Elsevier

Ophthalmology

Volume 119, Issue 8, August 2012, Pages 1539-1545
Ophthalmology

Original article
Glaucoma Risk Alleles at CDKN2B-AS1 Are Associated with Lower Intraocular Pressure, Normal-Tension Glaucoma, and Advanced Glaucoma

Presented in part at: American Society of Human Genetics/International Congress of Human Genetics Joint Meeting, October 11-15, 2011, Montreal Canada.
https://doi.org/10.1016/j.ophtha.2012.02.004Get rights and content

Purpose

Genetic variation at the 9p21 locus encompassing the CDKN2B-AS1, CDKN2A, and CDKN2B genes has been associated with primary open-angle glaucoma (POAG) in several independent studies. This study aimed to dissect the association further and to determine genotype–phenotype correlations between genetic variation at this locus and a range of glaucoma-related traits in a large cohort of POAG patients.

Design

Comparative case series and case-control study.

Participants

One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies.

Methods

Each patient was genotyped at 9 single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. Each SNP was assessed for association with each outcome measure using linear regression under an additive genetic model. Associated traits were explored further including adjustment for relevant covariates. Highest recorded intraocular pressure (IOP) also was analyzed both with and without correction for central corneal thickness (CCT) and was dichotomized into high-tension glaucoma and normal-tension glaucoma (NTG).

Main Outcome Measures

Intraocular pressure and vertical cup-to-disc ratio (VCDR).

Results

Glaucoma risk alleles at 9p21, particularly, rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. The SNP rs10120688 was associated with greater VCDR after adjustment for covariates (P = 0.003; β = 0.016; standard error, 0.006). In addition, multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT. The SNP most significantly associated with IOP was also rs10120688 (P = 0.001; β = −2.135; standard error, 0.634) after adjustment for covariates under an additive model. In a comparison of high-tension versus low-tension glaucoma, this SNP was also the most significantly associated, particularly when IOP was corrected for CCT before classification of the type of glaucoma (P = 0.0009; odds ratio, 0.63; 95% confidence interval, 0.48–0.83).

Conclusions

Patients with POAG carrying the glaucoma risk alleles at the 9p21 locus have larger VCDR and lower IOP than POAG patients without these alleles. Carriers of these alleles seem to be predisposed to POAG developing at lower IOP levels and exhibit stronger associations with NTG and advanced glaucoma phenotypes. This may be of relevance when setting target pressures in patients carrying these risk alleles.

Financial Disclosure(s)

The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Section snippets

Participants

Participants were drawn from the Australian & New Zealand Registry of Advanced Glaucoma, the Glaucoma Inheritance Study in Tasmania, the Blue Mountains Eye Study, and patients attending the eye clinic at Flinders Medical Centre, Adelaide, Australia. All participants were included in the study reporting the association of CDKN2B-AS1 with OAG, and the cohorts and clinical definitions are as described in detail in that report.1 Briefly, advanced glaucoma was defined by severe visual loss resulting

Results

Data from 1432 individuals with glaucoma were available. As expected, compared with the normal population, this cohort had elevated IOP, thinner CCT, and significant visual field defects (Table 1). The mean age at diagnosis of glaucoma was 62.4 years. Approximately 36% of the cohort had a highest recorded IOP of less than 22 mmHg, and 63% were classified as having advanced glaucoma. The mean IOP by subgroup is given in Table 2 (available at http://aaojournal.org), and the overlap between HTG

Discussion

An association between SNPs at chromosome 9p21 and VCDR was demonstrated previously in normal populations.3 The current study investigated patients with POAG, of which 63% had advanced disease. Because VCDR is a diagnostic feature of POAG and was used as an inclusion criterion for the definition of less severe glaucoma, this sample is skewed toward the upper range for this phenotype (i.e., >0.7). Although the association is not as strong as reported previously, it is still evident in this

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  • Cited by (0)

    Manuscript no. 2011-1555.

    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

    Supported by the National Health and Medical Research Council (NHMRC) of Australia (grant nos.: 535074, 577074, 974159, 211069, and 457349); NHMRC Career Development Award (KPB); NHMRC Practitioner Fellowship (JEC); and a Royal Australian and New Zealand College of Ophthalmology (RANZCO) Eye Foundation Grant. The sponsor or funding organization had no role in the design or conduct of this research.

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