Peripheral blood gene expression patterns discriminate among chronic inflammatory diseases and healthy controls and identify novel targets.
BACKGROUND
Chronic inflammatory diseases including inflammatory bowel disease (IBD; Crohn's disease and ulcerative colitis), psoriasis and rheumatoid arthritis (RA) afflict millions of people worldwide, but their pathogenesis is still not well understood. It is also not well known if distinct changes in gene expression characterize these diseases and if these patterns can discriminate between diseased and control patients and/or stratify the disease. The main focus of our work was the identification of novel markers that overlap among the 3 diseases or discriminate them from each other.


METHODS
Diseased (n = 13, n = 15 and n = 12 in IBD, psoriasis and RA respectively) and healthy patients (n = 18) were recruited based on strict inclusion and exclusion criteria; peripheral blood samples were collected by clinicians (30 ml) in Venous Blood Vacuum Collection Tubes containing EDTA and peripheral blood mononuclear cells were separated by Ficoll gradient centrifugation. RNA was extracted using Trizol reagent. Gene expression data was obtained using TaqMan Low Density Array (TLDA) containing 96 genes that were selected by an algorithm and the statistical analyses were performed in Prism by using non-parametric Mann-Whitney U test (P-values < 0.05).


RESULTS
Here we show that using a panel of 96 disease associated genes and measuring mRNA expression levels in peripheral blood derived mononuclear cells; we could identify disease-specific gene panels that separate each disease from healthy controls. In addition, a panel of five genes such as ADM, AQP9, CXCL2, IL10 and NAMPT discriminates between all samples from patients with chronic inflammation and healthy controls. We also found genes that stratify the diseases and separate different subtypes or different states of prognosis in each condition.


CONCLUSIONS
These findings and the identification of five universal markers of chronic inflammation suggest that these diseases have a common background in pathomechanism, but still can be separated by peripheral blood gene expression. Importantly, the identified genes can be associated with overlapping biological processes including changed inflammatory response. Gene panels based on such markers can play a major role in the development of personalized medicine, in monitoring disease progression and can lead to the identification of new potential drug targets in chronic inflammation.
Mesko
Bertalan
B
Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen, Hungary.
Poliska
Szilard
S
Szegedi
Andrea
A
Szekanecz
Zoltan
Z
Palatka
Karoly
K
Papp
Maria
M
Nagy
Laszlo
L
D000328:Adult; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002908:Chronic Disease; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000097:blood / Q000235:genetics*; D007962:Leukocytes / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011565:Psoriasis / Q000097:blood / Q000235:genetics*
D015415:Biomarkers
Mucosal Immunol. 2008 Nov;1 Suppl 1:S39-42
19079227
J Allergy Clin Immunol. 2003 Dec;112(6):1195-202
14657882
J Cell Biochem. 2008 May 15;104(2):453-64
18044712
Immunology. 2009 Jul;127(3):365-72
19191904
Diabetes. 1999 Jul;48(7):1353-8
10389838
J Clin Immunol. 2000 Sep;20(5):362-70
11051278
J Rheumatol. 2002 Jan;29(1):107-17
11824946
Arthritis Rheum. 1997 Apr;40(4):639-47
9125245
J Immunol. 2002 Jul 1;169(1):5-9
12077221
Am J Gastroenterol. 1997 Jul;92(7):1170-3
9219792
Arthritis Res. 2002;4 Suppl 3:S265-72
12110146
Eur J Dermatol. 2005 Jul-Aug;15(4):251-7
16048752
Gastroenterology. 2008 Nov;135(5):1624-1635.e24
18835392
J Mol Diagn. 2006 Feb;8(1):51-61
16436634
Gastroenterology. 2004 May;126(6):1504-17
15168363
Genomic Med. 2007;1(3-4):105-12
18923935
Arthritis Rheum. 2010 Jun;62(6):1602-7
20178127
Swiss Med Wkly. 2009 Mar 7;139(9-10):140-5
19274491
BMC Cancer. 2008 Nov 25;8:343
19032762
J Immunol. 2007 Feb 1;178(3):1748-58
17237424
J Interferon Cytokine Res. 2009 Jul;29(7):407-14
19450149
Arthritis Res Ther. 2003;5(4):R186-92
12823853
Arthritis Res Ther. 2008;10(3):R50
18454843
Mol Biol Cell. 2003 Jul;14(7):2861-75
12857870
J Interferon Cytokine Res. 2007 Oct;27(10):841-6
17970693
J Clin Immunol. 2009 Nov;29(6):761-8
19662520
Am J Physiol Gastrointest Liver Physiol. 2009 Feb;296(2):G175-84
19171847
Cytokine Growth Factor Rev. 2006 Dec;17(6):451-61
17045835
Genes Immun. 2005 Aug;6(5):388-97
15973463
Proc Natl Acad Sci U S A. 2003 May 13;100(10):5974-9
12714683
Clin Exp Immunol. 2002 Nov;130(2):331-7
12390324
Histochem Cell Biol. 2003 Sep;120(3):243-50
12915944
Semin Immunol. 2009 Dec;21(6):318-27
19446472
Arthritis Rheum. 2005 May;52(5):1381-91
15880344
Mol Syst Biol. 2009;5:307
19756046
Rheumatol Int. 2009 Oct;29(12):1411-6
19199100
Clin Cancer Res. 2006 Apr 15;12(8):2434-41
16638849
Rheumatology (Oxford). 2002 Jul;41(7):759-66
12096225
Exp Physiol. 2001 Sep;86(5):543-5
11571480
Genome Biol. 2003;4(10):R70
14519205
Ann Rheum Dis. 1998 Nov;57(11):691-3
9924213
Chin Med Sci J. 2009 Mar;24(1):50-4
19382425
Lab Invest. 2001 Mar;81(3):335-47
11310827
Rheumatology (Oxford). 2004 Nov;43(11):1346-52
15292528
Dig Dis Sci. 1996 Apr;41(4):660-9
8674385
Inflamm Bowel Dis. 2007 Jul;13(7):807-21
17262812
Ann Rheum Dis. 2005 Mar;64 Suppl 2:ii18-23; discussion ii24-5
15708928
Clin Exp Immunol. 1996 Mar;103(3):357-67
8608632
Arthritis Rheum. 2006 Jul;54(7):2084-95
16802343
Rheumatology (Oxford). 2004 Aug;43(8):973-9
15150433
Gastroenterology. 1999 Aug;117(2):359-67
10419917
Arthritis Res Ther. 2009;11(3):R96
19549314
Zhonghua Nei Ke Za Zhi. 2007 Jul;46(7):547-50
17959074
J Rheumatol. 2003 Dec;30(12):2553-6
14719193
Inflamm Bowel Dis. 2009 Feb;15(2):224-35
18942749