title: Evidence of a novel gene HERPUD1 in polypoidal choroidal vasculopathy.
abstract: Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy, with clinical features distinct from neovascular age-related macular degeneration (nAMD) which is the leading cause of irreversible blindness in the elderly. Our studies focused on the genetic background and function of a novel gene HERPUD1 in PCV. HERPUD1 has been reported to increase the level of amyloid β (Aβ), which is a component of drusen deposits underlying the retinal pigment epithelium (RPE) layer. To verify the genetic functional associations of HERPUD1 with PCV, exome sequencing of HERPUD1 was performed in unrelated Chinese individuals, including nAMD patients, PCV patients and control subjects. Immunohistochemistry assays for HERPUD1 were performed in the subretinal membranes of PCV patients. The relationship between HERPUD1 and amyloid beta precursor was determined using real-time PCR in HERPUD1-overexpressing RPE cells. The gene expression patterns of angiogenesis cytokines and chemokines in both Aβ-treated RPE cells and in Brown Norway rats that received Aβ subretinal injections were determined. We showed that HERPUD1 rs2217332 is significant associated with Chinese PCV, and HERPUD1 was expressed in PCV subretinal membranes. Besides, Plasma Aβ42 protein was significantly higher in PCV patients compared to nAMD and control subjects. Aβ could upregulate angiogenic factors, chemokines and matrix metalloproteinases both in RPE cells and in a rat model of subretinal Aβ injection. The imbalance of the cytokines may be one of the mechanisms for the formation and development of PCV. Our results strongly suggest that HERPUD1 is highly associated with PCV patients.
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
authors.forename: Enzhong
authors.initials: E
authors.lastname: Jin
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
authors.forename: Yujing
authors.initials: Y
authors.lastname: Bai
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
authors.forename: Lvzhen
authors.initials: L
authors.lastname: Huang
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Clinical Epidemiology & Biostatistics, Peking University People's Hospital Beijing 100044, P. R. China.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
authors.forename: Mingwei
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Department of Ophthalmology, Peking University People's Hospital; Key Laboratory of Vision Loss and Restoration, Ministry of Education; Beijing Key Laboratory of Diagnosis and Therapy of Retinal and Choroid Diseases Beijing 100044, P. R. China.
authors.forename: Xiaoxin
authors.initials: X
authors.lastname: Li
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D042501:Angiogenic Proteins / Q000378:metabolism; D000818:Animals; D016022:Case-Control Studies; D002460:Cell Line; D018925:Chemokines / Q000378:metabolism; D020256:Choroidal Neovascularization / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D010446:Peptide Fragments / Q000378:metabolism; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011914:Rats, Inbred BN; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology; D012307:Risk Factors; D013997:Time Factors; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D042501:Angiogenic Proteins; D018925:Chemokines; C485932:HERPUD1 protein, human; D008565:Membrane Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D020782:Matrix Metalloproteinases
keywords: HERPUD1; amyloid beta; angiogenesis; polypoidal choroidal vasculopathy; single-nucleotide polymorphism (SNP)
references.citation: Graefes Arch Clin Exp Ophthalmol. 2009 Jun;247(6):767-73
references.pmid: 19247683
references.citation: Eye (Lond). 2010 Mar;24(3):483-90
references.pmid: 20075967
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17505-10
references.pmid: 19805167
references.citation: Invest Ophthalmol Vis Sci. 2008 Mar;49(3):1101-5
references.pmid: 18326737
references.citation: Jpn J Ophthalmol. 2008 Jan-Feb;52(1):57-62
references.pmid: 18369702
references.citation: N Engl J Med. 2008 Jun 12;358(24):2606-17
references.pmid: 18550876
references.citation: Invest Ophthalmol Vis Sci. 2008 Nov;49(11):4729-37
references.pmid: 18586873
references.citation: Lancet. 2008 Nov 22;372(9652):1835-45
references.pmid: 19027484
references.citation: Nippon Ganka Gakkai Zasshi. 2008 Dec;112(12):1076-84
references.pmid: 19157028
references.citation: Aging Cell. 2009 Apr;8(2):162-77
references.pmid: 19239420
references.citation: Arch Ophthalmol. 1999 Nov;117(11):1503-10
references.pmid: 10565519
references.citation: Prog Retin Eye Res. 2000 Mar;19(2):205-21
references.pmid: 10674708
references.citation: Graefes Arch Clin Exp Ophthalmol. 2000 Sep;238(9):752-9
references.pmid: 11045343
references.citation: Retina. 2001;21(2):121-5
references.pmid: 11321137
references.citation: J Biol Chem. 2002 Apr 12;277(15):12915-20
references.pmid: 11799129
references.citation: Circ Res. 2002 Nov 15;91(10):877-87
references.pmid: 12433832
references.citation: Mol Vis. 2003 May 14;9:184-90
references.pmid: 12764254
references.citation: FEBS Lett. 2003 Oct 9;553(1-2):151-6
references.pmid: 14550564
references.citation: Arch Ophthalmol. 2003 Oct;121(10):1392-6
references.pmid: 14557174
references.citation: J Cell Physiol. 2003 Dec;197(3):453-62
references.pmid: 14566975
references.citation: Prog Retin Eye Res. 2003 Nov;22(6):721-48
references.pmid: 14575722
references.citation: Eye (Lond). 2004 May;18(5):455-9
references.pmid: 15131673
references.citation: Retina. 1990;10(1):1-8
references.pmid: 1693009
references.citation: Surv Ophthalmol. 1995 Mar-Apr;39(5):367-74
references.pmid: 7604360
references.citation: Cell. 2010 Apr 2;141(1):52-67
references.pmid: 20371345
references.citation: Invest Ophthalmol Vis Sci. 2010 Jun;51(6):3193-204
references.pmid: 20071679
references.citation: J Alzheimers Dis. 2010;20(2):569-76
references.pmid: 20164556
references.citation: Curr Opin Cell Biol. 2010 Oct;22(5):617-25
references.pmid: 20817428
references.citation: Surv Ophthalmol. 2010 Nov-Dec;55(6):501-15
references.pmid: 20850857
references.citation: Prog Retin Eye Res. 2010 Nov;29(6):500-19
references.pmid: 20488255
references.citation: Prog Retin Eye Res. 2011 Jul;30(4):217-38
references.pmid: 21440663
references.citation: Graefes Arch Clin Exp Ophthalmol. 2011 Jul;249(7):975-9
references.pmid: 21153654
references.citation: Biochim Biophys Acta. 2011 Aug;1810(8):790-8
references.pmid: 21600962
references.citation: Physiol Rev. 2011 Jul;91(3):1071-121
references.pmid: 21742796
references.citation: Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14578-83
references.pmid: 21844367
references.citation: Hum Mol Genet. 2012 Mar 1;21(5):963-77
references.pmid: 22045699
references.citation: Nat Med. 2012 May;18(5):791-8
references.pmid: 22484808
references.citation: N Engl J Med. 2012 Aug 23;367(8):768-70
references.pmid: 22913688
references.citation: Retina. 2013 Apr;33(4):686-716
references.pmid: 23455233
references.citation: Invest Ophthalmol Vis Sci. 2013 Mar;54(3):2225-37
references.pmid: 23462752
references.citation: J Biol Chem. 2009 Jul 3;284(27):18323-33
references.pmid: 19447887
references.citation: Exp Eye Res. 1996 Feb;62(2):155-69
references.pmid: 8698076
references.citation: Cell. 2005 May 6;121(3):335-48
references.pmid: 15882617
references.citation: J Clin Invest. 2005 Oct;115(10):2793-800
references.pmid: 16167083
references.citation: Curr Pharm Des. 2006;12(21):2645-60
references.pmid: 16842164
references.citation: Annu Rev Med. 2007;58:477-90
references.pmid: 16922634
references.citation: Nat Rev Mol Cell Biol. 2007 Mar;8(3):221-33
references.pmid: 17318226
references.citation: Am J Ophthalmol. 2007 Jul;144(1):15-22
references.pmid: 17509509
references.citation: Prog Retin Eye Res. 2007 Sep;26(5):516-54
references.pmid: 17532250
references.citation: Graefes Arch Clin Exp Ophthalmol. 2007 Oct;245(10):1441-5
references.pmid: 17406882
references.citation: Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5495-503
references.pmid: 19516002
references.citation: Proc Natl Acad Sci U S A. 2010 Jan 12;107(2):856-61
references.pmid: 20080765
references.citation: Prog Retin Eye Res. 2010 Jan;29(1):19-29
references.pmid: 19854291
references.citation: Annu Rev Pharmacol Toxicol. 2008;48:61-78
references.pmid: 17914929