Localized-Statistical Quantification of Human Serum Proteome Associated with Type 2 Diabetes

Background Recent advances in proteomics have shed light to discover serum proteins or peptides as biomarkers for tracking the progression of diabetes as well as understanding molecular mechanisms of the disease. Results In this work, human serum of non-diabetic and diabetic cohorts was analyzed by proteomic approach. To analyze total 1377 high-confident serum-proteins, we developed a computing strategy called localized statistics of protein abundance distribution (LSPAD) to calculate a significant bias of a particular protein-abundance between these two cohorts. As a result, 68 proteins were found significantly over-represented in the diabetic serum (p<0.01). In addition, a pathway-associated analysis was developed to obtain the overall pathway bias associated with type 2 diabetes, from which the significant over-representation of complement system associated with type 2 diabetes was uncovered. Moreover, an up-stream activator of complement pathway, ficolin-3, was observed over-represented in the serum of type 2 diabetic patients, which was further validated with statistic significance (p = 0.012) with more clinical samples. Conclusions The developed LSPAD approach is well fit for analyzing proteomic data derived from biological complex systems such as plasma proteome. With LSPAD, we disclosed the comprehensive distribution of the proteins associated with diabetes in different abundance levels and the involvement of ficolin-related complement activation in diabetes.

[1]  J. Kane,et al.  Characteristics of human lipoproteins isolated by selected-affinity immunosorption of apolipoprotein A-I. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[2]  R. Gregg,et al.  Identification of an apoC-II variant (apoC-IIBethesda) in a kindred with apoC-II deficiency and type I hyperlipoproteinemia. , 1988, Journal of lipid research.

[3]  B. Spiegelman,et al.  Adipsin and complement factor D activity: an immune-related defect in obesity , 1989, Science.

[4]  D E McMillan,et al.  Increased levels of acute-phase serum proteins in diabetes. , 1989, Metabolism: clinical and experimental.

[5]  J. Kane,et al.  Identification of proteins associated with apolipoprotein A-I-containing lipoproteins purified by selected-affinity immunosorption. , 1994, Biochemistry.

[6]  M. Taskinen,et al.  Enrichment with apolipoprotein E characterizes postprandial TG-rich lipoproteins in patients with non-insulin-dependent diabetes mellitus and coronary artery disease: a preliminary report. , 1994, Atherosclerosis.

[7]  B. Barraviera.  Acute-phase response in snakebite. , 1994, Revista do Instituto de Medicina Tropical de Sao Paulo.

[8]  L. French,et al.  Complement in human diseases: looking towards the 21st century. , 1995, Immunology today.

[9]  R. Havel,et al.  Identification, Characterization, Cloning, and Expression of Apolipoprotein C-IV, a Novel Sialoglycoprotein of Rabbit Plasma Lipoproteins (*) , 1996, The Journal of Biological Chemistry.

[10]  S. Thiel,et al.  A second serine protease associated with mannan-binding lectin that activates complement , 1997, Nature.

[11]  P. Duchateau,et al.  Apolipoprotein L, a New Human High Density Lipoprotein Apolipoprotein Expressed by the Pancreas , 1997, The Journal of Biological Chemistry.

[12]  K. Whaley,et al.  Complement and Complement Deficiencies , 1997, Seminars in liver disease.

[13]  S. Thiel,et al.  MASP-2, the C3 convertase generating protease of the MBLectin complement activating pathway. , 1998, Immunobiology.

[14]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[15]  Gerardo Heiss,et al.  Markers of inflammation and prediction of diabetes mellitus in adults (Atherosclerosis Risk in Communities study): a cohort study , 1999, The Lancet.

[16]  B. Duncan,et al.  Factor VIII and other hemostasis variables are related to incident diabetes in adults. The Atherosclerosis Risk in Communities (ARIC) Study. , 1999, Diabetes care.

[17]  B. Dahlbäck,et al.  A Novel Human Apolipoprotein (apoM)* , 1999, The Journal of Biological Chemistry.

[18]  J. Manson,et al.  C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. , 2001, JAMA.

[19]  L. Patrick,et al.  Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature. , 2001, Alternative medicine review : a journal of clinical therapeutic.

[20]  G. Rice,et al.  Proteomic analysis of human plasma: Failure of centrifugal ultrafiltration to remove albumin and other high molecular weight proteins , 2001, Proteomics.

[21]  G. Kaysen.  The microinflammatory state in uremia: causes and potential consequences. , 2001, Journal of the American Society of Nephrology : JASN.

[22]  S. Haffner,et al.  Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the insulin resistance atherosclerosis study. , 2002, Diabetes.

[23]  N. Anderson,et al.  The Human Plasma Proteome , 2002, Molecular & Cellular Proteomics.

[24]  J. Park,et al.  Elevated serum ceruloplasmin levels in subjects with metabolic syndrome: a population-based study. , 2002, Metabolism: clinical and experimental.

[25]  C. Lindgren,et al.  Contribution of known and unknown susceptibility genes to early-onset diabetes in scandinavia: evidence for heterogeneity. , 2002, Diabetes.

[26]  N. Ertel,et al.  ProteinChip technology: a new and facile method for the identification and measurement of high-density lipoproteins apoA-I and apoA-II and their glycosylated products in patients with diabetes and cardiovascular disease. , 2002, Journal of proteome research.

[27]  P. Macfarlane,et al.  The prognostic value of the electrocardiogram in the west of Scotland coronary prevention study , 2002 .

[28]  C. Meisinger,et al.  C-reactive protein as a predictor for incident diabetes mellitus among middle-aged men: results from the MONICA Augsburg cohort study, 1984-1998. , 2003, Archives of internal medicine.

[29]  Y. Matsuzawa,et al.  Identification of a Novel Variant in the Phosphoenolpyruvate Carboxykinase Gene Promoter in Japanese Patients with Type 2 Diabetes , 2003, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[30]  C. Shin,et al.  Polymorphisms of HLA Class II Predispose Children and Adolescents with Type 1 Diabetes Mellitus to Autoimmune Thyroid Disease , 2003, Autoimmunity.

[31]  A. Burlingame,et al.  Human apoC-IV: isolation, characterization, and immunochemical quantification in plasma and plasma lipoproteins. , 2003, Journal of lipid research.

[32]  M. Korc.  Diabetes Mellitus in the Era of Proteomics , 2003, Molecular & Cellular Proteomics.

[33]  J. Fernández-Real,et al.  A polymorphism in the promoter of the tumor necrosis factor-alpha gene (-308) is associated with coronary heart disease in type 2 diabetic patients. , 2003, Atherosclerosis.

[34]  P. Zimmet.  The burden of type 2 diabetes: are we doing enough? , 2003, Diabetes & Metabolism.

[35]  Aldons J Lusis,et al.  Thematic review series: The Pathogenesis of Atherosclerosis Published, JLR Papers in Press, April 1, 2004. DOI 10.1194/jlr.R400001-JLR200 The oxidation hypothesis of atherogenesis: the role of oxidized phospholipids and HDL , 2004, Journal of Lipid Research.

[36]  H. Parving,et al.  Association between mannose-binding lectin and vascular complications in type 1 diabetes. , 2004 .

[37]  G. Getz,et al.  Paraoxonase, a cardioprotective enzyme: continuing issues , 2004, Current opinion in lipidology.

[38]  H. Tian,et al.  Association of serum apolipoprotein C III levels and apolipoprotein C III gene Sst I polymorphism with carotid intima-media thickness in Chinese type 2 diabetic patients. , 2004, Diabetes research and clinical practice.

[39]  Deborah Pinchev,et al.  Mining biomarkers in human sera using proteomic tools , 2004, Proteomics.

[40]  H. Parving,et al.  Association between mannose-binding lectin and vascular complications in type 1 diabetes. , 2004, Diabetes.

[41]  K. Eriksson,et al.  Complement C 3 Is a Risk Factor for the Development of Diabetes A Population-Based Cohort Study , 2005 .

[42]  Per Leanderson,et al.  Lipoproteomics II: Mapping of proteins in high‐density lipoprotein using two‐dimensional gel electrophoresis and mass spectrometry , 2005, Proteomics.

[43]  A. Carter,et al.  The application of proteomics to diabetes , 2005, Diabetes & vascular disease research.

[44]  Ying Wang,et al.  The human plasma proteome: Analysis of Chinese serum using shotgun strategy , 2005, Proteomics.

[45]  T. Hansen,et al.  Mannose-binding Lectin (MBL) and Vascular Complications in Diabetes , 2005, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[46]  M. Heller,et al.  Mass spectrometry‐based analytical tools for the molecular protein characterization of human plasma lipoproteins , 2005, Proteomics.

[47]  S. Thiel,et al.  Complement activation and diabetic vascular complications. , 2005, Clinica chimica acta; international journal of clinical chemistry.

[48]  A. Boodhoo,et al.  The novel apolipoprotein A5 is present in human serum, is associated with VLDL, HDL, and chylomicrons, and circulates at very low concentrations compared with other apolipoproteins. , 2005, Clinical chemistry.

[49]  R. Nelson,et al.  Investigating diversity in human plasma proteins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[50]  R. Koopman,et al.  Changes in Age at Diagnosis of Type 2 Diabetes Mellitus in the United States, 1988 to 2000 , 2005, The Annals of Family Medicine.

[51]  K. Eriksson,et al.  Complement C3 is a risk factor for the development of diabetes: a population-based cohort study. , 2005, Diabetes.

[52]  Rong Zeng,et al.  High-sensitivity analysis of human plasma proteome by immobilized isoelectric focusing fractionation coupled to mass spectrometry identification. , 2005, Journal of proteome research.

[53]  Rong Zeng,et al.  Human plasma proteome analysis by multidimensional chromatography prefractionation and linear ion trap mass spectrometry identification. , 2005, Journal of proteome research.

[54]  Rafael A. Irizarry,et al.  Bioinformatics and Computational Biology Solutions using R and Bioconductor , 2005 .

[55]  H. Parving,et al.  Mannose-binding lectin and mortality in type 2 diabetes. , 2006, Archives of internal medicine.

[56]  M. Eberhardson,et al.  The use of proteomics in identifying differentially expressed serum proteins in humans with type 2 diabetes , 2006, Proteome Science.

[57]  P. McElduff,et al.  High C-reactive protein and low paraoxonase1 in diabetes as risk factors for coronary heart disease. , 2006, Atherosclerosis.

[58]  Farhad Rezaee,et al.  Proteomic analysis of high‐density lipoprotein , 2006, Proteomics.

[59]  A. A. Rao,et al.  Elevated butyrylcholinesterase and acetylcholinesterase may predict the development of type 2 diabetes mellitus and Alzheimer's disease. , 2007, Medical hypotheses.

[60]  O. Franco,et al.  Distributions of C-reactive protein and its association with metabolic syndrome in middle-aged and older Chinese people. , 2007, Journal of the American College of Cardiology.

[61]  Subramaniam Pennathur,et al.  Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. , 2007, The Journal of clinical investigation.

[62]  H. Park,et al.  Serum resistin as a biological marker for coronary artery disease and restenosis in type 2 diabetic patients. , 2007, Circulation journal : official journal of the Japanese Circulation Society.

[63]  R. Eliakim,et al.  Paraoxonases are associated with intestinal inflammatory diseases and intracellularly localized to the endoplasmic reticulum. , 2007, Free radical biology & medicine.

[64]  T. Fujita,et al.  Role of MBL-associated serine protease (MASP) on activation of the lectin complement pathway. , 2007, Advances in experimental medicine and biology.

[65]  Coral Barbas,et al.  Identification of oxidized proteins in rat plasma using avidin chromatography and tandem mass spectrometry , 2008, Proteomics.

[66]  A. A. Rao,et al.  Bioinformatics analysis of functional protein sequences reveals a role for brain-derived neurotrophic factor in obesity and type 2 diabetes mellitus. , 2008, Medical hypotheses.

[67]  L. V. Van Gaal,et al.  Variants in the FTO gene are associated with common obesity in the Belgian population. , 2008, Molecular genetics and metabolism.

[68]  R. Carter,et al.  Distribution of IgM and IgG antibodies to oxidized LDL in immune complexes isolated from patients with type 1 diabetes and its relationship with nephropathy. , 2008, Clinical immunology.

[69]  J. Pickup,et al.  NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X , 1997, Diabetologia.