NRS 0-10). Cold pain intensity values missing after CWT were recoded as 10 (maximum). Time-CPI curves of the different genotypes are shown (A–C) and CPI (±SEM) is plotted on y-axis and time on x-axis. Areas under the time-CPI curves (AUC%) were calculated by trapezoidal rule and are shown as genotype mean ± SEM (D–F). Withdrawal time (CWT; G–I) was used as an indicator of pain tolerance. Cold withdrawal time was analyzed using an additive genetic model and Cox proportional hazards model. The duration of the cold-pressor task is plotted on x-axis. The y-axis shows the cumulative proportion of cold withdrawal. Numbers in parentheses indicate n for each genotype group. Asterisks indicate the statistical significance of the genotype effects (*P < 0.05, linear regression, additive model; ****P < 0.0001, effect of genotype, 2-way ANOVA). ANOVA, analysis of variance; CWT, cold withdrawal time.
Figure 3.
Figure 3.
Meta-analysis of P2RX7 rs7958311 variants and pain in the cold-pressor task in the BrePainGen and Tromsø data sets. Experimental cold pain was assessed using the cold-pressor task. Cold withdrawal time (CWT) was analyzed using an additive genetic model and Cox proportional hazards model (Cox regression). Pain intensity (CPI) was assessed using numeric rating scale (NRS 0-10). Area under the time-CPI curve (CPI AUC%) was calculated as an indicator of pain intensity and analyzed using an additive genetic model and linear regression. The figure shows associations between CPI AUC% (A) and CWT (B) and SNP rs7958311 in the BrePainGen and Tromsø 6 cohorts as well as in the meta-analysis (fixed effect model, females). CI, confidence interval; CPI, cold pain intensity; HR, hazard ratio.
Figure 4.
Figure 4.
Human P2RX7 variant SNP rs7958311 reduces the intensity and incidence of clinical pain. Postoperative pain intensity was assessed in the BrePainGen cohort using the numeric rating scale (NRS 0-10) (A). Worst pain occurring at any site was recorded daily for 7 days after breast cancer surgery and used as the phenotype. Pain intensity was analysed using 2-way analysis of variances with time and genotype as independent variables (genotypes: AA, n = 45; AG, n = 351, GG, n = 527). In the figure, pain intensity is shown as genotype mean ± SEM. Asterisks indicate the effect of genotype (*P < 0.05, logistic regression; **P < 0.005, 2-way ANOVA). Chronic multisite pain was assessed in the Tromsø 6 cohort (B). Multisite pain was defined as pain with intensity of at least 4 on the numeric rating scale (NRS) which lasted at least for 3 months occurring daily at 4 or more body sites out of a total of 15. Patients fulfilling the phenotype criteria were considered as cases and the rest of the cohort as controls. Genotypes were compared using logistic regression (additive model; genotypes: AA, n = 116; AG, n = 620, GG, n = 902). Prevalence of chronic multisite pain in different genotypes is shown in panel (B). ANOVA, analysis of variance.

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