剥脱综合征遗传学联盟研究了罕见CYP39A1变异与累及前房的剥脱综合征的关系。2021年2月23日，该研究发表在《美国医学会杂志》上。
剥脱综合征是一种全身性疾病，临床表现为眼部前房异常纤维蛋白聚集体进行性聚集。这种疾病是青光眼最常见的病因，也是不可逆性失明的主要原因。
为了确定剥脱综合征是否与罕见的、预测会损害蛋白质功能的蛋白质变化变异有关，研究组进行了一项两阶段、病例对照、全外显子组测序关联研究，包括一个发现队列和两个独立确定的验证队列。1999年2月至2019年12月，来自14个国家的研究参与者被纳入研究。最后一次临床随访日期为2019年12月。
裂隙灯检查显示，受累参与者至少有1只眼的眼前节结构有脱落物质。未受累个体没有剥脱综合征的迹象。通过训练识别损害蛋白质功能改变的生物信息学算法，可预测具有破坏性的罕见编码序列遗传变异。主要结局为出现剥脱综合征。外显子组范围内检测到变异的显著性定义为P < 2.5 × 10−6。次要结局包括生化酶测定和基因表达分析。
发现队列共包括4028名剥脱综合征患者，中位年龄为78岁，59.0%为女性；以及5638名无剥脱综合征参与者，中位年龄为72岁，56.0%为女性。在发现队列中，剥脱综合征患者与没有剥脱综合征的参与者相比，携带破坏性CYP39A1变异的可能性显著增加，分别为1.3%和0.30%。
该结果在两个独立的队列中得到验证。第一个验证队列包括2337名剥脱综合征患者，中位年龄为74岁，1132名为女性，1934名有人口统计学数据；2813名没有剥脱综合征的参与者，中位年龄为72岁，1287名为女性，2421名有人口统计学数据。第二个验证队列包括1663名剥脱综合征患者，中位年龄为75岁，587名为女性，1064名有人口统计学数据；3962名没有剥脱综合征的参与者，中位年龄为74岁，951名为女性，1555名有人口统计学数据。
在两个验证队列的个体中，5.2%的剥脱综合征患者携带CYP39A1损伤等位基因，而没有剥脱综合征的参与者中为3.1%，比值比为1.82。生化分析将42个破坏性CYP39A1等位基因中的34个归类为功能缺陷型，与野生型CYP39A1相比，34个缺陷型的酶活性中位数降低了94.4%。与无剥脱综合征的参与者相比，剥脱综合征个体的睫状体组织中CYP39A1转录表达降低47%。
研究结果表明，在这项全外显子组测序病例对照研究中，剥脱综合征的存在与携带功能缺陷型CYP39A1序列变异显著相关。
附：英文原文
Title: Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye
Author: The Genetics of Exfoliation Syndrome Partnership, Zheng Li, Zhenxun Wang, Mei Chin Lee, Matthias Zenkel, Esther Peh, Mineo Ozaki, Fotis Topouzis, Satoko Nakano, Anita Chan, Shuwen Chen, Susan E. I. Williams, Andrew Orr, Masakazu Nakano, Nino Kobakhidze, Tomasz Zarnowski, Alina Popa-Cherecheanu, Takanori Mizoguchi, Shin-ichi Manabe, Ken Hayashi, Shigeyasu Kazama, Kenji Inoue, Yosai Mori, Kazunori Miyata, Kazuhisa Sugiyama, Tomomi Higashide, Etsuo Chihara, Ryuichi Ideta, Satoshi Ishiko, Akitoshi Yoshida, Kana Tokumo, Yoshiaki Kiuchi, Tsutomu Ohashi, Toshiya Sakurai, Takako Sugimoto, Hideki Chuman, Makoto Aihara, Masaru Inatani, Kazuhiko Mori, Yoko Ikeda, Morio Ueno, Daniel Gaston, Paul Rafuse, Lesya Shuba, Joseph Saunders, Marcelo Nicolela, George Chichua, Sergo Tabagari, Panayiota Founti, Kar Seng Sim, Wee Yang Meah, Hui Meng Soo, Xiao Yin Chen, Anthi Chatzikyriakidou, Christina Keskini, Theofanis Pappas, Eleftherios Anastasopoulos, Alexandros Lambropoulos, Evangelia S. Panagiotou, Dimitrios G. Mikropoulos, Ewa Kosior-Jarecka, Augustine Cheong, Yuanhan Li, Urszula Lukasik, Monisha E. Nongpiur, Rahat Husain, Shamira A. Perera, Lydia álvarez, Montserrat García, Héctor González-Iglesias, Andrés F. V. Cueto
Issue&Volume: 2021/02/23
Abstract:
Importance Exfoliation syndrome is a systemic disorder characterized by progressive accumulation of abnormal fibrillar protein aggregates manifesting clinically in the anterior chamber of the eye. This disorder is the most commonly known cause of glaucoma and a major cause of irreversible blindness.
Objective To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function.
Design, Setting, and Participants A 2-stage, case-control, whole-exome sequencing association study with a discovery cohort and 2 independently ascertained validation cohorts. Study participants from 14 countries were enrolled between February 1999 and December 2019. The date of last clinical follow-up was December 2019. Affected individuals had exfoliation material on anterior segment structures of at least 1 eye as visualized by slit lamp examination. Unaffected individuals had no signs of exfoliation syndrome.
Exposures Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function.
Main Outcomes and Measures The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as P<2.5×106. The secondary outcomes included biochemical enzymatic assays and gene expression analyses.
Results The discovery cohort included 4028 participants with exfoliation syndrome (median age, 78 years [interquartile range, 73-83 years]; 2377 [59.0%] women) and 5638 participants without exfoliation syndrome (median age, 72 years [interquartile range, 65-78 years]; 3159 [56.0%] women). In the discovery cohort, persons with exfoliation syndrome, compared with those without exfoliation syndrome, were significantly more likely to carry damaging CYP39A1 variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10]; P=6.1×107). This outcome was validated in 2 independent cohorts. The first validation cohort included 2337 individuals with exfoliation syndrome (median age, 74 years; 1132 women; n=1934 with demographic data) and 2813 individuals without exfoliation syndrome (median age, 72 years; 1287 women; n=2421 with demographic data). The second validation cohort included 1663 individuals with exfoliation syndrome (median age, 75 years; 587 women; n=1064 with demographic data) and 3962 individuals without exfoliation syndrome (median age, 74 years; 951 women; n=1555 with demographic data). Of the individuals from both validation cohorts, 5.2% with exfoliation syndrome carried CYP39A1 damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26]; P<.001). Biochemical assays classified 34 of 42 damaging CYP39A1 alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type CYP39A1, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants). CYP39A1 transcript expression was 47% lower (95% CI, 30%-64% lower; P<.001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome.
Conclusions and Relevance In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient CYP39A1 sequence variants. Further research is needed to understand the clinical implications of these findings.
DOI: 10.1001/jama.2021.0507
Source: https://jamanetwork.com/journals/jama/article-abstract/2776689
JAMA-Journal of The American Medical Association：《美国医学会杂志》，创刊于1883年。隶属于美国医学协会，最新IF：157.335
官方网址：https://jamanetwork.com/
投稿链接：http://manuscripts.jama.com/cgi-bin/main.plex
本期文章：《美国医学会杂志》：Vol 325 No 8
