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Published Online August 9, 2007
Science DOI: 10.1126/science.1146554

Reports

Submitted on June 15, 2007
Accepted on July 18, 2007

Common Sequence Variants in the LOXL1 Gene Confer Susceptibility to Exfoliation Glaucoma

Gudmar Thorleifsson 1, Kristinn P. Magnusson 1, Patrick Sulem 1, G. Bragi Walters 1, Daniel F. Gudbjartsson 1, Hreinn Stefansson 1, Thorlakur Jonsson 1, Adalbjorg Jonasdottir 1, Aslaug Jonasdottir 1, Gerdur Stefansdottir 1, Gisli Masson 1, Gudmundur A Hardarson 1, Hjorvar Petursson 1, Arsaell Arnarsson 2, Mehdi Motallebipour 3, Ola Wallerman 3, Claes Wadelius 3, Jeffrey R. Gulcher 1, Unnur Thorsteinsdottir 1, Augustine Kong 1, Fridbert Jonasson 4*, Kari Stefansson 1*

1 deCODE genetics Inc, 101 Reykjavik, Iceland.
2 Medical Faculty, University of Iceland, 101 Reykjavik, Iceland.
3 Department of Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
4 Medical Faculty, University of Iceland, 101 Reykjavik, Iceland.; Department of Ophthalmology, National University Hospital, 101 Reykjavik, Iceland.

* To whom correspondence should be addressed.
Fridbert Jonasson , E-mail: fridbert{at}landspitali.is
Kari Stefansson , E-mail: kstefans{at}decode.is

Glaucoma is a leading cause of irreversible blindness. A genome-wide search yielded multiple SNPs in the 15q24.1 region associated to glaucoma. Further investigation revealed that the association is confined to exfoliation glaucoma (XFG). Two non-synonymous SNPs in exon 1 of the gene LOXL1 explain the association and the data suggest that they confer risk to XFG mainly through exfoliation syndrome (XFS). Approximately 25% of the general population is homozygous for the highest risk haplotype and their risk of suffering XFG is over 100 times that of those only carrying low-risk haplotypes. The population attributable risk (PAR) is over 99%. The product of LOXL1 catalyses the formation of elastin fibers found to be a major component of the lesions in XFG.


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Lack of Association between LOXL1 Variants and Primary Open-Angle Glaucoma in Three Different Populations.
Y. Liu, S. Schmidt, X. Qin, J. Gibson, K. Hutchins, C. Santiago-Turla, J. L. Wiggs, D. L. Budenz, S. Akafo, P. Challa, et al. (2008)
Invest. Ophthalmol. Vis. Sci. 49, 3465-3468
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Microarray Technology and Applications in the Arena of Genome-Wide Association.
S. F. A. Grant and H. Hakonarson (2008)
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The LOXL1 Gene Variations Are Not Associated with Primary Open-Angle and Primary Angle-Closure Glaucomas.
S. Chakrabarti, K. N. Rao, I. Kaur, R. S. Parikh, A. K. Mandal, G. Chandrasekhar, and R. Thomas (2008)
Invest. Ophthalmol. Vis. Sci. 49, 2343-2347
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Exfoliation Syndrome: Beyond Glaucoma.
R. Ritch (2008)
Arch Ophthalmol 126, 859-861
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Association of LOXL1 Common Sequence Variants in German and Italian Patients with Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma.
F. Pasutto, M. Krumbiegel, C. Y. Mardin, D. Paoli, R. Lammer, B. H. F. Weber, F. E. Kruse, U. Schlotzer-Schrehardt, and A. Reis (2008)
Invest. Ophthalmol. Vis. Sci. 49, 1459-1463
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How to Interpret a Genome-wide Association Study.
T. A. Pearson and T. A. Manolio (2008)
JAMA 299, 1335-1344
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Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people.
A. W. Hewitt, S. Sharma, K. P. Burdon, J. J. Wang, P. N. Baird, D. P. Dimasi, D. A. Mackey, P. Mitchell, and J. E. Craig (2008)
Hum. Mol. Genet. 17, 710-716
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Association Between LOXL1 and Pseudoexfoliation.
J. L. Wiggs (2008)
Arch Ophthalmol 126, 420-421
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Genomic Promise: Personalized Medicine for Ophthalmology.
J. L. Wiggs (2008)
Arch Ophthalmol 126, 422-423
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Science. ISSN 0036-8075 (print), 1095-9203 (online)