A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study.
A Common Glaucoma-risk Variant of SIX6 Alters Retinal Nerve Fiber Layer and Optic Disc Measures in a European Population: The EPIC-Norfolk Eye Study.
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DOI：
10.1097/ijg.0000000000001026
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发表时间：
2018-09
影响因子：
2
通讯作者：
Foster PJ
中科院分区：
文献类型：
--
作者：
Khawaja AP;Chan MPY;Yip JLY;Broadway DC;Garway-Heath DF;Viswanathan AC;Luben R;Hayat S;Hauser MA;Wareham NJ;Khaw KT;Fortune B;Allingham RR;Foster PJ
SIX6基因（rs33912345）中一种常见的错义变异与原发性开角型青光眼（POAG）密切相关。我们的目的是研究rs33912345与欧洲人群视盘和视网膜神经纤维层（RNFL）测量的关系。我们检查了以人群为基础的EPIC-Norfolk眼科研究的参与者。参与者接受共聚焦激光扫描断层扫描（Heidelberg Retina Tomograph II， HRT）来估计视盘边缘面积和垂直杯盘比（VCDR）。扫描激光偏振法（GDxVCC）用于估计RNFL的平均厚度。考虑每个参与者的左右眼值的平均值。使用Affymetrix UK Biobank Axiom Array进行基因分型。采用多变量线性回归，以视神经头参数为结局变量，rs33912345基因型剂量为主要解释变量，对年龄、性别、椎间盘面积、轴长、眼压进行校正。我们进一步重复分析，按年龄分组。总共纳入了5433名HRT数据的参与者和3699名GDxVCC数据的参与者。rs33912345的每个“C”等位基因与较小的边缘面积（-0.030mm2 [95% CI -0.040, -0.020]， P=5.4 × 10-9）、较大的VCDR （0.025 [95% CI 0.017, 0.033]， P=3.3 × 10-10）和较薄的RNFL （-0.39μm [95% CI -0.62, -0.15]， P=0.001）相关。RNFL相关性在最高龄三分卫中最强，而边缘面积和VCDR相关性在最年轻和最高龄三分卫中最强。编码SIX6变体rs33912345的蛋白质，先前与POAG相关，对欧洲人青光眼相关视神经头特征具有功能影响。
A common missense variant in the SIX6 gene (rs33912345) is strongly associated with primary open-angle glaucoma (POAG). We aimed to examine the association of rs33912345 with optic disc and retinal nerve fiber layer (RNFL) measures in a European population. We examined participants of the population-based EPIC-Norfolk Eye Study. Participants underwent confocal laser scanning tomography (Heidelberg Retina Tomograph II, HRT) to estimate optic disc rim area and vertical cup-disc ratio (VCDR). Scanning laser polarimetry (GDxVCC) was used to estimate average RNFL thickness. The mean of right and left eye values was considered for each participant. Genotyping was performed using the Affymetrix UK Biobank Axiom Array. Multivariable linear regression with the optic nerve head parameter as outcome variable and dosage of rs33912345 genotype as primary explanatory variable was used, adjusted for age, sex, disc area, axial length and intraocular pressure. We further repeated analyses stratified into age tertiles. In total, 5,433 participants with HRT data and 3,699 participants with GDxVCC data were included. Each “C” allele of rs33912345 was associated with a smaller rim area (-0.030mm2 [95% CI -0.040, -0.020], P=5.4x10-9), a larger VCDR (0.025 [95% CI 0.017, 0.033], P=3.3x10-10) and a thinner RNFL (-0.39μm [95% CI -0.62, -0.15], P=0.001). The RNFL association was strongest in the oldest age tertile, whereas rim area and VCDR associations were strongest in the youngest and oldest age tertiles. The protein coding SIX6 variant rs33912345, previously associated with POAG, has a functional effect on glaucoma-associated optic nerve head traits in Europeans.