May 2008
Volume 49, Issue 13
Free
ARVO Annual Meeting Abstract  |   May 2008
Strong Evidence for Association With Age-Related Cataract at a Candidate Gene on 1p36
Author Affiliations & Notes
  • G. Jun
    Case Western Reserve Univ, Cleveland, Ohio
    Epidemiology and Biostatistics,
  • H. Guo
    Case Western Reserve Univ, Cleveland, Ohio
    Pharmacology,
  • B. E. K. Klein
    Ophthalmology and Visual Sciences, Univ of Wisconsin Medical School, Madison, Wisconsin
  • R. Klein
    Ophthalmology and Visual Sciences, Univ of Wisconsin Medical School, Madison, Wisconsin
  • J. J. Wang
    Ophthalmology, Univ of Sydney, Centre for Vision Research, Sydney, Australia
  • P. Mitchell
    Ophthalmology, Univ of Sydney, Centre for Vision Research, Sydney, Australia
  • D. Bardenstein
    Case Western Reserve Univ, Cleveland, Ohio
    Ophthalmology,
  • C. J. Hammond
    Twin Research and Genetic Epidemiology Unit, St. Thomas’ Hospital, London, United Kingdom
  • B.-C. Wang
    Case Western Reserve Univ, Cleveland, Ohio
    Pharmacology,
  • S. K. Iyengar
    Case Western Reserve Univ, Cleveland, Ohio
    Epidemiology and Biostatistics,
    Ophthalmology,
  • Footnotes
    Commercial Relationships  G. Jun, None; H. Guo, None; B.E.K. Klein, None; R. Klein, None; J.J. Wang, None; P. Mitchell, None; D. Bardenstein, None; C.J. Hammond, None; B. Wang, None; S.K. Iyengar, None.
  • Footnotes
    Support  U10EY06594, EY015286; EY13438; EY10605; EY015810; GM2835; 974159 and 211069 from NHMRC
Investigative Ophthalmology & Visual Science May 2008, Vol.49, 2872. doi:https://doi.org/
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      G. Jun, H. Guo, B. E. K. Klein, R. Klein, J. J. Wang, P. Mitchell, D. Bardenstein, C. J. Hammond, B.-C. Wang, S. K. Iyengar; Strong Evidence for Association With Age-Related Cataract at a Candidate Gene on 1p36. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2872. doi: https://doi.org/.

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

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Abstract

Purpose: : Converging evidence from a coarse association scan in the Beaver Dam Eye Study (BDES) and a novel knockout mouse with progressive age-related cataract (ARC) was used to focus on a candidate gene on 1p36 to perform deeper association analysis.

Methods: : Twenty-one SNPs in the candidate gene were selected and genotyped in a discovery (BDES; N = 1501) and two replication samples [United Kingdom Twin Study (UKTS; N = 196) and Blue Mountains Eye Study (BMES; N = 1618)]. Association was tested using ARC traits including cortical (CC), nuclear (NC), posterior subcapsular (PSC), and any (ANYCAT) cataract. A moving window haplotype test was performed in BDES and BMES. Exons, including intron-exon junctions, were scanned for mutations using re-sequencing (N=34).

Results: : Multiple SNPs in BDES and UKTS met genome-wide significance, but weaker association was found in BMES. The most significant combined P values were identified with ANYCAT (SNP7: P = 1 x 10-7), with severe CC (affected area ≥ 25% of the lens; SNP6: P = 6 x 10-8), and with NC (SNP8: P = 2 x 10-4). Haplotype analysis showed a common shared risk haplotype in BDES and BMES for multiple ARC traits. An additional common risk haplotype was found in BMES. Re-sequencing identified two potentially causal non-synonymous variants. The variants reside in conserved genomic regions and may play a role in alternative splicing and transcriptional regulation.

Conclusions: : We have identified a novel gene that causes age-related cataract with support from both human epidemiologic data and mouse models.

Keywords: cataract • gene mapping • aging 
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