PER3 variable number tandem repeat (VNTR) polymorphism modulates the circadian variation of the descending pain modulatory system in healthy subjects

Fabiana Carvalho,Mario Pedrazzoli,Andressa Souza,Assunta Gasparin,Iraci Da Silva Lucena Torres,Maxciel Zortea,Franciele Dos Santos,Wolnei Caumo,Felipe Fregni

doi:10.1038/s41598-019-45527-y

Abstract

We evaluated the circadian pattern of variation of the descending pain modulatory system (DPMS) using a conditioned pain modulation (CPM) paradigm according to the variable-number tandem-repeat (VNTR) of the clock gene PER3 polymorphism. We assessed the relationship between the genotypes PER34/4 and PER35/5 and the temporal pattern of variation across the day using the following measures: the heat pain threshold (HPT), the cold pressure test (CPT), and the serum levels of BDNF and S100-B protein. The ∆-values (from afternoon to morning) of these measures were used for the analysis. The circadian phenotype was according to the mid-point sleep time established by the Munich ChronoType Questionnaire (MCTQ). We included 18 healthy volunteers (15 women) ages 18 to 30. A Generalized Linear Model (GLM) revealed a significant difference in the ∆-CPM-task between Per34/4 and Per35/5 genotypes, with means (SDs) of −0.41 (0.78) vs. 0.67 (0.90) (χ2 = 7.256; df = 1′ P = 0.007), respectively. Both sleep deprivation of at least 2 h/day (B = −0.96, 95% confidence interval (CI) = −1.86 to −0.11)) and the ∆-S100-B protein (−0.03, 95% CI = −0.06 to −0.02) were negatively correlated with the ∆-CPM-task, while the ∆-BDNF was positively correlated with the ∆-CPM-task (0.015, 95% CI = 0.01 to 0.03). We observed a difference in the ∆-CPT between PER34/4 and PER35/5 (0.11 (4.51) vs. 4.00 (2.60), respectively) (χ2 = 22.251; df = 1 P = 0.001). These findings suggest that the polymorphism of PER35/5 is associated with a decrease in the inhibitory function of the DPMS over the course of the day. However, sleep deprivation is an independent factor that also reduces the inhibitory function of the DPMS, regardless of the PER3 VNTR polymorphism.

Highlights

(VNTR) of the clock gene PER3 polymorphism
This study confirmed the hypothesis that there is a circadian pattern in the inhibitory potency of the descending pain-modulating system (DPMS) according to the PER3 VNTR polymorphism
Our findings do not allow us to test predictions of polymorphism in the PER3 gene as downstream pathways regulated by the molecular clock, it is likely that the different genotypes (PER34/4 and PER35/5) may change neuroplasticity properties, which would explain the different responses in the circadian variation of psychophysical pain measures, nominally cold pressure test (CPT) and CPM-task

Summary

Introduction

(VNTR) of the clock gene PER3 polymorphism. We assessed the relationship between the genotypes PER34/4 and PER35/5 and the temporal pattern of variation across the day using the following measures: the heat pain threshold (HPT), the cold pressure test (CPT), and the serum levels of BDNF and S100-B protein. The PERIOD3 (PER3) clock gene plays a limited role in the primary clock mechanism, it does drive circadian rhythms in humans according to a variable number tandem repeat consisting of either 4 or 5 repeated 54-bp sequences encoding 18 amino acids (PER34 or PER35). The top-down inhibition of pain processing in the dorsal horn exhibits a rhythm across the day[20] All of these factors could influence the inhibitory function of the descending pain-modulating system (DPMS), which has a central role in the pathophysiology of chronic pain. Its poor function has been a predictor for postoperative pain[21,22]

Methods

Results

Conclusion