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A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome

Nature Genetics volume 47, pages 387392 (2015) | Download Citation

  • A Corrigendum to this article was published on 27 May 2015

This article has been updated

Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10−11). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10−217; non-Japanese: ORA allele = 0.49, P = 2.35 × 10−31). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

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Change history

  • 09 March 2015

    In the version of this article initially published online, the affiliation of author Nicole Weisschuh was incorrect. Her correct affiliation is the Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, Germany. The error has been corrected for the print, PDF and HTML versions of this article.

  • 27 April 2015

    In the version of this article initially published, the name of author Afsaneh Naderi Beni was misspelled. The error has been corrected in the HTML and PDF versions of the article.

Accessions

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Acknowledgements

The authors thank the staff and participants of all studies for their important contributions. We thank K.-K. Heng, X.-Y. Chen, H.-M. Soo, S.-Q. Mok, A. Jamuth, N. Foxworth and M. Elbl for technical assistance. This research was funded by the Biomedical Research Council, Agency for Science, Technology and Research, Singapore. J.L.W. acknowledges support from US National Institutes of Health/National Eye Institute grants (NIH/NEI R01 EY020928 and NIH/NEI P30 EY014104). S.W.M.J. acknowledges support from grant EY11721 from the US National Institutes of Health/National Eye Institute and is an investigator of the Howard Hughes Medical Institute. L.R.P. acknowledges support from a Harvard Medical School Distinguished Ophthalmology Scholar Award and the Harvard Glaucoma Center of Excellence. J.H.F. acknowledges support from US National Institutes of Health/National Eye Institute grants (EY023512 and EY018825). Z.Y. acknowledges support from the National Natural Science Foundation of China (81025006 and 81170883), as well as from the Department of Science and Technology of Sichuan Province, China (2012SZ0219 and 2011jtd0020). M.S. acknowledges support from Robert Bosch Stiftung (Stuttgart, Germany) and the German Cancer Consortium (DKTK), Germany. The Australian case cohort was funded by grants from the Ophthalmic Research Institute of Australia and National Health and Medical Research Council (NHMRC) project 535044. The Thessaloniki Eye Study was cofunded by the European Union (European Social Fund) and Greek national funds under act ‘Aristia’ of the operational program ‘Education and Lifelong Learning’ (Supplementary Note). Blue Mountains Eye Study (BMES) GWAS and genotyping costs were supported by the Australian NHMRC (Canberra, Australia; NHMRC project grants 512423, 475604 and 529912) and the Wellcome Trust, UK, as part of the Wellcome Trust Case Control Consortium 2 (A. Viswanathan, P. McGuffin, P. Mitchell, F. Topouzis, P. Foster; grants 085475/B/08/Z and 085475/08/Z). K.P.B. is an NHMRC Senior Research Fellow, and J.E.C. is an NHMRC Practitioner Fellow. M.A.B. is an NHMRC Principal Research Fellow. A.W.H. is an NHMRC Peter Doherty Fellow.

Author information

Author notes

    • Tin Aung
    • , Mineo Ozaki
    • , Takanori Mizoguchi
    •  & R Rand Allingham

    These authors contributed equally to this work.

    • Janey L Wiggs
    • , Francesca Pasutto
    • , Fotis Topouzis
    • , Michael Dubina
    • , Jamie E Craig
    • , Nagahisa Yoshimura
    • , Periasamy Sundaresan
    • , Simon W M John
    • , Robert Ritch
    • , Michael A Hauser
    •  & Chiea-Chuen Khor

    These authors jointly supervised this work.

Affiliations

  1. Singapore Eye Research Institute, Singapore.

    • Tin Aung
    • , Anita S Y Chan
    • , Mei Chin Lee
    • , Eranga N Vithana
    • , Tien Yin Wong
    • , Ching Yu Cheng
    • , Shamira A Perera
    • , Rahat Husain
    • , Arkasubhra Ghosh
    •  & Chiea-Chuen Khor
  2. Singapore National Eye Center, Singapore.

    • Tin Aung
    • , Anita S Y Chan
    • , Tien Yin Wong
    • , Shamira A Perera
    •  & Rahat Husain
  3. Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Tin Aung
    • , Tien Yin Wong
    • , Ching Yu Cheng
    •  & Chiea-Chuen Khor
  4. Division of Human Genetics, Genome Institute of Singapore, Singapore.

    • Tin Aung
    • , Zheng Li
    • , Kar Seng Sim
    • , Jia Nee Foo
    • , Kai-Yee Toh
    • , Yufen Goh
    • , Wee Yang Meah
    • , Su Qin Peh
    •  & Chiea-Chuen Khor
  5. Duke University–National University of Singapore Graduate Medical School, Singapore.

    • Tin Aung
  6. Ozaki Eye Hospital, Hyuga, Japan.

    • Mineo Ozaki
  7. Hayashi Eye Hospital, Fukuoka, Japan.

    • Mineo Ozaki
    • , Shin-ichi Manabe
    •  & Ken Hayashi
  8. Mizoguchi Eye Hospital, Sasebo, Japan.

    • Takanori Mizoguchi
  9. Department of Ophthalmology, Duke University Eye Center, Durham, North Carolina, USA.

    • R Rand Allingham
    • , Pratap Challa
    • , Yik Ying Teo
    •  & Michael A Hauser
  10. Intraocular Lens and Cataract Clinic, Aravind Eye Hospital, Madurai, India.

    • Aravind Haripriya
    • , Rangappa Ramakrishnan
    • , Kalpana Narendran
    •  & Rangaraj Venkatesh
  11. Department of Ophthalmology, Oita University Faculty of Medicine, Oita, Japan.

    • Satoko Nakano
    •  & Toshiaki Kubota
  12. Institute of Human Genetics, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany.

    • Steffen Uebe
    • , Mandy Krumbiegel
    • , André Reis
    •  & Francesca Pasutto
  13. Howard Hughes Medical Institute, Jackson Laboratory, Bar Harbor, Maine, USA.

    • Jeffrey M Harder
    • , Gareth R Howell
    •  & Simon W M John
  14. Department of Ophthalmology, Flinders University, Adelaide, South Australia, Australia.

    • Kathryn P Burdon
    • , Rhys A Fogarty
    •  & Jamie E Craig
  15. Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, Australia.

    • Kathryn P Burdon
    •  & Alex W Hewitt
  16. Department of Ophthalmology, First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.

    • Yury S Astakhov
    • , Sergei Y Astakhov
    • , Evgeny L Akopov
    •  & Michael Dubina
  17. Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia.

    • Khaled K Abu-Amero
    • , Essam A Osman
    •  & Saleh A Al-Obeidan
  18. Department of Ophthalmology, College of Medicine, University of Florida, Jacksonville, Florida, USA.

    • Khaled K Abu-Amero
  19. Department of Genetics, Institute of Ophthalmology Conde de Valenciana, Mexico City, Mexico.

    • Juan C Zenteno
    •  & Dalia Guadarrama-Vallejo
  20. Department of Biochemistry, Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico City, Mexico.

    • Juan C Zenteno
    •  & Dalia Guadarrama-Vallejo
  21. Department of Ophthalmology, Eskisehir Osmangazi University, Meselik, Turkey.

    • Yildirim Nilgün
    • , Yaz Yetkin
    •  & Çilingir Oğuz
  22. Department of Diagnostics and Microsurgery of Glaucoma, Medical University, Lublin, Poland.

    • Tomasz Zarnowski
    • , Ewa Kosior-Jarecka
    •  & Urszula Lukasik
  23. Department of Ophthalmology, Ophthalmic Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

    • Mohammad Pakravan
    • , Ohoud Owaidhah
    • , Leyla Al-Jasim
    • , Sami Al Shahwan
    • , Mozhgan Rezaei Kanavi
    • , Afsaneh Naderi Beni
    •  & Shahin Yazdani
  24. King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.

    • Leen Abu Safieh
    • , Bowen Zhao
    •  & Deepak P Edward
  25. Beijing Ophthalmology and Visual Sciences Key Laboratory, Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.

    • Liyun Jia
    • , Jinghong Sang
    • , Nihong Zhang
    •  & Ningli Wang
  26. Beijing Institute of Ophthalmology, Beijing Tongren Hospital, Capital University of Medical Science, Beijing, China.

    • Ya Xing Wang
    • , Qisheng You
    •  & Liang Xu
  27. Division of Ophthalmology, Department of Neurosciences, University of the Witwatersrand, Johannesburg, South Africa.

    • Susan Williams
    •  & Trevor Carmichael
  28. Department of Ophthalmology, Monfalcone Hospital, Gorizia, Italy.

    • Daniela Paoli
  29. Organización Médica de Investigación, Buenos Aires, Argentina.

    • Patricio G Schlottmann
  30. Sichuan Provincial Key Laboratory for Human Disease Gene Study, Hospital of the University of Electronic Science and Technology of China and Sichuan Provincial People's Hospital, Chengdu, China.

    • Lulin Huang
    •  & Zhenglin Yang
  31. School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.

    • Lulin Huang
    •  & Zhenglin Yang
  32. Sichuan Translational Medicine Hospital, Chinese Academy of Sciences, Chengdu, China.

    • Lulin Huang
    •  & Zhenglin Yang
  33. Department of Genomic Medical Sciences, Kyoto Prefectural University of Medicine, Kyoto, Japan.

    • Masakazu Nakano
    • , Kazuhiko Mori
    •  & Kei Tashiro
  34. Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

    • Yoko Ikeda
    • , Morio Ueno
    •  & Shigeru Kinoshita
  35. Glaucoma Services, Narayana Nethralaya Eye Hospital, Bangalore, India.

    • Rajesh S Kumar
    •  & Rohit Shetty
  36. Shinjo Eye Clinic, Miyazaki, Japan.

    • Shigeyasu Kazama
  37. Ideta Eye Hospital, Kumamoto, Japan.

    • Ryuichi Ideta
  38. Miyata Eye Hospital, Miyazaki, Japan.

    • Yosai Mori
    •  & Kazunori Miyata
  39. Department of Ophthalmology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.

    • Kazunori Miyata
    • , Takako Sugimoto
    •  & Hideki Chuman
  40. Department of Ophthalmology and Visual Science, Kanazawa University Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan.

    • Kazuhisa Sugiyama
    •  & Tomomi Higashide
  41. Sensho-kai Eye Institute, Kyoto, Japan.

    • Etsuo Chihara
  42. Inouye Eye Hospital, Tokyo, Japan.

    • Kenji Inoue
  43. Department of Medicine and Engineering Combined Research Institute, Asahikawa Medical University, Asahikawa, Japan.

    • Satoshi Ishiko
  44. Department of Ophthalmology, Asahikawa Medical University, Asahikawa, Japan.

    • Akitoshi Yoshida
  45. Department of Ophthalmology and Visual Science, Hiroshima University, Hiroshima, Japan.

    • Masahide Yanagi
    •  & Yoshiaki Kiuchi
  46. Yotsuya Shirato Eye Clinic, Tokyo, Japan.

    • Makoto Aihara
  47. Ohashi Eye Center, Sapporo, Japan.

    • Tsutomu Ohashi
  48. Tane Memorial Eye Hospital, Osaka, Japan.

    • Toshiya Sakurai
  49. Center for Genomic Medicine/INSERM U852, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Fumihiko Matsuda
    •  & Masahiro Miyake
  50. Department of Ophthalmology and Visual Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.

    • Kenji Yamashiro
    • , Norimoto Gotoh
    • , Masahiro Miyake
    •  & Nagahisa Yoshimura
  51. University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.

    • Paul Leo
    •  & Matthew A Brown
  52. Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, Canada.

    • Andrew C Orr
  53. Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.

    • Yutao Liu
    • , Allison E Ashley Koch
    •  & Michael A Hauser
  54. Department of Cellular Biology and Anatomy, Georgia Regents University, Augusta, Georgia, USA.

    • Yutao Liu
  55. Division of Ophthalmology, Faculty of Medicine and Health Sciences, University of Stellenbosch, Cape Town, South Africa.

    • Robyn M Rautenbach
    •  & Ari Ziskind
  56. Centre for Ophthalmology and Visual Science, Lions Eye Institute, University of Western Australia, Perth, Western Australia, Australia.

    • David A Mackey
  57. Centre for Eye Research Australia (CERA), University of Melbourne, Royal Victorian Eye and Ear Hospital, Melbourne, Victoria, Australia.

    • Alex W Hewitt
    • , Jonathan G Crowston
    •  & Michael Coote
  58. Centre for Vision Research, Department of Ophthalmology and Westmead Millennium Institute, University of Sydney, Sydney, New South Wales, Australia.

    • Paul Mitchell
    •  & Jie Jin Wang
  59. Department of Genetics, Aravind Medical Research Foundation, Madurai, India.

    • Saravanan Vijayan
    •  & Periasamy Sundaresan
  60. Department of Ophthalmology, Xin Hua Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai, China.

    • Peiquan Zhao
  61. Department of Ophthalmology, First Affiliated Hospital of Xinjiang Medical University, Urumchi, Xinjiang Uygur Autonomous Region, China.

    • Xueyi Chen
  62. National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore.

    • Su-Ling Ho
  63. Department of Ophthalmology, Friedrich Alexander Universität Erlangen-Nürnberg, Erlangen-Nürnberg, Germany.

    • Ulrich-Christoph Welge-Luessen
    • , Christian Mardin
    •  & Ursula Schloetzer-Schrehardt
  64. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.

    • Axel M Hillmer
  65. Institute of Human Genetics, University of Bonn, Bonn, Germany.

    • Stefan Herms
    •  & Markus M Nöthen
  66. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany.

    • Stefan Herms
    •  & Markus M Nöthen
  67. Division of Medical Genetics, University Hospital, Basel, Switzerland.

    • Stefan Herms
  68. Human Genetics Research Group, Department of Biomedicine, University of Basel, Basel, Switzerland.

    • Stefan Herms
  69. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Essen, Germany.

    • Susanne Moebus
  70. Institute for Ophthalmic Research, Department of Ophthalmology, Tübingen, Germany.

    • Nicole Weisschuh
  71. Genes, Repair and Regeneration in Ophthalmic Workstation Research Laboratory, Narayana Nethralaya Foundation, Bangalore, India.

    • Arkasubhra Ghosh
  72. Saw Swee Hock School of Public Health, National University of Singapore, Singapore.

    • Yik Ying Teo
  73. Centro Oftalmológico Lischinsky, Tucumán, Argentina.

    • Ignacio Lischinsky
  74. Department of Ophthalmology, University of Melbourne, Melbourne, Victoria, Australia.

    • Jonathan G Crowston
    •  & Michael Coote
  75. St. Petersburg Academic University, St. Petersburg, Russia.

    • Vera Vysochinskaya
    •  & Michael Dubina
  76. Department of Ophthalmology, Faculty of Medicine, Aristotle University of Thessaloniki, American Hellenic Educational Progressive Association Hospital, Thessaloniki, Greece.

    • Panayiota Founti
    • , Eleftherios Anastasopoulos
    •  & Fotis Topouzis
  77. Department of Biology and Genetics, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

    • Anthoula Chatzikyriakidou
    •  & Alexandros Lambropoulos
  78. Center for Community Outreach and Policy, Stein Eye Institute, David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, USA.

    • Anne L Coleman
  79. Wayne State University, Detroit, Michigan, USA.

    • M Roy Wilson
  80. Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, USA.

    • Douglas J Rhee
    • , Louis R Pasquale
    •  & Janey L Wiggs
  81. Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Jae Hee Kang
    •  & Louis R Pasquale
  82. Department of Ophthalmology, Military Hospital Begin, Paris, France.

    • Inna May-Bolchakova
  83. Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark.

    • Steffen Heegaard
  84. Department of Ophthalmology, Glostrup University Hospital, Glostrup, Denmark.

    • Steffen Heegaard
  85. Stephen A. Wynn Institute for Vision Research, University of Iowa, Iowa City, Iowa, USA.

    • Wallace L M Alward
    •  & John H Fingert
  86. Department of Ophthalmology and Visual Sciences, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA.

    • Wallace L M Alward
    •  & John H Fingert
  87. Department of Ophthalmology, Medical Faculty Mannheim of the Ruprecht Karls University Heidelberg, Heidelberg, Germany.

    • Jost B Jonas
  88. New York University School of Medicine, Manhattan Eye, Ear and Throat Hospital, New York, New York, USA.

    • Jeffrey M Liebmann
  89. Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre of Singapore, Singapore.

    • Balram Chowbay
  90. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

    • Elke Schaeffeler
    •  & Matthias Schwab
  91. Department of Clinical Pharmacology, University Hospital, Tübingen, Germany.

    • Matthias Schwab
  92. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany.

    • Matthias Schwab
  93. Fundación para el Estudio del Glaucoma, Buenos Aires, Argentina.

    • Fabian Lerner
  94. Department of Surgery, Section of Ophthalmology, University of Siena, Siena, Italy.

    • Paolo Frezzotti
  95. Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, Japan.

    • Masaru Inatani
  96. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.

    • Deepak P Edward
  97. Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.

    • Robert Ritch

Consortia

  1. Blue Mountains Eye Study GWAS Team

    A full list of members and affiliations appears in the Supplementary Note.

  2. Wellcome Trust Case Control Consortium 2

    A full list of members and affiliations appears in the Supplementary Note.

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Contributions

T.A., M.O. and C.-C.K. conceived the project. M.O., T.M., R.R.A., A.H., S.N., J.E.C., A.W.H., D.A.M., P.M., J.J.W., Y.S.A., J.C.Z., Y.N., T.Z., M.P., L.J., Y.X.W., S.W., D.P., P.G.S., Y.I., R.S.K., M.U., S. Manabe, K.H., S. Kazama, R.I., Y.M., K. Miyata, K.S., T.H., E.C., K.I., S.I., A.Y., M.Y., Y.K., M.A., T.O., T. Sakurai, T. Sugimoto, H.C., K.Y., S.Y.A., E.A.O., S.A.A.-O., O.O., L.A.-J., S.A.S., Y.Y., Ç.O., M.R.K., A.N.B., S.Y., E.L.A., E.K.-J., U.L., P.C., R.M.R., A.Z., T.C., R. Ramakrishnan, K.N., R.V., P.Z., X.C., D.G.-V., S.A.P., R.H., S.-L.H., U.-C.W.-L., C.M., U.S.-S., S. Moebus, N. Weisschuh, R.S., A.G., I.L., J.G.C., M.C., Q.Y., V.V., P. Founti, A.C., A.L., E.A., A.L.C., M.R.W., D.J.R., I.M.-B., K. Mori, S. Heegaard, W.L.M.A., J.B.J., L.X., J.M.L., F.L., N. Wang, P. Frezzotti, S. Kinoshita, J.H.F., M.I., D.P.E., L.R.P., T.K., J.L.W., F.T., N.Y. and R. Ritch conducted patient recruitment and phenotyping. Z.L., S.U., M.K., K.P.B., M.A.B., J.J.W., Y.G., K.-Y.T., L.H., P.S., W.Y.M., S.Q.P., B.Z., J.S., N.Z., Z.Y. and S.V. performed genotyping experiments. J.M.H., A.S.Y.C., M.C.L., E.N.V., G.R.H. and S.W.M.J. led and performed immunohistochemistry and immunofluorescence experiments. Z.L., K.P.B., R.A.F., P.L., K.K.A.-A., L.A.S., L.H., K.S.S., J.N.F., M.N., F.M., N.G., M.M., S.U., M.K., Y.Y.T., J.H.K., A.E.A.K., S. Herms, Y.L., K.T., B.Z., J.S., N.Z., S.V., Z.Y., G.R.H., P.S., A.C.O., F.P. and A.G. performed analysis. E.N.V., T.Y.W., C.Y.C., P.S., A.M.H., M.M.N., B.C., E.S., M.S. and A.R. contributed genetic and genotyping data from control populations. The manuscript was drafted by C.-C.K., with critical input from T.A., R.R.A., L.R.P., J.L.W., F.P., F.T., M.D., S.W.M.J., R. Ritch and M.A.H. The manuscript was approved by all authors. C.-C.K. was responsible for obtaining financial support for this study.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Tin Aung or Chiea-Chuen Khor.

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    Supplementary Text and Figures

    Supplementary Figures 1–13, Supplementary Tables 1–10 and Supplementary Note.

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DOI

https://doi.org/10.1038/ng.3226

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