Original article
CDKN2B-AS1 Genotype–Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients From the United States

https://doi.org/10.1016/j.ajo.2012.07.023Get rights and content

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.

Section snippets

Description of the Study Populations

The GLAUGEN study consists of POAG cases and controls drawn from the Nurses’ Health Study (NHS), the Health Professionals Follow-up Study (HPFS), and the Genetic Etiologies of Primary Open-Angle Glaucoma study (GEP). The former 2 studies are population-based, nested case-control studies and the latter study is a clinic-based case-control study from the Massachusetts Eye and Ear Infirmary (MEEI). Details regarding the inclusion/exclusion criteria for the GLAUGEN POAG case-control cohort have

Results

The 976 GLAUGEN patients and 1971 NEIGHBOR patients for whom we recorded the age at diagnosis represents 100% (976/976) and 90.8% (1971/2170) of the POAG cases, respectively, that completed high-throughput genotyping in these cohorts. Tables 2 and 3 summarize the demographic and ocular features for POAG cases. The mean age at diagnosis was slightly less in GLAUGEN than in NEIGHBOR. The minimal age at diagnosis in these studies corresponds to the minimal age criteria for inclusion in the

Discussion

POAG cases with the minor alleles in rs3217992 (which increases POAG risk) had larger cup-to-disc ratios at diagnosis and a higher PSD on the earliest available VF manifesting functional loss, despite having lower IOP at DNA collection. In contrast, cases with minor alleles in selected SNPs that reduce POAG risk had smaller cup-to-disc ratios at diagnosis and increased chance of peripheral VF loss only on the earliest VF, despite an increased IOP at DNA collection. These data suggest that

Louis Pasquale is the Glaucoma Service Director at Massachusetts Eye and Ear Infirmary and Associate Professor of Ophthalmology at Harvard Medical School, Boston, Massachusetts. He is also co-director of the Harvard Glaucoma Center of Excellence. He is also an National Institutes of Health (NIH) Principal Investigator with continuous support since 2006. In 2011, Dr Pasquale was appointed as Distinguished Scholar in Ophthalmology at Harvard Medical School. He seeks opportunities to translate

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  • Cited by (0)

    Louis Pasquale is the Glaucoma Service Director at Massachusetts Eye and Ear Infirmary and Associate Professor of Ophthalmology at Harvard Medical School, Boston, Massachusetts. He is also co-director of the Harvard Glaucoma Center of Excellence. He is also an National Institutes of Health (NIH) Principal Investigator with continuous support since 2006. In 2011, Dr Pasquale was appointed as Distinguished Scholar in Ophthalmology at Harvard Medical School. He seeks opportunities to translate basic science discoveries into better treatments for glaucoma patients.

    Supplemental Material available at AJO.com.

    Dr McCarty is now at Essentia Institute of Rural Health, Duluth, Minnesota, and Dr Yaspan is now at Genentech Inc, San Francisco, California.

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