title: Huntington's disease biomarker progression profile identified by transcriptome sequencing in peripheral blood.
abstract: With several therapeutic approaches in development for Huntington's disease, there is a need for easily accessible biomarkers to monitor disease progression and therapy response. We performed next-generation sequencing-based transcriptome analysis of total RNA from peripheral blood of 91 mutation carriers (27 presymptomatic and, 64 symptomatic) and 33 controls. Transcriptome analysis by DeepSAGE identified 167 genes significantly associated with clinical total motor score in Huntington's disease patients. Relative to previous studies, this yielded novel genes and confirmed previously identified genes, such as H2AFY, an overlap in results that has proven difficult in the past. Pathway analysis showed enrichment of genes of the immune system and target genes of miRNAs, which are downregulated in Huntington's disease models. Using a highly parallelized microfluidics array chip (Fluidigm), we validated 12 of the top 20 significant genes in our discovery cohort and 7 in a second independent cohort. The five genes (PROK2, ZNF238, AQP9, CYSTM1 and ANXA3) that were validated independently in both cohorts present a candidate biomarker panel for stage determination and therapeutic readout in Huntington's disease. Finally we suggest a first empiric formula predicting total motor score from the expression levels of our biomarker panel. Our data support the view that peripheral blood is a useful source to identify biomarkers for Huntington's disease and monitor disease progression in future clinical trials.
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Anastasios
authors: A
authors: Mastrokolias
authors: Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.
authors: Yavuz
authors: Y
authors: Ariyurek
authors: Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, The Netherlands.|Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
authors: Jelle J
authors: JJ
authors: Goeman
authors: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.|Center for Mental Health Care Delfland, Jorisweg 2, Delft, The Netherlands.
authors: Erik
authors: E
authors: van Duijn
authors: Department of Neurology, Leiden University Medical Centre, RC, Leiden, The Netherlands.
authors: Raymund A C
authors: RA
authors: Roos
authors: Department of Psychiatry, Leiden University Medical Center, Leiden, The Netherlands.
authors: Roos C
authors: RC
authors: van der Mast
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: GertJan B
authors: GB
authors: van Ommen
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.|Leiden Genome Technology Center, Leiden University Medical Center, Leiden, The Netherlands.
authors: Johan T
authors: JT
authors: den Dunnen
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Peter A C
authors: PA
authors: 't Hoen
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
authors: Willeke M C
authors: WM
authors: van Roon-Mom
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000378:metabolism*; D016022:Case-Control Studies; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D006816:Huntington Disease / Q000235:genetics*; D008297:Male; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D059467:Transcriptome / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D035683:MicroRNAs
references: Pharmacogenomics J. 2004;4(3):193-207
references: 15037859
references: Bioinformatics. 2004 Jan 1;20(1):93-9
references: 14693814
references: Lancet. 1972 Jun 24;1(7765):1356-8
references: 4113563
references: Hum Mol Genet. 2005 Mar 1;14(5):565-74
references: 15649949
references: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):11023-8
references: 16043692
references: Cell. 2005 Dec 29;123(7):1241-53
references: 16377565
references: Hum Mol Genet. 2006 Mar 15;15(6):965-77
references: 16467349
references: Glia. 2006 May;53(7):723-32
references: 16506224
references: J Biol Chem. 2006 Jun 16;281(24):16672-80
references: 16595660
references: Nucleic Acids Res. 2006;34(19):e133
references: 17028099
references: Hum Mol Genet. 2007 Mar 1;16(5):483-98
references: 17213233
references: J Neurosci. 2007 Jun 27;27(26):6972-83
references: 17596446
references: J Proteome Res. 2007 Jul;6(7):2833-40
references: 17552550
references: J Neurosci. 2007 Jul 18;27(29):7869-78
references: 17634381
references: Proc Natl Acad Sci U S A. 2007 Sep 4;104(36):14424-9
references: 17724341
references: Proc Natl Acad Sci U S A. 2010 Apr 13;107(15):6557-8
references: 20385830
references: BMC Med Genomics. 2010;3:15
references: 20444268
references: Parkinsonism Relat Disord. 2010 Jun;16(5):345-50
references: 20236854
references: Neurosci Lett. 2010 Nov 19;485(2):129-33
references: 20831894
references: Exp Neurol. 2011 Jan;227(1):172-9
references: 21035445
references: Nature. 2011 Jan 13;469(7329):156-7
references: 21228852
references: Neurosci Lett. 2011 May 2;494(3):245-9
references: 21406216
references: Exp Neurol. 2011 Sep;231(1):127-34
references: 21684277
references: Proc Natl Acad Sci U S A. 2011 Oct 11;108(41):17141-6
references: 21969577
references: BMC Genomics. 2012;13:28
references: 22257641
references: BMC Mol Biol. 2008;9:84
references: 18844975
references: J Neurosci. 2008 Sep 24;28(39):9723-31
references: 18815258
references: EMBO J. 2012 Mar 7;31(5):1190-202
references: 22234186
references: Nucleic Acids Res. 2008 Dec;36(21):e141
references: 18927111
references: J Neurosci. 2008 Dec 31;28(53):14341-6
references: 19118166
references: J Clin Psychiatry. 2008 Nov;69(11):1804-10
references: 19026253
references: Biol Psychiatry. 2009 Apr 15;65(8):702-5
references: 19135651
references: Lancet Neurol. 2009 Aug;8(8):765-74
references: 19608102
references: Drug Discov Today. 2009 Dec;14(23-24):1123-9
references: 19822222
references: Mov Disord. 2009 Nov 15;24(15):2277-81
references: 19844910
references: Bioinformatics. 2010 Jan 15;26(2):149-52
references: 19933165
references: J Clin Oncol. 2010 Feb 1;28(4):698-704
references: 20038718
references: Biom J. 2010 Feb;52(1):70-84
references: 19937997
references: Eur J Neurosci. 2007 Oct;26(8):2269-78
references: 17953619
references: PLoS One. 2008;3(2):e1662
references: 18301740
references: J Neurosci. 2008 Mar 26;28(13):3277-90
references: 18367595
references: J Neurosci. 2008 May 28;28(22):5817-26
references: 18509043
references: J Exp Med. 2008 Aug 4;205(8):1869-77
references: 18625748
references: Brain Res. 2012 Jun 26;1462:61-80
references: 22445064
references: J Neurol Sci. 2012 Dec 15;323(1-2):134-40
references: 23040263
references: J Mol Med (Berl). 2013 Jun;91(6):673-81
references: 23546523
references: Lancet Neurol. 2013 Jul;12(7):637-49
references: 23664844
references: Nature. 2013 Sep 26;501(7468):506-11
references: 24037378
references: Nat Biotechnol. 2013 Nov;31(11):1015-22
references: 24037425
references: Genome Biol. 2014;15(2):R29
references: 24485249
references: Nature. 2002 May 23;417(6887):405-10
references: 12024206
references: Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1896-901
references: 12578971
references: Circulation. 2004 Jun 29;109(25 Suppl 1):IV20-1
references: 15226247