Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome,Ophthalmology

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Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome
Ophthalmology ( IF 13.1 ) Pub Date : 2021-11-08 , DOI: 10.1016/j.ophtha.2021.11.001
Katharina Bell ₁ , Mineo Ozaki ₂ , Kazuhiko Mori ₃ , Takanori Mizoguchi ₄ , Satoko Nakano ₅ , Natalia Porporato ₁ , Yoko Ikeda ₃ , Etsuo Chihara ₆ , Kenji Inoue ₇ , Shinichi Manabe ₈ , Ken Hayashi ₈ , Tomomi Higashide ₉ , Ryuichi Ideta ₁₀ , Kana Tokumo ₁₁ , Yoshiaki Kiuchi ₁₁ , Masakazu Nakano ₁₂ , Morio Ueno ₁₃ , Shigeru Kinoshita ₁₄ , Kei Tashiro ₁₂ , Chie Sotozono ₃ , Masaru Inatani ₁₅ , Kazuhisa Sugiyama ₁₀ , Toshiaki Kubota ₅ , Zheng Li ₁₆ , Zhenxun Wang ₁₇ , Chiea Chuen Khor ₁₇ , Tin Aung ₁₈

Affiliation

Singapore Eye Research Institute and Singapore National Eye Center, Singapore; Duke-NUS Medical School, Singapore.
Ozaki Eye Hospital, Hyuga, Miyazaki, Japan; Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Mizoguchi Eye Hospital, Sasebo, Nagasaki, Japan.
Department of Ophthalmology, Oita University Faculty of Medicine, Yufu-City, Oita, Japan.
Sensho-kai Eye Institute, Uji, Kyoto, Japan.
Inouye Eye Hospital, Tokyo, Japan.
Hayashi Eye Hospital, Fukuoka, Japan.
Department of Ophthalmology Kanazawa University Graduate School of Medical Science, Kanazawa, Japan.
Ideta Heisei Retina Consultants, Kumamoto, Japan.
Hiroshima University Department of Ophthalmology and Visual Sciences, Hiroshima, Japan.
Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.
Genome Institute of Singapore, Singapore.
Singapore Eye Research Institute and Singapore National Eye Center, Singapore; Genome Institute of Singapore, Singapore.
Singapore Eye Research Institute and Singapore National Eye Center, Singapore; Duke-NUS Medical School, Singapore; Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

Purpose

Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation.

Design

Retrospective case study.

Participants

A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort.

Methods

Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account.

Main Outcome Measures

Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation.

Results

The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7–20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4–11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001).

Conclusions

Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

中文翻译：

CYP39A1 G204E 遗传变异与剥脱综合征患者青光眼和失明风险增加的关联

目的

最近有报道称，CYP39A1基因功能缺陷突变的携带者发生剥脱综合征 (XFS) 的风险增加 2 倍。本研究的目的是评估携带功能丧失 CYP39A1 G204E 突变的 XFS 患者与没有任何CYP39A1突变的 XFS 患者相比的失明风险和相关临床表型。

设计

回顾性案例研究。

参与者

从日本 XFS 队列中随机选择了 35 名被诊断为携带CYP39A1 G204E 突变的 XFS 患者和 150 名没有任何CYP39A1突变的 XFS 患者。

方法

使用 alpha 水平 < 0.05 的双边 Fisher 精确检验来估计所有分类测量的计算优势比 (OR) 的显着性。使用线性混合效应模型进行受试者组之间的比较，将组作为随机效应并考虑受试者内眼睛之间可能的依赖性。

主要观察指标

初步分析比较了失明的发生率（定义为视力 [VA] < 小数点 0.05）、剥脱性青光眼 (XFG) 的患病率、青光眼手术史和青光眼严重程度指数，例如视野 (VF) 平均偏差 (MD) 、 CYP39A1 G204E 携带者与没有任何CYP39A1突变的携带者之间的眼压 (IOP) 和垂直杯盘比 (CDR) 。

结果

与没有任何CYP39A1突变的 XFS 患者相比，携带CYP39A1 G204E 变体的 XFS 患者（10/35 [28.6%]）的总体失明风险显着更高（8/150 [5.4%]；优势比 [OR]，7.1； 95% 置信区间 [CI]，2.7–20.2]；P < 0.001)。与对照组相比，更高比例的具有CYP39A1 G204E 突变的 XFS 患者（23/35 [65.7%]）至少有一只眼睛出现 XFG（41/150 [27.3%]；OR，5.1；95% CI , 2.4–11.4]；P < 0.0001)。在CYP39A1 G204E 变异携带者中也发现了显着更高的峰值 IOP、更大的垂直 CDR 和更差的 VF MD （ P < 0.001）。此外，患有与没有任何CYP39A1突变的患者相比， CYP39A1 G204E 突变（18/35 [51.4%]）需要更多的激光或青光眼手术干预（32/150 [21.3%]，P < 0.001）。