Association of Rare <i>CYP39A1</i> Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye
Authors: 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 Fernández-Vega Cueto, Luis Fernández-Vega Cueto, Federico Martinón-Torres, Antonio Salas, Çilingir Oguz, Nevbahar Tamcelik, Eray Atalay, Bilge Batu, Murat Irkec, Dilek Aktas, Burcu Kasim, Yury S. Astakhov, Sergei Y. Astakhov, Eugeny L. Akopov, Andreas Giessl, Christian Mardin, Claus Hellerbrand, Jessica N. Cooke Bailey, Robert P. Igo, Jonathan L. Haines, Deepak P. Edward, Steffen Heegaard, Sonia Davila, Patrick Tan, Jae H. Kang, Louis R. Pasquale, Friedrich E. Kruse, André Reis, Trevor R. Carmichael, Michael Hauser, Michele Ramsay, Georg Mossböck, Nilgun Yildirim, Kei Tashiro, Anastasios G. P. Konstas, Miguel Coca-Prados, Jia Nee Foo, Shigeru Kinoshita, Chie Sotozono, Toshiaki Kubota, Michael Dubina, Robert Ritch, Janey L. Wiggs, Francesca Pasutto, Ursula Schlötzer-Schrehardt, Ying Swan Ho, Tin Aung, Wai Leong Tam, Chiea Chuen Khor
Journal: JAMA (2021)

<h3>Importance</h3> 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. <h3>Objective</h3> To determine if exfoliation syndrome is associated with rare, protein-changing variants predicted to impair protein function. <h3>Design, Setting, and Participants</h3> 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. <h3>Exposures</h3> Rare, coding-sequence genetic variants predicted to be damaging by bioinformatic algorithms trained to recognize alterations that impair protein function. <h3>Main Outcomes and Measures</h3> The primary outcome was the presence of exfoliation syndrome. Exome-wide significance for detected variants was defined as<i>P</i> &lt; 2.5 × 10<sup>−6</sup>. The secondary outcomes included biochemical enzymatic assays and gene expression analyses. <h3>Results</h3> 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<i>CYP39A1</i>variants (1.3% vs 0.30%, respectively; odds ratio, 3.55 [95% CI, 2.07-6.10];<i>P</i> = 6.1 × 10<sup>−7</sup>). 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<i>CYP39A1</i>damaging alleles vs 3.1% without exfoliation syndrome (odds ratio, 1.82 [95% CI, 1.47-2.26];<i>P</i> &lt; .001). Biochemical assays classified 34 of 42 damaging<i>CYP39A1</i>alleles as functionally deficient (median reduction in enzymatic activity compared with wild-type<i>CYP39A1</i>, 94.4% [interquartile range, 78.7%-98.2%] for the 34 deficient variants).<i>CYP39A1</i>transcript expression was 47% lower (95% CI, 30%-64% lower;<i>P</i> &lt; .001) in ciliary body tissues from individuals with exfoliation syndrome compared with individuals without exfoliation syndrome. <h3>Conclusions and Relevance</h3> In this whole-exome sequencing case-control study, presence of exfoliation syndrome was significantly associated with carriage of functionally deficient<i>CYP39A1</i>sequence variants. Further research is needed to understand the clinical implications of these findings.