Purpose: To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin-dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients. Design: Retrospective observational case series. Methods: We studied associations between 10 CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results. Results: For 9 of the 10 protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (eg, the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-to-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: -0.08, -0.03; P = 6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P = 5.45E-06). For the 1 adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-to-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P = 4.74E-04) despite having lower IOP (-0.57 mm Hg per A allele at DNA collection; 95% CI: -0.84, -0.29; P = 6.55E-05). Conclusion: Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.
Bibliographical noteFunding Information:
All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Pasquale has received funding from Merck for unrelated investigator-initiated research. He was also reimbursed for travel to an ARVO-Pfizer meeting on biomarkers in glaucoma research in May 2011. Dr T. Gaasterland has received an honorarium for a lecture given on glaucoma genomics by Sequenom. Dr Yaspan contributed to this research while he was at Vanderbilt University and is currently an employee of Genentech. He has no other financial conflicts to declare. Dr Grosskreutz is an employee of Novartis and retains stock options from her employer. She has no other financial conflicts to declare. The following coauthors declare the following financial activities for work outside the scope of the current publication. Dr Budenz is a consultant to Alcon Labs, Allergan, Santen, Ivantis, and Alimera. His institution receives grant support from Carl Zeiss Meditec and New World Medical . Dr Budenz is on the speakers bureau for Merck, Alcon, and Allergan. Dr Chen receives grant support from the Harvard Catalyst group, the National Institutes of Health (NIH), and the Agency for Healthcare Research . She also receives royalties from Elsevier for her role as a book editor. Dr Friedman is a consultant for Alcon, Bausch & Lomb, Merck, Pfizer, and QLT. Dr D. Gaasterland has been paid royalties as inventor of the G probe for Iridex. He also owns a small amount of IRIDEX stock. Dr Lee receives research support from National Eye Institute (NEI) and the American Glaucoma Society . He is also on the speakers bureaus of Merck and Pfizer. Dr Lee receives royalties from Pharmigen and has been reimbursed for meeting travel by Alcon. Dr Realini is a consultant for Alcon and received payment for manuscript preparation from this company. He is also on the speakers bureau for Lumenis. Dr Morio receives grant support from Merck and NEI as well as royalties from Lippicott. Dr Rhee is a consultant for Alcon, Allergan, Merck, Novagali, and Santen. He also receives grant support from Alcon and Merck . Dr Schuman receives grant support from the NIH and is an inventor on a patent (paid to University of Pittsburgh). He receives royalties from Carl Zeiss Meditec. Dr Singh is consultant to Alcon, Allergan, Santen, and Bausch & Lomb. Dr Wollstein receives grant support from NIH. Drs Allingham and Pericak-Vance receive grant support from NIH . Dr Zack retains Board membership with Alcon and has received grant support form Merck . Dr Weinreb is a consultant to Alcon, Allergan, Merck, Bausch & Lomb, Zeis Meditec and Optovue. He also receives grant support from Novartis, Nidek, Topcon, and Aeries . Dr Richards receives grant support from NIH , Research to Prevent Blindness, and the Sramek Foundation. She also receives royalties for authoring a textbook from Elsevier and has been reimbursed for travel to a Think Tank meeting by the Glaucoma Foundation, NYC.
Publication of this article was supported by the following: a Horizon Grant to MEEI from Allergan (Irvine, California) supported the collection of some glaucoma feature data. The Harvard Glaucoma Center of Excellence and Margolis fund (Boston, Massachusetts) support W.A., L.R.P., and J.L.W.. L.R.P., J.E.R., and J.L.W. are also supported by Research to Prevent Blindness, Inc (New York, New York). The Glaucoma Research Foundation (San Francisco, California), American Health Assistance Foundation (Clarksburg, Maryland), and the Glaucoma Foundation (New York, New York) support Y.L. The following National Institutes of Health grants support the maintenance of the Nurses Health Study and Health Professionals Follow-up , allowing these health professionals to contribute to this analysis: CA87969, CA49449, CA55075, HL35464, and NEI R01 EY015473 (L.R.P.). The following grants from the National Human Genome Research Institute (Bethesda, Maryland) supported GLAUGEN : HG004728 (L.R.P.), HG004424 (Broad Institute to support genotyping), HG004446 (C. Laurie, U. Washington, to support genotype data cleaning and analysis). Genotyping services for the NEIGHBOR study were provided by the Center for Inherited Disease Research (CIDR) and were supported by the National Eye Institute through grant HG005259-01 (J.L.W.). Additionally, CIDR is funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number HHSN268200782096C . The National Eye Institute (Bethesda, Maryland), through ARRA grants 3R01EY015872-05S1 (J.L.W.) and 3R01EY019126-02S1 (M.A.H.), supported the collection and processing of samples for the NEIGHBOR dataset. Funding for the collection of cases and controls was provided by National Institutes of Health (Bethesda, Maryland) grants: EY015543 (R.R.A.), EY006827 (D.G.), HL073389 (Hauser, E); EY13315 (M.A.H.); EY09611 (Hankinson, S), EY009149 (P.R.L.), HG004608 (C.A.M.), EY008208 (Medeiros, P), EY015473 (L.R.P.), EY012118 (M.A.P.V.), EY015682 (T.R.), EY011671 (J.E.R.), EY09580 (J.E.R.), EY013178 (J.S.S.), EY015872 (J.L.W.), EY010886 (J.L.W.), EY009847 (J.L.W.), EY011008 (Zangwill, L), EY144428 (K.Z.), EY144448 (K.Z.), EY18660 (K.Z.).