@article {1580466, title = {Association of Rare CYP39A1 Variants With Exfoliation Syndrome Involving the Anterior Chamber of the Eye}, journal = {JAMA}, volume = {325}, number = {8}, year = {2021}, month = {2021 02 23}, pages = {753-764}, 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 {\texttimes} 10-6. 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 {\texttimes} 10-7). 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.}, issn = {1538-3598}, doi = {10.1001/jama.2021.0507}, author = {Genetics of Exfoliation Syndrome Partnership and Li, Zheng and Wang, Zhenxun and Lee, Mei Chin and Zenkel, Matthias and Peh, Esther and Ozaki, Mineo and Topouzis, Fotis and Nakano, Satoko and Chan, Anita and Chen, Shuwen and Williams, Susan E I and Orr, Andrew and Nakano, Masakazu and Kobakhidze, Nino and Zarnowski, Tomasz and Popa-Cherecheanu, Alina and Mizoguchi, Takanori and Manabe, Shin-Ichi and Hayashi, Ken and Kazama, Shigeyasu and Inoue, Kenji and Mori, Yosai and Miyata, Kazunori and Sugiyama, Kazuhisa and Higashide, Tomomi and Chihara, Etsuo and Ideta, Ryuichi and Ishiko, Satoshi and Yoshida, Akitoshi and Tokumo, Kana and Kiuchi, Yoshiaki and Ohashi, Tsutomu and Sakurai, Toshiya and Sugimoto, Takako and Chuman, Hideki and Aihara, Makoto and Inatani, Masaru and Mori, Kazuhiko and Ikeda, Yoko and Ueno, Morio and Gaston, Daniel and Rafuse, Paul and Shuba, Lesya and Saunders, Joseph and Nicolela, Marcelo and Chichua, George and Tabagari, Sergo and Founti, Panayiota and Sim, Kar Seng and Meah, Wee Yang and Soo, Hui Meng and Chen, Xiao Yin and Chatzikyriakidou, Anthi and Keskini, Christina and Pappas, Theofanis and Anastasopoulos, Eleftherios and Lambropoulos, Alexandros and Panagiotou, Evangelia S and Mikropoulos, Dimitrios G and Kosior-Jarecka, Ewa and Cheong, Augustine and Li, Yuanhan and Lukasik, Urszula and Nongpiur, Monisha E and Husain, Rahat and Perera, Shamira A and {\'A}lvarez, Lydia and Garc{\'\i}a, Montserrat and Gonz{\'a}lez-Iglesias, H{\'e}ctor and Cueto, Andr{\'e}s F V and Cueto, Luis F V and Martin{\'o}n-Torres, Federico and Salas, Antonio and Oguz, {\c C}ilingir and Tamcelik, Nevbahar and Atalay, Eray and Batu, Bilge and Irkec, Murat and Aktas, Dilek and Kasim, Burcu and Astakhov, Yury S and Astakhov, Sergei Y and Akopov, Eugeny L and Giessl, Andreas and Mardin, Christian and Hellerbrand, Claus and Cooke Bailey, Jessica N and Igo, Robert P and Haines, Jonathan L and Edward, Deepak P and Heegaard, Steffen and Davila, Sonia and Tan, Patrick and Kang, Jae H and Pasquale, Louis R and Kruse, Friedrich E and Reis, Andr{\'e} and Carmichael, Trevor R and Hauser, Michael and Ramsay, Michele and Mossb{\"o}ck, Georg and Yildirim, Nilgun and Tashiro, Kei and Konstas, Anastasios G P and Coca-Prados, Miguel and Foo, Jia Nee and Kinoshita, Shigeru and Sotozono, Chie and Kubota, Toshiaki and Dubina, Michael and Ritch, Robert and Wiggs, Janey L and Pasutto, Francesca and Schl{\"o}tzer-Schrehardt, Ursula and Ho, Ying Swan and Aung, Tin and Tam, Wai Leong and Khor, Chiea Chuen} }