Department of Ophthalmology, Flinders University, Flinders Medical Centre, Adelaide, Australia.
Ophthalmology. 2012 Aug;119(8):1539-45. doi: 10.1016/j.ophtha.2012.02.004. Epub 2012 Apr 21.
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.
Comparative case series and case-control study.
One thousand four hundred thirty-two POAG patients and 595 unaffected controls recruited from 2 population-based and 2 cross-sectional studies.
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).
Intraocular pressure and vertical cup-to-disc ratio (VCDR).
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).
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.
在几项独立的研究中，9p21 基因座上包含 CDKN2B-AS1、CDKN2A 和 CDKN2B 基因的遗传变异与原发性开角型青光眼（POAG）有关。本研究旨在进一步剖析这种关联，并确定该基因座遗传变异与大量 POAG 患者一系列青光眼相关特征之间的基因型-表型相关性。
比较病例系列和病例对照研究。
1432 名 POAG 患者和 595 名未受影响的对照者，均来自 2 项基于人群的研究和 2 项横断面研究。
每位患者均在 9p21 基因座上的 9 个先前与 POAG 相关的单核苷酸多态性（SNP）上进行了基因分型。每个 SNP 均采用加性遗传模型下的线性回归来评估与每个结局指标的关联。对相关性状进行了进一步探讨，包括对相关协变量的调整。还分析了最高记录的眼压（IOP），并分别在不校正和校正中央角膜厚度（CCT）的情况下进行了分析，并将其分为高眼压性青光眼和正常眼压性青光眼（NTG）。
眼压和垂直杯盘比（VCDR）。
9p21 上的青光眼风险等位基因，尤其是 rs7049105 和 rs10120688，与 NTG 和晚期 POAG 的存在均有关。在调整协变量后，SNP rs10120688 与 VCDR 增加相关（P = 0.003；β = 0.016；标准误，0.006）。此外，该区域的多个 SNP 与校正 CCT 前后的 IOP 降低有关。与 IOP 相关性最显著的 SNP 也是 rs10120688（P = 0.001；β = -2.135；标准误，0.634），在加性模型下调整协变量后。在比较高眼压性与低眼压性青光眼时，当根据 CCT 校正后再对青光眼类型进行分类时，该 SNP 也是与眼压最显著相关的 SNP（P = 0.0009；比值比，0.63；95%置信区间，0.48-0.83）。
携带 9p21 基因座上青光眼风险等位基因的 POAG 患者的 VCDR 较大，IOP 较低。携带这些等位基因的患者似乎更容易在较低的 IOP 水平下发生 POAG，并且与 NTG 和晚期青光眼表型的相关性更强。这可能与携带这些风险等位基因的患者设定目标压力有关。
