Link Between Glaucoma Risk Alleles at CDKN2B-AS1 and IOP, NTG, and Advanced Glaucoma
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. Researchers in Australia conducted the following comparative case series and case-control study 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. Included in their study were 1,432 POAG patients and 595 unaffected controls recruited from two population-based and two cross-sectional studies.
The researchers genotyped each patient at nine single nucleotide polymorphisms (SNPs) previously associated with POAG at the 9p21 locus. They assessed each SNP for association with each outcome measure using linear regression under an additive genetic model. They explored associated traits further including adjustment for relevant covariates and they also analyzed highest recorded intraocular pressure (IOP) both with and without correction for central corneal thickness (CCT) and dichotomized these pressures into high-tension glaucoma and normal-tension glaucoma (NTG). IOP and vertical cup-to-disc ratio (VCDR) were the main outcome measures.
According to the study researchers, glaucoma risk alleles at 9p21, particularly rs7049105 and rs10120688, were associated with the presence of both NTG and advanced POAG. They also noted that the SNP rs10120688 was associated with greater VCDR after adjustment for covariates (p=0.003;β=0.016; standard error, 0.006). They reported that multiple SNPs in the region were associated with reduced IOP, before and after adjustment for CCT and that 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, the researchers found that 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).
In conclusion, 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 PAOG 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.