Association of Rare CYP39A1 Variants with Exfoliation Syndrome Involving the Anterior Chamber of the Eye
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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.
| Original language | English |
|---|---|
| Journal | JAMA - Journal of the American Medical Association |
| Volume | 325 |
| Issue number | 8 |
| Pages (from-to) | 753-764 |
| ISSN | 0098-7484 |
| DOIs | |
| Publication status | Published - 2021 |
Bibliographical note
Funding Information:
reported receiving grants from Pfizer, Thea Pharmaceuticals, Novartis, Rheon, Alcon, Omikron, Bayer, and Bausch & Lomb; and receiving personal fees from Novartis and Omikron. Dr Chan reported receiving grants from Santen Pharmaceutical Co Ltd, Menarini Biomarker Singapore, and the National Medical Research Council. Dr Inoue reported receiving grants from Santen Pharmaceutical Co Ltd, Alcon Japan Ltd, Senju Pharmaceutical Co Ltd, Allergan Japan, and Teijin Pharma Limited; and receiving personal fees from Santen Pharmaceutical Co Ltd, Otsuka Pharmaceutical Co Ltd, Senju Pharmaceutical Co Ltd, Kowa Pharmaceutical Co Ltd, Allergan Japan, Novartis Pharma, Wakamoto Pharmaceutical Co Ltd, Hoya Corporation, Carl Zeiss Meditec, and Pfizer Japan Inc. Dr Y. Mori reported receiving grants from Alcon, AMO Pharma Ltd, Hoya Corporation, Otsuka Pharmaceutical, and Mitsubishi Chemical Medience; and receiving personal fees from Alcon, Hoya Corporation, Santen Pharmaceutical Co Ltd, AMO Pharma Ltd, and Novartis. Dr Ideta reported receiving personal fees from Santen Pharmaceutical Co Ltd, Senjyu, and Kowa. Dr K. Mori reported receiving grants from the Japan Society for the Promotion of Science; receiving personal fees from Santen Pharmaceutical Co Ltd, Kowa, and Senju Pharmaceutical Co; and having a patent pending with Santen Pharmaceutical Co Ltd that is unrelated to the article. Dr Nicolela reported receiving grants from Allergan Inc, Aerie Pharmaceutics, and Alcon Canada; and receiving personal fees from Allergan Canada, Baush & Lomb Canada, and Labtician-Thea. Dr Founti reported receiving personal fees from Thea Pharmaceuticals. Dr Pasquale reported receiving personal fees from Bausch & Lomb, Nicox, Verily, Eyenovia, and Emerald Biosciences. Dr Konstas reported receiving grants from Allergan, Santen Pharmaceutical Co Ltd, Pharmaten, and Omni Vision; and receiving personal fees from Merck Sharp and Dohme, Vianex, and Santen Pharmaceutical Co Ltd. Dr Kinoshita reported receiving grants from Santen Pharmaceutical Co Ltd, Senju Pharmaceutical Co, Otsuka Pharmaceutical, Kowa, Hoya Corporation, Oncolys Biopharma Inc, Lion Corporation, and CorneaGen; and receiving personal fees from Santen Pharmaceutical Co Ltd, Alcon Japan, AMO Pharma Ltd, Novartis, Astellas Pharma, Senju Pharmaceutical Co, Otsuka Pharmaceutical, Kowa, CorneaGen, and Aerie Pharmaceuticals. No other disclosures were reported.
Funding Information:
Funding/Support: The study was funded by grant NRF-NRFI2018-01 from the National Research Foundation of Singapore. Additional support was provided by grants R01 EY020928, P30 EY014104, UM1 CA186107, U01 CA167552, and EY015473 from the US National Eye Institute of the National Institutes of Health, funding from the Glaucoma Research Foundation of Canada, and grants X052 and CIRG17may053 from the National Medical Research Council of Singapore.
Funding Information:
Greece: Patients with exfoliation syndrome were identified from the Thessaloniki Eye Study. This was a comprehensive prevalenceⵢased study of eye diseases in Thessaloniki, Greece5. Ethical approval for the Thessaloniki Eye Study was granted by the Aristotle University Medical School Ethics Committee. The Thessaloniki Eye Study was co?funded by the European Union (European Social Fund) and Greek national funds under the Act "Aristia" of the Operational Program "Education and Lifelong Learning". Unaffected controls were age and ancestry matched participants from the Thessaloniki Eye Study who were verified to have no exfoliation syndrome and no other forms of glaucoma after an eye examination.
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