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Editors Selection IGR 14-3

Basic Research - Gene Studies: CDKN2B-AS SNPs and susceptibility to optic neuropathy

Janey Wiggs

Comment by Janey Wiggs on:

50261 Glaucoma Risk Alleles at CDKN2B-AS1 Are Associated with Lower Intraocular Pressure, Normal-Tension Glaucoma, and Advanced Glaucoma, Burdon KP; Crawford A; Casson RJ et al., Ophthalmology, 2012; 119: 1539-1545


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Since 2010, genome-wide association studies (GWAS) have identified five genes/genomic regions that are significantly associated with primary open-angle glaucoma.1-3 Of these, the CDKN2B-AS region on chromosome 9p21 demonstrates the most robust association. CDKN2B-AS, also known as ANRIL, is an antisense RNA that inhibits the expression of CDKN2B (as well as CDKN2A). CDKN2B is an inhibitor of the cell-cycle regulator CDK4 (cyclin dependent kinase4). Before the association with POAG was recognized, CDKN2BAS was also associated with vertical cup-to-disc ratio (VCDR) as a quantitative trait in normal populations. In this study by Burdon et al., comparative case series and case-control analyses provides additional information about the ocular phenotype correlated with the CDKN2B-AS risk alleles identified by the GWASs. Nine SNPs were assessed for highest intraocular pressure measurement (with and without CCT correction), as well as vertical cup-to-disc ratio in the study population of 1,432 POAG cases and 595 controls using linear regression under an additive genetic model. The results confirm an association between CDKN2B-AS SNPs and VCDR and also show that these SNPs are associated with lower IOP in POAG cases. After dividing the POAG cases into HTG and NTG groups, the authors show that the CDKN2B-AS SNPs are significantly associated with NTG. A significant association between CDKN2B-AS SNPs and NTG has also been identified in Caucasian and Japanese GWASs.3-5 Additionally, these findings are consistent with those recently reported by Pasquale et al., also showing a significant association between CDKN2B-AS SNPs and lower IOP in POAG cases.6

These results provide strong evidence that CDKN2B-AS gene variants influence susceptibility to optic nerve disease in glaucoma

Collectively these results provide strong evidence that CDKN2BAS gene variants influence susceptibility to optic-nerve disease in glaucoma, and that individuals who carry CDKN2B-AS risk alleles have a greater tendency toward more severe optic-nerve disease despite low or normal IOP. These results have important clinical implications. Firstly, individuals who are carriers of CDKN2B-AS risk alleles may require lower IOP target pressures than POAG cases without these genetic risk factors. The CDKN2BAS risk alleles are common (approximately 60-70% of POAG patients carry at least one risk allele), so these findings impact a significant number of glaucoma patients. Secondly, the association between CDKN2B-AS and optic-nerve disease points to the importance of CDKN2B and CDK4 in ganglion cell survival in glaucoma. Understanding the role of these proteins in ganglion cell biology may help define novel targets for neuro-protective therapies.

References

  1. Thorleifsson G, Walters GB, Hewitt AW, et al. Common variants near CAV1 and CAV2 are associated with primary open-angle glaucoma. Nat Genet 2010; 42(10): 906-909.
  2. Burdon KP, Macgregor S, Hewitt AW, et al. Genome-wide association study identifies susceptibility loci for open angle glaucoma at TMCO1 and CDKN2B-AS1. Nat Genet 2011; 43(6): 574-578.
  3. Wiggs JL, Yaspan BL, Hauser MA, et al. Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma. PLoS Genet 2012; 8(4): e1002654.
  4. Nakano M, Ikeda Y, Tokuda Y, et al. Common variants in CDKN2B- AS1 associated with optic-nerve vulnerability of glaucoma identified by genome-wide association studies in Japanese. PLoS One 2012; 7(3): e33389.
  5. Takamoto M, Kaburaki T, Mabuchi A, et al. Common variants on chromosome 9p21 are associated with normal tension glaucoma. PLoS One 2012; 7(7): e40107.
  6. Pasquale LR, Loomis SJ, Kang JH, et al. CDKN2B-AS1 Genotype- Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients From the United States. Am J Ophthalmol 2013; 155(2):342-353.

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