AGE

, 36:9627

In-depth analyses unveil the association and possible functional involvement of novel RAD51B polymorphisms in age-related macular degeneration

  • Xi K. Chu
  • Catherine B. Meyerle
  • Xiaoling Liang
  • Emily Y. Chew
  • Chi-Chao Chan
  • Jingsheng Tuo
Article

DOI: 10.1007/s11357-014-9627-2

Cite this article as:
Chu, X.K., Meyerle, C.B., Liang, X. et al. AGE (2014) 36: 9627. doi:10.1007/s11357-014-9627-2

Abstract

The contribution of DNA damage to the pathogenesis of age-related macular degeneration (AMD) has been reported. Recently, a genomewide association study detected the association of a single-nucleotide polymorphism (SNP) in RAD51B (rs8017304 A>G) with AMD. RAD51B is involved in recombinational repair of DNA double-strand breaks. We analyzed RAD51B influence on AMD using two cohorts from Caucasian and Han Chinese populations. The Caucasian set replicated the rs8017304 A>G association and revealed two novel AMD-associated SNPs in RAD51B, rs17105278 T>C and rs4902566 C>T. Under the dominant model, these two SNPs exhibit highly significant disease risk. SNP–SNP interaction analysis on rs17105278 T>C and rs4902566 C>T homozygous demonstrated a synergistic effect on AMD risk, reaching an odds ratio multifold higher than well-established AMD susceptibility loci in genes such as CFH, HTRA1, and ARMS2. Functional study revealed lower RAD51B mRNA expression in cultured primary human fetal retinal pigment epithelium (hfRPE) carrying rs17105278 T>C variants than in hfRPE carrying rs17105278 wild type. We concluded that the risk of developing AMD exhibits dose dependency as well as an epistatic combined effect in rs17105278 T>C and rs4902566 C>T carriers and that the elevated risk for rs17105278 T>C carriers may be due to decreased transcription of RAD51B. This study further confirms the role of DNA damage/DNA repair in AMD pathogenesis.

Keywords

Age-related macular degeneration RAD51B DNA repair Single-nucleotide polymorphism Functional genomicsl Gene expression 

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Xi K. Chu
    • 1
  • Catherine B. Meyerle
    • 2
  • Xiaoling Liang
    • 3
  • Emily Y. Chew
    • 2
  • Chi-Chao Chan
    • 1
  • Jingsheng Tuo
    • 1
  1. 1.Laboratory of Immunology, National Eye InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Division of Epidemiology and Clinical Applications, National Eye InstituteNational Institutes of HealthBethesdaUSA
  3. 3.State Key Laboratory of OphthalmologyZhongshan Ophthalmic CenterGuangzhouChina

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