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

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 wellestablished 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.

Wnt signaling in age-related macular degeneration: human macular tissue and mouse model

“…The study group demographics are summarized in Table 1 . Participant selection and clinical evaluation have been previously defined [ 17 – 20 ]. AMD cases were all in advanced stages and the controls presented either no drusen or fewer than 5 small drusen (<63 µm in diameter) and no signs of other retinal diseases, including but not limited to high myopia, retinal dystrophies, central serous retinopathy, vein occlusion, diabetic retinopathy, or uveitis.…”

Functional single nucleotide polymorphism in IL−17A 3′ untranslated region is targeted by miR‐4480 in vitro and may be associated with age‐related macular degeneration

“…Evidence of the pathogenic role of IL‐17A in AMD without a known genetic component led us to search for SNPs in IL‐17A that influence the development of AMD in our Caucasian NEI cohort [Tuo et al, ; Ardeljan et al, ; Chu et al, ]. Out of six SNPs tested, we found evidence of a single SNP, rs7747909, in the 3′UTR of IL‐17A that associates with AMD with a dominant logistic model.…”

RAD51B (rs8017304 and rs2588809), TRIB1 (rs6987702, rs4351379, and rs4351376), COL8A1 (rs13095226), and COL10A1 (rs1064583) Gene Variants with Predisposition to Age-Related Macular Degeneration

“…Chu et al analyzed RAD51B influence on AMD using two cohorts from Caucasian and Han Chinese populations, as well. Scientists identified two new SNPs in RAD51B (rs17105278 and rs4902566) and confirmed the association between rs8017304 and AMD development in Caucasians [37], suggesting a significant role of RAD51B associated with DNA damage/DNA repair mechanism in AMD pathogenesis.…”

“…Also, literature review explains that risk alleles at RAD51B rs8017304, rs13081855 near COL8A1/FILIP1L locus, and rs3812111 in COL10A1 are associated with a greater risk for advanced AMD development [25]. Other three GWAS proved RAD51B gene association with AMD as well [26, 37, 38]. Seddon et al conducted a 12-year follow-up study of 2765 individuals and revealed that RAD51B (HR: 0.8; 95% CI: 0.60-0.97, p = 0.03) was significantly related to AMD progression [26].…”

“…While the oxidative stress has been linked to the various types of DNA damage playing a significant role in ageing and age-related disorders [33, 34], few studies [35, 36] revealed a significant association between oxidative stress-linked DNA damage and AMD development. Recently, GWAS pinpointed new genetic variations in the RAD51B gene associated with AMD [25, 26, 37, 38]. RAD51B is involved in homologous recombinational repair of DNA double-strand breaks by promoting the activity of the central recombinase [39].…”