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J. E. Craig, A. W. Hewitt, S. Sharma, K. P. Burdon, J. Wang, P. N. Baird, D. P. Dimasi, D. A. Mackey, P. Mitchell; Ancestral LOXL1 Coding Variants Are Associated With Pseudoexfoliation Syndrome in Caucasian Australians but With Markedly Lower Penetrance Than in Nordic People. Invest. Ophthalmol. Vis. Sci. 2008;49(13):5866.
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© ARVO (1962-2015); The Authors (2016-present)
Lysyl Oxidase Like-1 (LOXL1) sequence variation has recently been associated with pseudoexfoliation syndrome (PEX) in Nordic populations. We investigated: 1) LOXL1 haplotypes in 2508 Caucasian Australian individuals in the Blue Mountains Eye Study (BMES), 2) LOXL1 haplotypes in a further 242 South Australian individuals with advanced glaucoma and matched controls, and 3) the ocular expression profile of LOXL1.
Haplotypes at LOXL1 were determined using 12 tagging SNPs. LOXL1 expression was examined in human ocular tissue by RT-PCR and Western blotting.
86 (3.4%) of BMES individuals had PEX. Two non-synonymous variants in exon 1 of LOXL1 (rs1048661:Arg141Leu; rs3825942:Gly153Asp) were strongly associated with PEX. Each of the disease-associated alleles is extremely common in the normal population, and cross-species homology indicates that they represent the ancestral version of LOXL1. Two copies a high risk haplotype at these SNPs (G,G) conferred an age-adjusted risk for PEX of 7.20 (95%CI: 3.04-20.75) compared with no copies of the high risk haplotype. Examination of the LOXL1 haplotypes in glaucoma cases from the BMES and the advanced glaucoma cohort indicated that LOXL1 does not confer risk in non-PEX glaucoma. LOXL1 expression was shown by RT-PCR in all ocular tissues except retina. LOXL1 protein was demonstrated with specific bands of approximately 130 and 80 kDa, representing polymerised protein forms in cornea, iris, ciliary body, lens capsule and optic nerve.
Common ancestral LOXL1 sequence variation is strongly associated with PEX in both Anglo-Celtic and Nordic populations. Our Anglo-Celtic population has a nine-fold lower incidence of PEX but very similar LOXL1 allelic architecture. This suggests that additional genetic or environmental factors have a major influence on the phenotypic expression of the PEX syndrome.
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