April 2010
Volume 51, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2010
Identification of a LOXL1 Promoter Region SNP That Independently Modifies Risk of Exfoliation Syndrome
Author Affiliations & Notes
  • B. Fan
    Dept of Ophthalmology - Harvard Med Sch, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
  • L. Pasquale
    Dept of Ophthalmology - Harvard Med Sch, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
  • C. Grosskreutz
    Dept of Ophthalmology - Harvard Med Sch, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
  • D. Rhee
    Dept of Ophthalmology - Harvard Med Sch, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
  • T. Chen
    Dept of Ophthalmology - Harvard Med Sch, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
  • J. L. Haines
    Ctr Human Genetics Res-Med Ctr, Vanderbilt University, Nashville, Tennessee
  • J. L. Wiggs
    Dept of Ophthalmology - Harvard Med Sch, Massachusetts Eye & Ear Infirmary, Boston, Massachusetts
Investigative Ophthalmology & Visual Science April 2010, Vol.51, 1642. doi:
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    • Get Citation

      B. Fan, L. Pasquale, C. Grosskreutz, D. Rhee, T. Chen, J. L. Haines, J. L. Wiggs; Identification of a LOXL1 Promoter Region SNP That Independently Modifies Risk of Exfoliation Syndrome. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1642.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: : The G153D SNP in lysyl oxidase-like 1 (LOXL1) is a major risk factor for exfoliation syndrome (ES). The G153D risk allele frequency is very high in exfoliation patients worldwide, but is also consistently prevalent in control samples, suggesting that other LOXL1 variants and/or other genetic or environmental factors can contribute to this disease. In the present study, we evaluated polymorphisms across the whole gene region of LOXL1 and the corresponding promoter region as secondary risk factors for ES.

Methods: : Nineteen tag SNPs in the vicinity of LOXL1, representing over 99% of the gene sequence, were genotyped in 196 Caucasian patients with ES and 201 controls. Single-SNP association was initially analyzed using chi-square test and further evaluated using logistic regression after adjusting for age and 3 SNPs known to be associated with ES: R141L, G153D and rs2165241.

Results: : Eleven SNPs including 4 SNPs in the promoter region were significantly associated with ES after correction for multiple testing (p<0.0008). After adjusting for age and 3 known SNPs, one SNP, rs12914489, remained significantly associated (p=0.037). Logistic regression showed an additive effect between rs12914489 and G153D. Individuals carrying risk alleles in both SNPs had a significantly increased risk of ES (OR=20.40) compared to those carrying only the G153D risk allele (OR=8.73). The genetic test using both SNPs increased the accuracy from 52.2% to 70.1% compared to that using only G153D.

Conclusions: : SNP rs12914489 is located in an evolutionarily conserved region ~20kb upstream from the LOXL1 transcription start site. This SNP, or another variant in linkage disequilibrium with rs12914489, may contribute to exfoliation risk by influencing LOXL1 gene expression. Our results suggest that rs12914489 independently contributes to ES, and that testing for risk alleles of both rs12914489 and G153D markedly improves the accuracy of genetic testing for ES.

Keywords: gene modifiers • gene screening • genetics 
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