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Abstract. Light AR, Bateman L, Jo D, Hughen RW, VanHaitsma TA, White AT, Light KC (University of Utah, Salt Lake City, UT, USA). Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome. J Intern Med 2012; 271: 64–81.
Objectives. To determine mRNA expression differences in genes involved in signalling and modulating sensory fatigue, and muscle pain in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM) at baseline, and following moderate exercise.
Design. Forty-eight patients with CFS only, or CFS with comorbid FM, 18 patients with FM that did not meet criteria for CFS, and 49 healthy controls underwent moderate exercise (25 min at 70% maximum age-predicted heart rate). Visual-analogue measures of fatigue and pain were taken before, during and after exercise. Blood samples were taken before and 0.5, 8, 24 and 48 h after exercise. Leucocytes were immediately isolated from blood, number coded for blind processing and analyses and flash frozen. Using real-time, quantitative PCR, the amount of mRNA for 13 genes (relative to control genes) involved in sensory, adrenergic and immune functions was compared between groups at baseline and following exercise. Changes in amounts of mRNA were correlated with behavioural measures and functional clinical assessments.
Results. No gene expression changes occurred following exercise in controls. In 71% of patients with CFS, moderate exercise increased most sensory and adrenergic receptor’s and one cytokine gene’s transcription for 48 h. These postexercise increases correlated with behavioural measures of fatigue and pain. In contrast, for the other 29% of patients with CFS, adrenergic α-2A receptor’s transcription was decreased at all time-points after exercise; other genes were not altered. History of orthostatic intolerance was significantly more common in the α-2A decrease subgroup. FM-only patients showed no postexercise alterations in gene expression, but their pre-exercise baseline mRNA for two sensory ion channels and one cytokine were significantly higher than controls.
Conclusions. At least two subgroups of patients with CFS can be identified by gene expression changes following exercise. The larger subgroup showed increases in mRNA for sensory and adrenergic receptors and a cytokine. The smaller subgroup contained most of the patients with CFS with orthostatic intolerance, showed no postexercise increases in any gene and was defined by decreases in mRNA for α-2A. FM-only patients can be identified by baseline increases in three genes. Postexercise increases for four genes meet published criteria as an objective biomarker for CFS and could be useful in guiding treatment selection for different subgroups.
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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), as defined by the Fukuda research criteria , is an otherwise unexplained cluster of symptoms lasting at least 6 months that includes profound, remitting/relapsing fatigue that impairs functioning and is not relieved by rest or recovery. Four or more of the following eight symptoms must also be present: (i) postexertional malaise (described as greatly increased fatigue and the feeling of sickness beginning 6–24 h after exercise and continuing for several days or weeks), (ii) unrefreshing sleep, (iii) muscle pain, (iv) joint pain, (v) new or a change in headaches, (vi) impairment of memory or concentration, (vii) sore throat and (viii) tender lymph nodes .
The Canadian Clinical Criteria for CFS require a significant degree of new onset physical and mental fatigue that substantially reduces activity levels and also requires (from above criteria) #1, #2, one of #3–#5, neurocognitive symptoms (including impairment of concentration and short-term memory, inability to focus vision, ataxia, muscle weakness, photophobia, periods of anxiety), and at least one symptom from each of the following categories: immune manifestations (tender lymph nodes, sore throat or new sensitivities to food and medications and/or chemicals), autonomic manifestations (orthostatic intolerance, POTS, extreme pallor, nausea and irritable bowel syndrome, palpitations, exertional dyspnoea) or neuroendocrine manifestations (subnormal temperature, sweating episodes, intolerance of heat and cold, weight changes, anorexia or abnormal appetite, worsening of symptoms with stress) .
Up to 70% of patients with ME/CFS (hereafter referred to as CFS) also meet the criteria set by the American College of Rheumatology for Fibromyalgia Syndrome (FM) as a condition of unknown aetiology that consists of widespread muscle/connective tissue pain present in four quadrants of the body (bilateral, upper and lower body) for 3 months or longer. There is also painful sensitivity to pressure at tender points (with pain reported for at least 11 of 18 tender points) . Recent guidelines published by ACR experts, but not yet validated, have suggested altering this definition to permit easier application in the clinical setting . In both CFS and FM, the major symptoms, and most of the ancillary symptoms, are subjectively determined.
For CFS, the major symptom, ‘fatigue’, is a clinical measure that is only loosely associated with the physiologists’ traditional definition of ‘fatigue’ which is the inability to voluntarily contract skeletal muscle . The clinical ‘fatigue’ includes both the sensation of tiredness and increased effort in skeletal muscle contraction and also increased effort in mental functions. For FM, the major symptom is muscle pain, which has been poorly studied in comparison to cutaneous pain.
Recently, our laboratory was able to identify some of the molecular receptors responsible for the sensory neuron signalling of muscle fatigue and muscle pain . In addition, we have discovered that adrenergic receptors can also contribute to enhanced muscle pain [7, 8]. We further discovered that these molecular receptors are expressed by human leucocytes, and that their expression is altered by exercise that worsens muscle pain and muscle fatigue . In patients with CFS, we showed that mRNAs of sensory and adrenergic molecular receptors as well as two cytokines were dramatically increased 30 min to at least 48 h following moderate exercise (25 min of combined arm and leg exercise) . These findings are similar to previous reports suggesting that patients with CFS have complex dysregulation of several physiological systems including the immune system (cytokines), the central nervous system, cellular energy and transport and cardiovascular system . Dysregulation of these systems singly or together could contribute to some or all of the symptoms that define CFS and FM, but especially could help explain the important symptom of postexertional malaise.
Here, we report on an increased sample of patients with CFS and compare their gene regulation with that of patients with FM. With the larger sample, we confirmed our original finding of increased gene expression of a number of sensory, adrenergic and cytokine genes and discovered a major subgroup of CFS that is characterized by a large postexercise decrease in gene expression of the adrenergic alpha 2A receptor (α-2A). This subgroup was also characterized by a predominance of orthostatic intolerance when compared with other patients with CFS. We also discovered that patients with FM only (who do not meet criteria for CFS) do not show large gene expression changes following exercise, but, rather have baseline increases in gene expression for two sensory molecular receptors and the immune cytokine IL10.
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Data were obtained from 48 patients with CFS, 18 patients with FM and 49 control subjects. Table 1 summarizes the characteristics of these groups, with the patients with CFS divided into the two major subgroups suggested by the data in this study. Age and gender were well matched between controls and the CFS patient groups, but less well matched for the FM group; however, neither gender nor age were significant covariates in the patient with FM analyses.
Table 1. Subject characteristics for controls, chronic fatigue syndrome (CFS) patients, and fibromyalgia syndrome (FM) patients
|Characteristic||Controls (n = 49; 29F)||All CFS Patients (n = 48; 33F)||α-2A increase CFS Patients (n = 34; 25F)||α-2A decrease CFS Patients (n = 14; 8F)||FM patients (n = 18, 15F)||All CFS P*||α-2A+ CFS Patients P*||α-2A− CFS Patients P*||FM P*|
|Age (years)||42.0 ± 1.9||41.8 ± 1.9||41.4 ± 2.2||42.8 ± 3.5||50.4 ± 2.6||0.998||0.979||0.971||0.037|
|BMI (kg m−2)||23.9 ± 0.7||26.2 ± 0.8||26.5 ± 0.9||25.6 ± 1.3||26.5 ± 1.4||0.055||0.050||0.448||0.135|
|Resting SBP (mmHg)||126.4 ± 1.9||123.0 ± 2.6||120.9 ± 3.0||128.3 ± 5.0||126.1 ± 3.0||0.550||0.216||0.902||0.994|
|Resting DBP (mmHg)||80.5 ± 1.6||80.6 ± 1.5||80.2 ± 1.8||81.7 ± 2.9||87.1 ± 2.2||0.996||0.990||0.909||0.048|
|Exercise SBP (mmHg)||157.0 ± 3.2||148.7 ± 3.7||147.8 ± 4.6||150.9 ± 6.4||161.1 ± 5.9||0.199||0.195||0.660||0.766|
|Exercise DBP (mmHg)||90.8 ± 1.8||88.6 ± 1.6||88.2 ± 2.1||89.6 ± 2.6||95.7 ± 3.1||0.600||0.545||0.931||0.253|
|Resting HR (baseline)||76.7 ± 1.8||82.4 ± 2.4||83.4 ± 2.7||80.1 ± 5.0||80.2 ± 3.8||0.144||0.087||0.687||0.683|
|Exercise HR (BPM)||126.8 ± 1.4||119.8 ± 2.2||121.6 ± 2.5||115.6 ± 4.4||122.8 ± 3.2||0.017||0.172||0.067||0.446|
|Exercise HR (%PMHR)||71.3 ± 0.5||67.3 ± 1.1||68.1 ± 1.1||65.4 ± 2.5||61.7 ± 1.9||0.004||0.031||0.081||<0.001|
|Exercise WR (Kcal kg−1 per min)||7.6 ± 0.7||4.3 ± 0.2||4.1 ± 0.2||4.7 ± 0.4||5.1 ± 0.4||<0.001||<0.001||0.002||0.023|
|Exercise RPE||3.1 ± 0.1||5.0 ± 0.2||5.0 ± 0.3||5.1 ± 0.5||4.5 ± 0.4||<0.001||<0.001||0.004||0.012|
|No. of Ortho intolerance||NA||18 (38%)||8 (24%)||10 (71%)||0|| ||0.0003||0.008|| |
|Viral onset||NA||29 (60%)||19 (56%)||10 (71%)||1 (5%)|| || || || |
|Tested on pain med||1||15 (31%)||11 (32%)||4 (29%)||3 (16%)|| || || || |
|On anti-convulsants||0||11 (23%)||6 (18%)||5 (36%)||5 (28%)|| || || || |
|On anti-depressant||12 (24%)||35 (73%)||24 (71%)||11 (79%)||10 (56%)|| || || || |
We attempted to adjust for fitness-level mismatches by exercising all patients and controls at the same relative exercise intensity, to 70% of age-predicted, maximal heart rate. The majority of patients with CFS and FM were able to attain the 70% level, but a few could not, leading to small, but significantly lower percentages of maximal heart rate in all patient groups. In spite of lower relative exercise intensities and lower work rates, all patient groups reported higher perceived exertion (RPE) during the exercise task than controls (see Table 1).
Figure 1 depicts mean ratings of mental fatigue, physical fatigue and pain on our 0–100 scale in the various groups before, during and after the exercise task. In control subjects, exercise did not increase ratings of mental fatigue or pain at any time-point; and physical fatigue was increased only at mid-exercise and not at any postexercise time. In sharp contrast, exercise caused significant increases in all fatigue and pain measures at all time-points during and after exercise in CFS only and in CFS + FM patients. Patients with FM reported increases in pain and physical fatigue at all time-points and increases in mental fatigue at all time-points except during and immediately after exercise. As can be seen in Fig. 1, the two CFS subgroups distinguished by postexercise adrenergic α-2A increases versus decreases (described in detail below) did not differ from each other in ratings of pain or fatigue. Not surprisingly (because these patients were defined by having less pain than FM or CFS + FM patients), patients with CFS only had lower pain scores during and immediately after exercise than the CFS + FM or FM groups. Thus, this very moderate level of exercise for 25 min caused postexertional malaise lasting 48 h in all CFS and FM patient groups, but not controls.
Gene expression results
Patients with CFS compared with patients with CFS who also have comorbid FM. Initially, we divided the patients with CFS into those that had CFS, but did not meet criteria for FM, and those patients with CFS who also met criteria for FM, i.e., they had both CFS and FM (CFS + FM). None of the descriptive variables in Table 1 were significantly different between these groups. Likewise, comparison of these two groups showed very similar gene expression both before and after exercise. Only postexercise ASIC3 AUC was greater in the CFS + FM versus the CFS-only patients (P < 0.046). For this reason, in all of the following analyses, CFS-only and CFS + FM patients are grouped together.
Patients with CFS showed no baseline changes in gene expression from controls; patients with FM showed baseline increases in three genes. Table 2 contains the average baseline values and significance values for postexercise AUC (0.5, 8, 24 and 48 h after exercise) for mRNA increases from baseline levels. None of the CFS subgroups differed from controls in expression of any gene at baseline, either as separate subgroups or combined into a single CFS group (all P values >0.145). In contrast, the FM group showed several differences from controls at baseline before exercise. They had significantly higher baseline quantities of mRNA for sensory receptors P2X4 (P < 0.001) and TRPV1 (P < 0.005), and for the cytokine IL10 (P < 0.031). Figure 2 graphs these differences. These differences were unaltered after covarying for age and gender differences.
Table 2. manova results, baseline means + SEs and anova results for all mRNAs relative to TF2B, and anova results for postexercise Area Under Curve (AUC) mRNA differences from controls in Patients with chronic fatigue syndrome (CFS) and patients with fibromyalgia syndrome (FM)
| ||Controls Baseline N = 49||All Patients with CFS Baseline N = 48||CFS α-2A Increase Baseline N = 34||CFS α-2A Decrease Baseline N = 14||FM Baseline N = 18||All Patients with CFS Baseline P||FM Baseline P||All CFS Patients AUC P N = 48||CFS α-2A Increase AUC P N = 34||CFS α-2A Decrease AUC P N = 14||FM AUC P N = 18|
| ASIC3||9.02E-03 ± 5.17E-04||7.79E-03 ± 7.03E-04||8.02E-03 ± 8.56E-04||7.26E-03 ± 8.32E-04||9.81E-03 ± 1.09E-03||0.298||0.462||0.200||0.54||0.443||0.925|
| P2X4||2.00E-01 ± 1.05E-02||1.86E-01 ± 1.38E-02||1.97E-01 ± 1.80E-02||1.62E-01 ± 1.50E-02||2.74E-01 ± 2.36E-02||0.693||0.001||0.002||0.002||0.547||0.570|
| P2X5||2.33E-01 ± 2.00E-02||2.43E-01 ± 2.47E-02||1.97E-01 ± 1.80E-02||3.23E-01 ± 4.23E-02||2.75E-01 ± 3.35E-02||0.395||0.282||0.043||0.022||0.888||0.629|
| TRPV1||1.23E-02 ± 7.94E-04||1.41E-02 ± 1.00E-03||1.35E-02 ± 1.12E-03||1.51E-02 ± 1.64E-03||1.66E-02 ± 1.09E-03||0.272||0.005||0.027||0.020||0.645||0.939|
| α-2A||5.42E-03 ± 6.87E-04||7.04E-03 ± 1.59E-03||7.68E-03 ± 2.10E-03||5.75E-03 ± 1.40E-03||3.61E-03 ± 6.32E-04||0.619||0.128||0.023||0.0005||0.019||0.297|
| β-1||3.25E-02 ± 1.03E-02||7.27E-02 ± 5.30E-02||9.15E-02 ± 7.43E-02||3.13E-02 ± 1.80E-02||5.92E-02 ± 3.68E-02||0.648||0.344||0.056||0.012||0.994||0.999|
| β-2||1.13E+00 ± 8.85E-02||9.98E-01 ± 7.17E-02||1.97E+00 ± 5.87E-01||9.09E-01 ± 6.96E-02||1.05E+00 ± 2.02E-01||0.481||0.673||0.002||0.001||0.998||0.594|
| COMT||2.33E-01 ± 1.88E-02||1.89E-01 ± 1.75E-02||1.90E-01 ± 1.91E-02||1.89E-01 ± 3.30E-02||2.29E-01 ± 1.82E-02||0.145||0.906||0.009||0.032||0.102||0.845|
| IL6||3.69E-03 ± 1.19E-03||3.98E-03 ± 4.86E-04||4.17E-03 ± 6.07E-04||3.55E-03 ± 7.14E-04||4.64E-03 ± 1.17E-03||0.966||0.651||0.253||0.135||0.998||0.701|
| IL10||4.61E-03 ± 3.81E-04||2.09E-02 ± 1.45E-02||2.85E-02 ± 2.02E-02||5.04E-03 ± 7.51E-04||6.24E-03 ± 6.47E-04||0.509||0.031||0.003||0.002||0.153||0.799|
| αLT||7.95E-02 ± 1.41E-02||8.21E-02 ± 1.29E-02||8.38E-02 ± 1.64E-02||7.84E-02 ± 1.75E-02||6.55E-02 ± 7.54E-03||0.985||0.550||0.307||0.140||0.974||0.980|
| TLR4||4.54E-01 ± 6.13E-02||4.34E-01 ± 3.95E-02||4.80E-01 ± 4.88E-02||3.31E-01 ± 5.10E-02||3.64E-01 ± 2.09E-02||0.939||0.376||0.196||0.110||0.995||0.973|
| CD14||2.14E+00 ± 1.34E-01||2.11E+00 ± 1.80E-01||2.30E+00 ± 2.27E-01||1.73E+00 ± 2.01E-01||2.37E+00 ± 2.21E-01||0.990||0.374||0.658||0.724||0.877||0.840|
Figure 2. Comparison of baseline gene expression in patients with fibromyalgia syndrome (FM) to that of age- and gender-matched controls. Because of the large differences in the amount of mRNA for different genes, the average baseline value of each of the significantly increased genes for the patients with FM was matched in magnitude for this graph. The scale for each of the genes (in amount relative to the control gene, TF2B) is indicated to the left of each bar. Con = Control subjects. Controls also marked with cross hatching. Colours are the same as for genes in Fig. 3.
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Postexercise gene expression changes in patient subgroups versus controls. Although their gene expression did not differ from controls prior to exercise, after exercise patients with CFS showed greater increases in mRNA than controls for seven of the genes under study. With all CFS subgroups combined, patients with CFS showed greater postexercise AUC increases than controls for P2X4, P2X5, TRPV1, α-2A, β-2, COMT and IL10 (P < 0.05 to P < 0.001;see Table 2).
In our previous study, unusual gene expression patterns in some patients with CFS suggested a possible subgroup, which was confirmed clinically by Dr Bateman. With the additional data from the present study, on the basis of changes in gene expression levels following exercise, we could define two major subgroups of patients with CFS. These subgroups were defined by postexercise increases versus decreases in mRNA of the adrenergic α-2A receptor. The larger CFS subgroup (71% of all patients with CFS) had increases in the α-2A receptor mRNA at one or more time-points following exercise (α-2A increase patients with CFS). This group showed large increases in all seven genes listed above as well as increases in β-1 AUC (See Table 2). As can be seen in Fig. 3 (compare A with B), increases in expression of the genes listed above compared to controls were observed at 30 min following the exercise period and lasted for the duration of the study, 48 h after the exercise period. This was confirmed by repeated measures analyses showing significant time effects after exercise indicating increases above baseline that were sustained throughout the postexercise period.
Figure 3. Graphs comparing gene expression increases following moderate exercise in patients with chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FM). All graphs plotted in log10 scale. For all graphs, baselines for all genes were normalized to 1. Scale on graphs is fold changes from baseline in mRNA quantity. Significant differences in the sum of all time-points for each gene (area under the curve) are indicated by * in the legend boxes to the right of each graph. Metabolite-detecting receptors are coloured in blues, adrenergic receptors and COMT are coloured in reds, and cytokine-related genes are coloured in greens. (a) Averages of mRNA fold changes after exercise for 49 Control subjects. No significant differences from baselines were noted. (b) Averages of mRNA fold changes after exercise in 34 patients with CFS and patients with CFS that also made criteria for FM that did not show decreases in α-2A adrenergic receptor mRNA following exercise. Significant differences are noted by asterisks in the legend box at right. See key under this graph for P value of asterisks. (c) Averages of mRNA fold changes after exercise for 14 patients with CFS and patients with CFS that also made criteria for FM that showed decreases in α-2A adrenergic receptor mRNA at all times following exercise. Only α-2A adrenergic receptor mRNA showed significant changes. For this graph, the data for ASIC3 from one extreme outlier were dropped. (d) Averages of mRNA fold changes after exercise for 18 patients with FM only. No differences from controls were seen at any time after exercise. This contrasts with baseline changes seen in Fig. 2.
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As shown inFig. 3candTable 2, the smaller subgroup (29% of all patients with CFS) demonstrated large decreases in α-2A mRNA at all time-points following exercise (α-2A decrease group). This group was also distinguished by a clinical history of orthostatic intolerance in most of the patients (see Table 1, No. of Ortho intolerance). Ten of the 14 α-2A decrease patients had clinical orthostatic intolerance compared with only 8 of 34 α-2A increase patients with CFS (71% vs. 18%, Χ2P < 0.008). In addition to this high rate of orthostatic intolerance, the α-2A decrease patients demonstrated no significant increases in expression of any of the other genes measured in this study compared to the Control group (see Fig. 3c and Table 2). Chronic fatigue syndrome-only and CFS + FM patients were similarly represented in both subgroups; the α-2A decrease group had six CFS-only patients and eight CFS + FM patients, while the α-2A increase group had nine CFS-only patients and 25 CFS + FM patients.
To ensure that these findings were not solely because of differences in exertion, we performed a secondary analysis after reducing our sample to the CFS and Control subjects who were matched on RPE. This analysis confirmed our central findings. This comparison examined 15 controls with the highest RPE (mean 3.89) matched with 27 patients with overlapping RPEs (mean 3.87). Even though this reduced our sample size and statistical power substantially, 6 of the 7 genes’ AUCs were still significantly greater in patients with CFS than controls [P2X4 (P < 0.05), TRPV1 (P < 0.02), α-2A (P < 0.03), β-2 (P < 0.03), COMT (P < 0.04), and IL10 (P < 0.01)]. The only gene not reliably different was P2X5 (P = 0.12).
Gene expression varied with the clinical severity of CFS. Figure 4 graphs the four severity groups for the α-2A increase patients with CFS (n = 34). In this subgroup, there were three patients with severity 1 (9%), 11 with severity 2 (32%), 14 with severity 3 (41%) and four with severity 4 (12%). Two patients were not included for this analysis because they were less severe than 4. This graph indicates that, relative to controls, gene expression was increased most in patients with the highest severity and least increased in patients with the lowest severity. When the average of all gene AUC was compared, groups 1 and 2 were significantly greater that that of groups 3 and 4 (P < 0.011).
Figure 4. Graph of severity groups’ gene expression. For this graph, gene expression increases for all four time periods of exercise were summed and a single value shown. Severity scale was: (1) House- or bed-bound, with minimal activity tolerance, marked cognitive dysfunction, and dependent on others for activities of daily living. (2) Only able to do self-care activities of daily living, sedentary, <10 h per week of light activities, but could live alone with occasional help. (3) Able to do part-time school/work/other activities 10–30 h per week, but easily relapses, and frequent rest needed 4. Able to work full time 30–40 h but ‘nothing left over’, high symptom burden and limitations. Controls are graphed on top of each of the severity groups in grey cross hatching so that patients can be easily compared with control gene expression levels.
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The minor subgroup, the α-2A decrease group (n = 14), had one patient with severity 1 (7%), four patients with severity 2 (29%), six patients with severity 3 (43%) and two patients with severity 4 (14%). One patient had a severity score less severe than 4. This distribution was very similar to that of the major subgroup (Χ2P > 0.85).
Effects of medications
As described previously, 11 patients with CFS were on anticonvulsants, and 15 were on opioids during testing while the other patients with CFS either had not used them or were withdrawn from them prior to testing. To determine whether these medications might have affected the gene expression, we compared the total postexercise AUC gene expression of patients on these medications with the AUC of those not on the medications. There was a trend in the direction of lesser postexercise increases in our selected genes among patients with CFS on anticonvulsants versus CFS on no medications (P = 0.055), but even this medicated CFS group still differed from controls (P < 0.05). Patients with CFS on opioid pain medications alone did not differ from other patients with CFS (P > 0.245). These findings suggest that anticonvulsant drugs may reduce the postexercise gene expression increases in some patients with CFS, but they also indicate that withdrawal from these medications prior to testing is not critical when attempting to differentiate their responses from those of healthy individuals.
When the 30 patients with CFS tested on versus the 18 not on antidepressants were compared, no statistical difference in expression of mRNA was observed (P > 0.614). Likewise, when the 11 control subjects also were on antidepressants were compared with the 38 other controls, there were no differences in gene expression.
Table 3 shows the correlations between the behavioural scores for fatigue and pain and AUC gene expression measures, as well as inter-correlations between the various genes. These indicate strong positive relationships between postexercise pain and fatigue and increases in P2X4, TRPV1, α-2A, β-2 and IL10. Relationships between the behavioural measures were weaker for the ASIC3, P2X5 and the other cytokine genes measured.
Table 3. Correlations of post-exercise area under the curve (AUC) gene expression measures with post-exercise AUC fatigue and pain and with each other (All α-2A increase CFS patients and controls included in this analysis)
|P2X5|| || ||–||+0.76||+0.27||NS||+0.30||+0.61||+0.33||+0.24||NS|
|TRPV1|| || || ||–||+0.30||NS||+0.31||+0.63||+0.55||+0.55||+0.46|
|α-2A|| || || || ||–||+0.59||+0.76||+0.29||+0.34||+0.49||+0.34|
|β-1|| || || || || ||–||+0.62||NS||+0.30||+0.45||NS|
|β-2|| || || || || || ||–||+0.37||+0.45||+0.51||+0.36|
|COMT|| || || || || || || ||–||+0.33||+0.44||+0.29|
|IL6|| || || || || || || || ||–||+0.66||+0.34|
|IL10|| || || || || || || || || ||–||+0.50|