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

Autor:	Li Z; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Wang Z; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore., Lee MC; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore., Zenkel M; Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Peh E; Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore., Ozaki M; Ozaki Eye Hospital, Miyazaki, Japan., Topouzis F; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.; iScreen Research Team, Center for Interdisciplinary Research and Innovation, Aristotle University of Thessaloniki, Thessaloniki, Greece., Nakano S; Department of Ophthalmology, Faculty of Medicine, Oita University, Oita, Japan., Chan A; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.; Duke-NUS Medical School, Singapore., Chen S; Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore., Williams SEI; Division of Ophthalmology, Department of Neurosciences, University of Witwatersrand, Johannesburg, South Africa., Orr A; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.; Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada., Nakano M; Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan., Kobakhidze N; Chichua Medical Center Mzera, Tbilisi, Georgia., Zarnowski T; Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland., Popa-Cherecheanu A; Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.; Department of Ophthalmology, University Emergency Hospital, Bucharest, Romania., Mizoguchi T; Mizoguchi Eye Hospital, Nagasaki, Japan., Manabe SI; Hayashi Eye Hospital, Fukuoka, Japan., Hayashi K; Hayashi Eye Hospital, Fukuoka, Japan., Kazama S; Shinjo Eye Clinic, Miyazaki, Japan., Inoue K; Inouye Eye Hospital, Tokyo, Japan., Mori Y; Miyata Eye Hospital, Miyazaki, Japan., Miyata K; Miyata Eye Hospital, Miyazaki, Japan., Sugiyama K; Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan., Higashide T; Department of Ophthalmology, Kanazawa University Graduate School of Medical Science, Kanazawa, Japan., Chihara E; Sensho-kai Eye Institute, Kyoto, Japan., Ideta R; Ideta Heisei Retina Consultants, Kumamoto, Japan., Ishiko S; Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan., Yoshida A; Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan., Tokumo K; Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan., Kiuchi Y; Department of Ophthalmology and Visual Sciences, Hiroshima University, Hiroshima, Japan., Ohashi T; Ohashi Eye Center, Sapporo, Japan., Sakurai T; Tane Memorial Eye Hospital, Osaka, Japan., Sugimoto T; Department of Ophthalmology, Miyazaki Medical College Hospital, Miyazaki, Japan., Chuman H; Department of Ophthalmology, Miyazaki Medical College Hospital, Miyazaki, Japan., Aihara M; Department of Ophthalmology, University of Tokyo, Tokyo, Japan., Inatani M; Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan., Mori K; Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan., Ikeda Y; Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan., Ueno M; Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan., Gaston D; Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada., Rafuse P; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada., Shuba L; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada., Saunders J; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada., Nicolela M; Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada., Chichua G; Chichua Medical Center Mzera, Tbilisi, Georgia., Tabagari S; David Tvildiani Medical University, Tbilisi, Georgia., Founti P; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece.; Glaucoma Unit, Moorfields Eye Hospital NHS Foundation Trust, London, England., Sim KS; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Meah WY; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Soo HM; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Chen XY; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Chatzikyriakidou A; Laboratory of Medical Biology-Genetics, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Keskini C; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Pappas T; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Anastasopoulos E; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Lambropoulos A; Laboratory of Medical Biology-Genetics, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Panagiotou ES; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Mikropoulos DG; First Department of Ophthalmology, Faculty of Health Sciences, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Kosior-Jarecka E; Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland., Cheong A; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore., Li Y; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore., Lukasik U; Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland., Nongpiur ME; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.; Duke-NUS Medical School, Singapore., Husain R; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore., Perera SA; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore., Álvarez L; Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.; Fernández-Vega Ophthalmological Institute, Oviedo, Spain., García M; Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.; Fernández-Vega Ophthalmological Institute, Oviedo, Spain., González-Iglesias H; Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.; Fernández-Vega Ophthalmological Institute, Oviedo, Spain., Fernández-Vega Cueto A; Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.; Fernández-Vega Ophthalmological Institute, Oviedo, Spain., Fernández-Vega Cueto L; Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.; Fernández-Vega Ophthalmological Institute, Oviedo, Spain., Martinón-Torres F; Translational Pediatrics and Infectious Diseases, Hospital Clínico Universitario de Santiago and GENVIP Research Group, Instituto de Investigación Sanitaria, University of Santiago de Compostela, Santiago de Compostela, Spain., Salas A; Unidade de Xenética, Instituto de Ciencias Forenses, Facultade de Medicina, Universidade de Santiago de Compostela, and GenPoB Research Group, Instituto de Investigación Sanitaria, Hospital Clínico Universitario de Santiago, Galicia, Spain., Oguz Ç; Department of Genetics, Eskisehir Osmangazi University, Eskisehir, Turkey., Tamcelik N; Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey., Atalay E; Department of Ophthalmology, Eskisehir Osmangazi University, Eskisehir, Turkey., Batu B; Faculty of Medicine, Istanbul University-Cerrahpasa, Istanbul, Turkey., Irkec M; Department of Ophthalmology, Faculty of Medicine, Hacettepe University, Ankara, Turkey., Aktas D; DAMAGEN Genetic Diagnostic Center, Ankara, Turkey., Kasim B; Department of Ophthalmology, Faculty of Medicine, Hacettepe University, Ankara, Turkey., Astakhov YS; Department of Ophthalmology, Pavlov First Saint Petersburg State Medical University, St Petersburg, Russia., Astakhov SY; Department of Ophthalmology, Pavlov First Saint Petersburg State Medical University, St Petersburg, Russia., Akopov EL; Department of Ophthalmology, Pavlov First Saint Petersburg State Medical University, St Petersburg, Russia., Giessl A; Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Mardin C; Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Hellerbrand C; Institute of Biochemistry, Emil-Fischer-Zentrum, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Cooke Bailey JN; Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio., Igo RP Jr; Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio., Haines JL; Institute for Computational Biology, Department of Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio., Edward DP; King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.; Department of Ophthalmology and Visual Sciences, University of Illinois College of Medicine, Chicago., Heegaard S; Department of Ophthalmology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.; Eye Pathology Section, Department of Pathology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Davila S; SingHealth Duke-NUS Institute of Precision Medicine, Singapore.; Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, Singapore., Tan P; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; SingHealth Duke-NUS Institute of Precision Medicine, Singapore.; Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore., Kang JH; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts., Pasquale LR; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York., Kruse FE; Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Reis A; Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany., Carmichael TR; Division of Ophthalmology, Department of Neurosciences, University of Witwatersrand, Johannesburg, South Africa., Hauser M; Department of Medicine, Duke University, Durham, North Carolina.; Department of Ophthalmology, Duke University, Durham, North Carolina., Ramsay M; Sydney Brenner Institute for Molecular Bioscience, Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa., Mossböck G; Department of Ophthalmology, Medical University Graz, Graz, Austria., Yildirim N; Department of Ophthalmology, Eskisehir Osmangazi University, Eskisehir, Turkey., Tashiro K; Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan., Konstas AGP; First and Third Departments of Ophthalmology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Coca-Prados M; Fernández-Vega University Institute and Foundation of Ophthalmological Research, University of Oviedo, Oviedo, Spain.; Fernández-Vega Ophthalmological Institute, Oviedo, Spain.; Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut., Foo JN; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore., Kinoshita S; Department of Frontier Medical Science and Technology for Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan., Sotozono C; Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan., Kubota T; Department of Ophthalmology, Faculty of Medicine, Oita University, Oita, Japan., Dubina M; State Research Institute of Highly Pure Biopreparations FMBA Russia, St Petersburg, Russia., Ritch R; Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York., Wiggs JL; Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston., Pasutto F; Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany., Schlötzer-Schrehardt U; Department of Ophthalmology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Ho YS; Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore., Aung T; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.; Duke-NUS Medical School, Singapore.; Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Tam WL; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Cancer Science Institute of Singapore, National University of Singapore, Singapore.; Nanyang Technological University School of Biological Sciences, Singapore.; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore., Khor CC; Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.; Singapore Eye Research Institute, Singapore National Eye Centre, Singapore.; Duke-NUS Medical School, Singapore.
Jazyk:	angličtina
Zdroj:	JAMA [JAMA] 2021 Feb 23; Vol. 325 (8), pp. 753-764.
DOI:	10.1001/jama.2021.0507
Abstrakt:	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.
Databáze:	MEDLINE
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