Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma

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Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10⁻¹⁸), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10⁻¹¹). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10⁻¹²) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10⁻¹⁰). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Vyšlo v časopise: Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma. PLoS Genet 8(4): e32767. doi:10.1371/journal.pgen.1002654
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002654

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Zdroje

1. QuiqleyHABromanAT 2006 The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 90 262 267

2. CaprioliJVarmaR 2011 Intraocular pressure: modulation as treatment for glaucoma. Am J Ophthalmol 152 340 344

3. GirkinCASamplePALiebmannJMJainSBowdC 2010 African Descent and Glaucoma Evaluation Study (ADAGES): II. Ancestry differences in optic disc, retinal nerve fiber layer, and macular structure in healthy subjects. Arch Ophthalmol 128 541 550

4. GroverDSBudenzDL 2011 Ocular perfusion pressure and glaucoma. Int Ophthalmol Clin 5 19 25

5. WangXHarmonJZabrieskieNChenYGrobSWilliamsB 2010 Using the Utah Population Database to assess familial risk of primary open angle glaucoma. Vision Res 50 2391 2395

6. MedeirosFAWeinrebRNSamplePAGomiCFBowdC 2005 Validation of a predictive model to estimate the risk of conversion from ocular hypertension to glaucoma. Arch Ophthalmol 123 1351 1360

7. AndersonDRDranceSMSchulzerM Collaborative Normal-Tension Glaucoma Study Group 2001 Natural history of normal-tension glaucoma. Ophthalmology 108 247 253

8. FanBJWiggsJL 2010 Glaucoma: genes, phenotypes, and new directions for therapy. J Clin Invest 120 3064 3072

9. FingertJH 2011 Primary open-angle glaucoma genes. Eye (Lond) 25 587 595

10. ThorleifssonGWaltersGBHewittAWMassonGHelgasonA 2010 Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 42 906 909

11. WiggsJLKangJHYaspanBLMirelDBLaurieC 2011 Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma in Caucasians from the USA. Hum Mol Genet 20 4707 4713

12. BurdonKPMacgregorSHewittAWSharmaSChidlowG 2011 Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 43 574 578

13. AungTRezaieTOkadaKViswanathanACChildAH 2005 Clinical features and course of patients with glaucoma with the E50K mutation in the optineurin gene. Invest Ophthalmol Vis Sci 46 2816 2822

14. FingertJHRobinALStoneJLRoosBRDavisLK 2011 Copy number variations on chromosome 12q14 in patients with normal tension glaucoma. Hum Mol Genet 20 2482 2494

15. MeguroAInokoHOtaMMizukiNBahramS Writing Committee for the Normal Tension Glaucoma Genetic Study Group of Japan Glaucoma Society 2010 Genome-wide association study of normal tension glaucoma: common variants in SRBD1 and ELOVL5 contribute to disease susceptibility. Ophthalmology 117 1331 1338

16. CornelisMCAgrawalAColeJWHanselNNBarnesKC 2010 The Gene, Environment Association Studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions. Genet Epidemiol 34 364 372

17. WiggsJLHauserMAAbdrabouWAllinghamRRBudenzDL 2011 The NEIGHBOR Consortium Primary Open Angle Glaucoma Genome-wide Association Study: Rationale, Study design and Clinical variables. In press Journal of Glaucoma

18. WillerCJLiYAbecasisGR 2010 METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 26 2190 2191

19. MacgregorSHewittAWHysiPGRuddleJBMedlandSE 2010 Genome-wide association identifies ATOH7 as a major gene determining human optic disc size. Hum Mol Genet 19 2716 2724

20. RamdasWDvan KoolwijkLMIkramMKJansoniusNMde JongPT 2010 A genome-wide association study of optic disc parameters. PLoS Genet 6 e1000978 doi:10.1371/journal.pgen.1000978

21. KhorCCRamdasWDVithanaENCornesBKSimX 2011 Genome-wide association studies in Asians confirm the involvement of ATOH7 and TGFBR3, and further identify CARD10 as a novel locus influencing optic disc area. Hum Mol Genet 20 1864 1872

22. AxenovichTZorkoltsevaIBelonogovaNvan KoolwijkLBorodinP 2011 Linkage and association analyses of glaucoma related traits in a large pedigree from a Dutch genetically isolated population. J Med Genet 48 802 809

23. GastenARamdasWBroerLvan KoolwijkLIkramM 2012 A genetic epidemiologic study of candidate genes involved in the optic nerve head morphology. Invest Ophthalmol Vis Sci 2012 Jan 20. [Epub ahead of print]

24. RamdasWDvan KoolwijkLMLemijHGPasuttoFCreeAJ 2011 Common genetic variants associated with open-angle glaucoma. Hum Mol Genet 20 2464 2471

25. CunningtonMSSantibanez KorefMMayosiBMBurnJKeavneyB 2010 Chromosome 9p21 SNPs Associated with Multiple Disease Phenotypes Correlate with ANRIL Expression. PLoS Genet 6 e1000899 doi:10.1371/journal.pgen.1000899

26. HesselberthJRChenXZhangZSaboPJSandstromRReynoldsAPThurmanRENephSKuehnMSNobleWSFieldsSStamatoyannopoulosJA 2009 Global mapping of protein-DNA interactions in vivo by digital genomic footprinting. Nat Methods 6 283 289

27. BirneyEStamatoyannopoulosJADuttaAGuigóR ENCODE Project Consortium 2007 Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project. Nature 447 799 816

28. BurdCEJeckWRLiuYSanoffHKWangZSharplessNE 2010 Expression of linear and novel circular forms of an INK4/ARF-associated non-coding RNA correlates with atherosclerosis risk. PLoS Genet 6 e1001233 doi:10.1371/journal.pgen.1001233

29. ThorleifssonGMagnussonKPSulemPWaltersGBGudbjartssonDF 2007 Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science 317 1397 1400

30. LiuYSchmidtSQinXGibsonJHutchinsK 2008 Lack of association between LOXL1 variants and primary open-angle glaucoma in three different populations. Invest Ophthalmol Vis Sci 49 3465 3468

31. HannonGJBeachD 1994 p15INK4B is a potential effector of TGF-beta-induced cell cycle arrest. Nature 371 257 261

32. GamazonERZhangWKonkashbaevADuanSKistnerEO 2010 SCAN: SNP and copy number annotation. Bioinformatics 26 259 262

33. UchidaDOmoteharaFNakashiroKTateishiYHinoS 2003 Posttranscriptional regulation of TSC-22 (TGF-beta-stimulated clone-22) gene by TGF-beta 1. Biochem Biophys Res Commun 305 846 854

34. YaspanBLBushWSTorstensonESMaDPericak-VanceMA 2011 Genetic analysis of biological pathway data through genomic randomization. Hum Genet 129 563 571

35. FanBJWangDYPasqualeLRHainesJLWiggsJL 2011 Genetic variants associated with optic nerve vertical cup-to-disc ratio are risk factors for primary open angle glaucoma in a US Caucasian population. Invest Ophthalmol Vis Sci 52 1788 1792

36. RamdasWDvan KoolwijkLMLemijHGPasuttoFCreeAJ 2011 Common genetic variants associated with open-angle glaucoma. Hum Mol Genet 20 2464 2471

37. GreeneLALiuDXTroyCMBiswasSC 2007 Cell cycle molecules define a pathway required for neuron death in development and disease. Biochim Biophys Acta 1772 392 401

38. HarismendyONotaniDSongXRahimNGTanasaB 2011 9p21 DNA variants associated with coronary artery disease impair interferon-γ signaling response. Nature 470 264 268

39. HowellGRMacalinaoDGSousaGLWaldenMSotoI 2011 Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma. J Clin Invest 21 1429 1444

40. PogueAICuiJGLiYYZhaoYCulicchiaFLukiwWJ 2010 Micro RNA-125b (miRNA-125b) function in astrogliosis and glial cell proliferation. Neuroscience Letters 476 18 22

41. TrifanOCTraboulsiEIStoilovaDAlozieINguyenR 1998 A third locus (GLC1D) for adult-onset primary open-angle glaucoma maps to the 8q23 region. Am J Ophthalmol 126 17 28

42. CrooksKRAllinghamRRQinXLiuYGibsonJR 2011 Genome-wide Linkage Scan for Primary Open Angle Glaucoma: Influences of Ancestry and Age at Diagnosis. PLoS ONE 6 e21967 doi:10.1371/journal.pone.0021967

43. FossettNTevosianSGGajewskiKZhangQOrkinSHSchulzRA 2001 The Friend of GATA proteins U-shaped, FOG-1, and FOG-2 function as negative regulators of blood, heart, and eye development in Drosophila. Proc Natl Acad Sci U S A 98 7342 7347

44. PanagisLZhaoXGeYRenLMittagTWDaniasJ 2011 Retinal gene expression changes related to IOP exposure and axonal loss in DBA/2J mice. Invest Ophthalmol Vis Sci 52 7807 7816

45. CuzzoLMRoss-CisnerosFNYeeKMWangMYSadunAA 2011 Low-density lipoprotein receptor-related protein is decreased in optic neuropathy of Alzheimer disease. J Neuroophthalmol 31 139 146

46. VethKNWillerJRColleryRFGrayMPWillerGB 2011 Mutations in zebrafish lrp2 result in adult-onset ocular pathogenesis that models myopia and other risk factors for glaucoma. PLoS Genet 7 e1001310 doi:10.1371/journal.pgen.1001310

47. PrasadSSKojicLWenYHChenZXiongW 2010 Retinal gene expression after central retinal artery ligation: effects of ischemia and reperfusion. Invest Ophthalmol Vis Sci 51 6207 6319

48. WangDYRayARodgersKErgorulCHymanBT 2010 Global gene expression changes in rat retinal ganglion cells in experimental glaucoma. Invest Ophthalmol Vis Sci 51 4084 4095

49. JohnsonECJiaLCepurnaWODoserTAMorrisonJC 2007 Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model. Invest Ophthalmol Vis Sci 48 3161 3177

50. BattleMAMaherVMMcCormickJJ 2003 ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways. Biochemistry 42 7270 7282

51. ChoiSJMoonJHAhnYWAhnJHKimDUHanTH 2005 Tsc-22 enhances TGF-beta signaling by associating with Smad4 and induces erythroid cell differentiation. Mol Cell Biochem 1 23 28

52. KillerHEMillerNRFlammerJMeyerPWeinrebRN 2011 Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma. Br J Ophthalmol 2011 Nov 24. [Epub ahead of print]

53. BerdahlJPAllinghamRRJohnsonDH 2008 Cerebrospinal fluid pressure is decreased in primary open-angle glaucoma. Ophthalmology 115 763 768

54. HanHWeckerTGrehnFSchlunckG 2011 Elasticity-Dependent Modulation of TGF-{beta} Responses in Human Trabecular Meshwork Cells. Invest Ophthalmol Vis Sci 52 2889 2896

55. PasqualeLRDorman-PeaseMELuttyGAQuigleyHAJampelHD 1993 Immunolocalization of TGF-beta 1, TGF-beta 2, and TGF-beta 3 in the anterior segment of the human eye. Invest Ophthalmol Vis Sci 34 23 30

56. MiaoHCrabbAWHernandezMRLukasTJ 2010 Modulation of factors affecting optic nerve head astrocyte migration. Invest Ophthalmol Vis Sci 51 4096 4103

57. KirwanRPLeonardMOMurphyMClarkAFO'BrienCJ 2005 Transforming growth factor-beta-regulated gene transcription and protein expression in human GFAP-negative lamina cribrosa cells. Glia 52 309 324

58. SethiAMaoWWordingerRJClarkAF 2011 Transforming Growth Factor Beta Induces Extracellular Matrix Protein Crosslinking Lysyl Oxidase (LOX) Genes in Human Trabecular Meshwork Cells. Invest Ophthalmol Vis Sci May 5 [Epub ahead of print] (2011)

59. ZodeGSClarkAFWordingerRJ 2009 Bone morphogenetic protein 4 inhibits TGF-beta2 stimulation of extracellular matrix proteins in optic nerve head cells: role of gremlin in ECM modulation. Glia 57 755 766

60. AliMMcKibbinMBoothAParryDAJainP 2009 Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 84 664 671

61. FanBJPasqualeLRRheeDLiTHainesJLWiggsJL 2011 LOXL1 promoter haplotypes are associated with exfoliation syndrome in a U.S. Caucasian population. Invest Ophthalmol Vis Sci 52 2372 2378

62. LoomisSJOlsonLMPasqualeLRWiggsJMirelD 2010 Feasibility of High-Throughput Genome-Wide Genotyping using DNA from Stored Buccal Cell Samples. Biomark Insights 5 49 55

63. GundersonKLSteemersFJRenHNgPZhouL 2006 Whole-genome genotyping. Methods Enzymol 410 359 376

64. PurcellSNealeBTodd-BrownKThomasLFerreiraMA 2007 PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81 559 575

65. LiYWillerCJSannaSAbecasisGR 2009 Genotype Imputation. Annu Rev Genomics Hum Genet 10 387 406

66. LiYWillerCJDingJScheetPAbecasisGR 2010 MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 34 816 834

67. WahlinKJHacklerLJrAdlerRZackDJ 2010 Alternative splicing of neuroligin and its protein distribution in the outer plexiform layer of the chicken retina. J Comp Neurol 518 4938 4962

68. LiuWLiuYQinXJSchmidtSHauserMAAllinghamRR 2010 AQP1 and SLC4A10 as candidate genes for primary open-angle glaucoma. Mol Vis 16 93 97

69. DesronvilTLogan-WyattDAbdrabouWTrianaMJonesR 2010 Distribution of COL8A2 and COL8A1 gene variants in Caucasian primary open angle glaucoma patients with thin central corneal thickness. Mol Vis 16 2185 2191