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Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson's disease.
Proc Natl Acad Sci U S A. 2015 Feb 17; 112(7):2257-62.PN

Abstract

Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Network-based metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were up- and down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD.

Authors+Show Affiliations

Cellular and Molecular Pharmacology Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064.Cellular and Molecular Pharmacology Department, Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064 judy.potashkin@rosalindfranklin.edu.

Pub Type(s)

Journal Article
Meta-Analysis
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

25646437

Citation

Santiago, Jose A., and Judith A. Potashkin. "Network-based Metaanalysis Identifies HNF4A and PTBP1 as Longitudinally Dynamic Biomarkers for Parkinson's Disease." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 7, 2015, pp. 2257-62.
Santiago JA, Potashkin JA. Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson's disease. Proc Natl Acad Sci U S A. 2015;112(7):2257-62.
Santiago, J. A., & Potashkin, J. A. (2015). Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson's disease. Proceedings of the National Academy of Sciences of the United States of America, 112(7), 2257-62. https://doi.org/10.1073/pnas.1423573112
Santiago JA, Potashkin JA. Network-based Metaanalysis Identifies HNF4A and PTBP1 as Longitudinally Dynamic Biomarkers for Parkinson's Disease. Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2257-62. PubMed PMID: 25646437.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Network-based metaanalysis identifies HNF4A and PTBP1 as longitudinally dynamic biomarkers for Parkinson's disease. AU - Santiago,Jose A, AU - Potashkin,Judith A, Y1 - 2015/02/02/ PY - 2015/2/4/entrez PY - 2015/2/4/pubmed PY - 2015/5/6/medline KW - HNF4A KW - PTBP1 KW - Parkinson's disease KW - blood biomarkers KW - network analysis SP - 2257 EP - 62 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 112 IS - 7 N2 - Environmental and genetic factors are likely to be involved in the pathogenesis of Parkinson's disease (PD), the second most prevalent neurodegenerative disease among the elderly. Network-based metaanalysis of four independent microarray studies identified the hepatocyte nuclear factor 4 alpha (HNF4A), a transcription factor associated with gluconeogenesis and diabetes, as a central regulatory hub gene up-regulated in blood of PD patients. In parallel, the polypyrimidine tract binding protein 1 (PTBP1), involved in the stabilization and mRNA translation of insulin, was identified as the most down-regulated gene. Quantitative PCR assays revealed that HNF4A and PTBP1 mRNAs were up- and down-regulated, respectively, in blood of 51 PD patients and 45 controls nested in the Diagnostic and Prognostic Biomarkers for Parkinson's Disease. These results were confirmed in blood of 50 PD patients compared with 46 healthy controls nested in the Harvard Biomarker Study. Relative abundance of HNF4A mRNA correlated with the Hoehn and Yahr stage at baseline, suggesting its clinical utility to monitor disease severity. Using both markers, PD patients were classified with 90% sensitivity and 80% specificity. Longitudinal performance analysis demonstrated that relative abundance of HNF4A and PTBP1 mRNAs significantly decreased and increased, respectively, in PD patients during the 3-y follow-up period. The inverse regulation of HNF4A and PTBP1 provides a molecular rationale for the altered insulin signaling observed in PD patients. The longitudinally dynamic biomarkers identified in this study may be useful for monitoring disease-modifying therapies for PD. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/25646437/Network_based_metaanalysis_identifies_HNF4A_and_PTBP1_as_longitudinally_dynamic_biomarkers_for_Parkinson's_disease_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=25646437 DB - PRIME DP - Unbound Medicine ER -