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Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls - a hypothesis-generating pilot study.

Bäckryd E, Ghafouri B, Carlsson AK, Olausson P, Gerdle B - J Pain Res (2015)

Bottom Line: Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age.Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients).The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.

ABSTRACT
Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin-angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin-angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

No MeSH data available.


Related in: MedlinePlus

Interaction map for the four genes coding for the seven proteins having the highest discriminatory power between patients and healthy controls.Notes:AGT codes for angiotensinogen, HP for haptoglobin, SERPINA1 for alpha-1-antitrypsin, and SERPINF1 for pigment epithelium-derived factor. The online tool Pain Networks was used (http://www.painnetworks.org), accessed June 9, 2015, and the “physical” filtering option was chosen, ie, the map displays only interactions with evidence of the proteins physically touching. Known pain-related genes are highlighted in grey.
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f4-jpr-8-321: Interaction map for the four genes coding for the seven proteins having the highest discriminatory power between patients and healthy controls.Notes:AGT codes for angiotensinogen, HP for haptoglobin, SERPINA1 for alpha-1-antitrypsin, and SERPINF1 for pigment epithelium-derived factor. The online tool Pain Networks was used (http://www.painnetworks.org), accessed June 9, 2015, and the “physical” filtering option was chosen, ie, the map displays only interactions with evidence of the proteins physically touching. Known pain-related genes are highlighted in grey.

Mentions: In order to analyze our results from a systems biology perspective,45 the four genes coding for the above-mentioned seven proteins were entered into a human Pain Networks search (http://www.painnetworks.org, accessed June 9, 2015).46 Using “AGT SERPINA1 HP SERPINF1” as an entry for query genes (AGT codes for angiotensinogen, HP for haptoglobin, SERPINA1 for alpha-1-antitrypsin, and SERPINF1 for pigment epithelium-derived factor), and using the “physical” filtering option (ie, only including interactions with evidence of the proteins physically touching), an interaction map was generated (Figure 4). The map features two known pain-related genes (highlighted in grey in Figure 4): 1) MME codes for neprilysin, which is important for the destruction of opioid peptides,47 and MME interacts with AGT (codes for angiotensinogen); 2) APOE codes for apolipoprotein E, an isoform of which (spot 3107) has VIP =1.53 (Table 3) and interacts with haptoglobin (Figure 4 and as per Salvatore et al48).


Multivariate proteomic analysis of the cerebrospinal fluid of patients with peripheral neuropathic pain and healthy controls - a hypothesis-generating pilot study.

Bäckryd E, Ghafouri B, Carlsson AK, Olausson P, Gerdle B - J Pain Res (2015)

Interaction map for the four genes coding for the seven proteins having the highest discriminatory power between patients and healthy controls.Notes:AGT codes for angiotensinogen, HP for haptoglobin, SERPINA1 for alpha-1-antitrypsin, and SERPINF1 for pigment epithelium-derived factor. The online tool Pain Networks was used (http://www.painnetworks.org), accessed June 9, 2015, and the “physical” filtering option was chosen, ie, the map displays only interactions with evidence of the proteins physically touching. Known pain-related genes are highlighted in grey.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492642&req=5

f4-jpr-8-321: Interaction map for the four genes coding for the seven proteins having the highest discriminatory power between patients and healthy controls.Notes:AGT codes for angiotensinogen, HP for haptoglobin, SERPINA1 for alpha-1-antitrypsin, and SERPINF1 for pigment epithelium-derived factor. The online tool Pain Networks was used (http://www.painnetworks.org), accessed June 9, 2015, and the “physical” filtering option was chosen, ie, the map displays only interactions with evidence of the proteins physically touching. Known pain-related genes are highlighted in grey.
Mentions: In order to analyze our results from a systems biology perspective,45 the four genes coding for the above-mentioned seven proteins were entered into a human Pain Networks search (http://www.painnetworks.org, accessed June 9, 2015).46 Using “AGT SERPINA1 HP SERPINF1” as an entry for query genes (AGT codes for angiotensinogen, HP for haptoglobin, SERPINA1 for alpha-1-antitrypsin, and SERPINF1 for pigment epithelium-derived factor), and using the “physical” filtering option (ie, only including interactions with evidence of the proteins physically touching), an interaction map was generated (Figure 4). The map features two known pain-related genes (highlighted in grey in Figure 4): 1) MME codes for neprilysin, which is important for the destruction of opioid peptides,47 and MME interacts with AGT (codes for angiotensinogen); 2) APOE codes for apolipoprotein E, an isoform of which (spot 3107) has VIP =1.53 (Table 3) and interacts with haptoglobin (Figure 4 and as per Salvatore et al48).

Bottom Line: Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age.Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients).The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

View Article: PubMed Central - PubMed

Affiliation: Division of Community Medicine, Department of Medical and Health Sciences, Faculty of Health Sciences, Linköping University, Linköping, Sweden ; Pain and Rehabilitation Centre, Anaesthetics, Operations and Specialty Surgery Centre, Region Östergötland, Linköping, Sweden.

ABSTRACT
Pain medicine lacks objective biomarkers to guide diagnosis and treatment. Combining two-dimensional gel proteomics with multivariate data analysis by projection, we exploratively analyzed the cerebrospinal fluid of eleven patients with severe peripheral neuropathic pain due to trauma and/or surgery refractory to conventional treatment and eleven healthy controls. Using orthogonal partial least squares discriminant analysis, we identified a panel of 36 proteins highly discriminating between the two groups. Due to a possible confounding effect of age, a new model with age as outcome variable was computed for patients (n=11), and four out of 36 protein spots were excluded due to a probable influence of age. Of the 32 remaining proteins, the following seven had the highest discriminatory power between the two groups: an isoform of angiotensinogen (upregulated in patients), two isoforms of alpha-1-antitrypsin (downregulated in patients), three isoforms of haptoglobin (upregulated in patients), and one isoform of pigment epithelium-derived factor (downregulated in patients). It has recently been hypothesized that the renin-angiotensin system may play a role in the pathophysiology of neuropathic pain, and a clinical trial of an angiotensin II receptor antagonist was recently published. It is noteworthy that when searching for neuropathic pain biomarkers with a purely explorative methodology, it was indeed a renin-angiotensin system protein that had the highest discriminatory power between patients and controls in the present study. The results from this hypothesis-generating pilot study have to be confirmed in larger, hypothesis-driven studies with age-matched controls, but the present study illustrates the fruitfulness of combining proteomics with multivariate data analysis in hypothesis-generating pain biomarker studies in humans.

No MeSH data available.


Related in: MedlinePlus