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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number9627
Pages (from-to)1453-1462
Number of pages10
JournalAGE
Volume36
Issue number3
DOIs
StatePublished - Jun 2014
Externally publishedYes

Keywords

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

ASJC Scopus subject areas

  • Aging
  • Geriatrics and Gerontology

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