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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

Spot optical densities in parts per million (ppm) for the seven most discriminating protein spots (patients vs healthy controls).Notes: (A) Angiotensinogen isoform, spot 3409, P<0.001; (B) alpha-1-antitrypsin isoform, spot 5106, P=0.001; (C) alpha-1-antitrypsin isoform, spot 1505, P=0.002; (D) haptoglobin isoform, spot 1211, P=0.008; (E) haptoglobin isoform, spot 1203, P=0.013; (F) haptoglobin isoform, spot 2205, P=0.013; (G) pigment epithelium-derived factor isoform, spot 3308, P=0.013. Median values are represented by horizontal lines and the interquartile ranges by boxes. In the absence of points (representing outliers) and asterisks (representing extremes), the ends of the whiskers represent minimum and maximum values. Outliers and extremes numbers refer to study subject ID. P-values refer to group differences (patients vs controls).
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f2-jpr-8-321: Spot optical densities in parts per million (ppm) for the seven most discriminating protein spots (patients vs healthy controls).Notes: (A) Angiotensinogen isoform, spot 3409, P<0.001; (B) alpha-1-antitrypsin isoform, spot 5106, P=0.001; (C) alpha-1-antitrypsin isoform, spot 1505, P=0.002; (D) haptoglobin isoform, spot 1211, P=0.008; (E) haptoglobin isoform, spot 1203, P=0.013; (F) haptoglobin isoform, spot 2205, P=0.013; (G) pigment epithelium-derived factor isoform, spot 3308, P=0.013. Median values are represented by horizontal lines and the interquartile ranges by boxes. In the absence of points (representing outliers) and asterisks (representing extremes), the ends of the whiskers represent minimum and maximum values. Outliers and extremes numbers refer to study subject ID. P-values refer to group differences (patients vs controls).

Mentions: As underlined in the “Discussion” section, angiotensinogen should not simplistically be thought of as only a vasoactive substance, as it is produced locally in the central nervous system.44 In the present study, the isoform spot 3409 of angiotensinogen was significantly upregulated in patients (Figure 2A, P<0.001), and had the highest discriminatory power between patients and healthy controls (Table 3). In total, five angiotensinogen isoforms were identified, and total angiotensinogen (ie, the sum of the five isoforms) did not differ between groups (P=0.533). Isoform spot 3409 represented 46% (median value) of total angiotensinogen in patients, compared to 12% in controls (P=0.001), indicating a shift in the balance between angiotensinogen isoforms.


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)

Spot optical densities in parts per million (ppm) for the seven most discriminating protein spots (patients vs healthy controls).Notes: (A) Angiotensinogen isoform, spot 3409, P<0.001; (B) alpha-1-antitrypsin isoform, spot 5106, P=0.001; (C) alpha-1-antitrypsin isoform, spot 1505, P=0.002; (D) haptoglobin isoform, spot 1211, P=0.008; (E) haptoglobin isoform, spot 1203, P=0.013; (F) haptoglobin isoform, spot 2205, P=0.013; (G) pigment epithelium-derived factor isoform, spot 3308, P=0.013. Median values are represented by horizontal lines and the interquartile ranges by boxes. In the absence of points (representing outliers) and asterisks (representing extremes), the ends of the whiskers represent minimum and maximum values. Outliers and extremes numbers refer to study subject ID. P-values refer to group differences (patients vs controls).
© Copyright Policy
Related In: Results  -  Collection

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

f2-jpr-8-321: Spot optical densities in parts per million (ppm) for the seven most discriminating protein spots (patients vs healthy controls).Notes: (A) Angiotensinogen isoform, spot 3409, P<0.001; (B) alpha-1-antitrypsin isoform, spot 5106, P=0.001; (C) alpha-1-antitrypsin isoform, spot 1505, P=0.002; (D) haptoglobin isoform, spot 1211, P=0.008; (E) haptoglobin isoform, spot 1203, P=0.013; (F) haptoglobin isoform, spot 2205, P=0.013; (G) pigment epithelium-derived factor isoform, spot 3308, P=0.013. Median values are represented by horizontal lines and the interquartile ranges by boxes. In the absence of points (representing outliers) and asterisks (representing extremes), the ends of the whiskers represent minimum and maximum values. Outliers and extremes numbers refer to study subject ID. P-values refer to group differences (patients vs controls).
Mentions: As underlined in the “Discussion” section, angiotensinogen should not simplistically be thought of as only a vasoactive substance, as it is produced locally in the central nervous system.44 In the present study, the isoform spot 3409 of angiotensinogen was significantly upregulated in patients (Figure 2A, P<0.001), and had the highest discriminatory power between patients and healthy controls (Table 3). In total, five angiotensinogen isoforms were identified, and total angiotensinogen (ie, the sum of the five isoforms) did not differ between groups (P=0.533). Isoform spot 3409 represented 46% (median value) of total angiotensinogen in patients, compared to 12% in controls (P=0.001), indicating a shift in the balance between angiotensinogen isoforms.

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