Association of Rare CYP39A1 Variants with Exfoliation Syndrome Involving the Anterior Chamber of the Eye

Li Z, Wang Z, Lee MC, Zenkel M, Peh E, Ozaki M, Topouzis F, Nakano S, Chan A, Chen S, Williams SE, Orr A, Nakano M, Kobakhidze N, Zarnowski T, Popa-Cherecheanu A, Mizoguchi T, Manabe SI, Hayashi K, Kazama S, Inoue K, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Ideta R, Ishiko S, Yoshida A, Tokumo K, Kiuchi Y, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Aihara M, Inatani M, Mori K, Ikeda Y, Ueno M, Gaston D, Rafuse P, Shuba L, Saunders J, Nicolela M, Chichua G, Tabagari S, Founti P, Sim KS, Meah WY, Soo HM, Chen XY, Chatzikyriakidou A, Keskini C, Pappas T, Anastasopoulos E, Lambropoulos A, Panagiotou ES, Mikropoulos DG, Kosior-Jarecka E, Cheong A, Li Y, Lukasik U, Nongpiur ME, Husain R, Perera SA, Álvarez L, García M, González-Iglesias H, Cueto AF, Cueto LF, Martinón-Torres F, Salas A, Oguz Ç, Tamcelik N, Atalay E, Batu B, Irkec M, Aktas D, Kasim B, Astakhov YS, Astakhov SY, Akopov EL, Gießl A, Mardin CY, Hellerbrand C, Cooke Bailey JN, Igo RP, Haines JL, Edward DP, Heegaard S, Davila S, Tan P, Kang JH, Pasquale LR, Kruse F, Reis A, Carmichael TR, Hauser M, Ramsay M, Mossböck G, Yildirim N, Tashiro K, Konstas AG, Coca-Prados M, Foo JN, Kinoshita S, Sotozono C, Kubota T, Dubina M, Ritch R, Wiggs JL, Pasutto F, Schlötzer-Schrehardt U, Ho YS, Aung T, Tam WL, Khor CC (2021)

Publication Type: Journal article

Publication year: 2021


Book Volume: 325

Pages Range: 753-764

Journal Issue: 8

DOI: 10.1001/jama.2021.0507


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 × 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 × 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.

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Involved external institutions

Oita University / 大分大学 JP Japan (JP) National University of Singapore (NUS) SG Singapore (SG) Kyoto Prefectural University of Medicine / 京都府立医科大学 JP Japan (JP) State Research Institute of Highly Pure Biopreparations / Государственный научно‑исследовательский институт особо чистых биопрепаратов RU Russian Federation (RU) Veterans Affairs Healthcare System Boston and Harvard Medical School US United States (USA) (US) Aristotle University of Thessaloniki GR Greece (GR) Ozaki Eye Hospital JP Japan (JP) Bioprocessing Technology Institute (BTI) SG Singapore (SG) Medical University of Lublin / Uniwersytet Medyczny w Lublinie PL Poland (PL) Chichua Medical Centre Mzera GE Georgia (GE) Kanazawa University / 金沢大学 JP Japan (JP) Dalhousie University CA Canada (CA) Hayashi Eye Hospital JP Japan (JP) University of Miyazaki / 宮崎大学 JP Japan (JP) Sensho-kai Eye Institute JP Japan (JP) Genome Institute of Singapore SG Singapore (SG) Miyata Eye Hospital JP Japan (JP) Tbilisi State Medical University GE Georgia (GE) Hiroshima University JP Japan (JP) Shinjo Eye Hospital JP Japan (JP) Universidad de Oviedo ES Spain (ES) Asahikawa Medical University JP Japan (JP) Hacettepe University TR Turkey (TR) Duke-NUS Medical School / 杜克—国大医学研究生院 SG Singapore (SG) Duke University US United States (USA) (US) University of the Witwatersrand (WITS) ZA South Africa (ZA) Istanbul University Cerrahpaşa / İstanbul Üniversitesi Cerrahpaşa (IUC) TR Turkey (TR) Complejo Hospitalario Universitario de Santiago de Compostela ES Spain (ES) Case Western Reserve University US United States (USA) (US) Icahn School of Medicine at Mount Sinai US United States (USA) (US) First Pavlov State Medical University of St. Petersburg RU Russian Federation (RU) Eskişehir Osmangazi Üniversitesi TR Turkey (TR) New York Eye and Ear Infirmary of Mount Sinai US United States (USA) (US) King Khaled Eye Specialist Hospital SA Saudi Arabia (SA) Tane Memorial Eye Hospital JP Japan (JP) Fukui University of Technology / 福井工業大学 JP Japan (JP) Carol Davila University of Medicine and Pharmacy / Universitatea de Medicină și Farmacie „Carol Davila” (UMF București) RO Romania (RO) Medizinische Universität Graz AT Austria (AT) DAMAGEN Genetik Araştırma ve Tanı Tic. Ltd. Şti. TR Turkey (TR) University of Tokyo JP Japan (JP) Inouye Eye Hospital JP Japan (JP) Ideta Eye Hospital JP Japan (JP) Mizoguchi Eye Hospital JP Japan (JP) University of Copenhagen DK Denmark (DK)

How to cite


Li, Z., Wang, Z., Lee, M.C., Zenkel, M., Peh, E., Ozaki, M.,... Khor, C.C. (2021). Association of Rare CYP39A1 Variants with Exfoliation Syndrome Involving the Anterior Chamber of the Eye. Journal of the American Medical Association, 325(8), 753-764.


Li, Zheng, et al. "Association of Rare CYP39A1 Variants with Exfoliation Syndrome Involving the Anterior Chamber of the Eye." Journal of the American Medical Association 325.8 (2021): 753-764.

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