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 C, 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

Journal

Book Volume: 325

Pages Range: 753-764

Journal Issue: 8

DOI: 10.1001/jama.2021.0507

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 × 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.

Authors with CRIS profile

Involved external institutions

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

How to cite

APA:

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. https://doi.org/10.1001/jama.2021.0507

MLA:

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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