Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Autor: Janey L Wiggs, Brian L Yaspan, Michael A Hauser, Jae H Kang, R Rand Allingham, Lana M Olson, Wael Abdrabou, Bao J Fan, Dan Y Wang, Wendy Brodeur, Donald L Budenz, Joseph Caprioli, Andrew Crenshaw, Kristy Crooks, Elizabeth Delbono, Kimberly F Doheny, David S Friedman, Douglas Gaasterland, Terry Gaasterland, Cathy Laurie, Richard K Lee, Paul R Lichter, Stephanie Loomis, Yutao Liu, Felipe A Medeiros, Cathy McCarty, Daniel Mirel, Sayoko E Moroi, David C Musch, Anthony Realini, Frank W Rozsa, Joel S Schuman, Kathleen Scott, Kuldev Singh, Joshua D Stein, Edward H Trager, Paul Vanveldhuisen, Douglas Vollrath, Gadi Wollstein, Sachiko Yoneyama, Kang Zhang, Robert N Weinreb, Jason Ernst, Manolis Kellis, Tomohiro Masuda, Don Zack, Julia E Richards, Margaret Pericak-Vance, Louis R Pasquale, Jonathan L Haines
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Zdroj: PLoS Genetics, Vol 8, Iss 4, p e1002654 (2012)
Druh dokumentu: article
ISSN: 1553-7390
1553-7404
DOI: 10.1371/journal.pgen.1002654
Popis: 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.
Databáze: Directory of Open Access Journals
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