Single nucleotide polymorphism rs13079080 is associated with differential regulation of the succinate receptor 1 (SUCNR1) gene by miRNA-4470

Oxidative stress is a feature of many common diseases. It leads to excessive formation and subsequent release of the mitochondrial metabolite succinate, which acts as a signalling molecule through binding the succinate receptor (SUCNR1). Recently, a potential role for SUCNR1 was proposed in age-related macular degeneration (AMD), a common cause of vision loss in the elderly associated with increased oxidative stress. Here, we evaluated the potential effect of genetic variants in <i>SUCNR1</i> on its expression through differential micro-RNA (miRNA) binding to target mRNA, and investigated the relevance of altered <i>SUCNR1</i> expression in AMD pathogenesis. We analysed common <i>SUCNR1</i> SNPs for potential miRNA binding sites and identified rs13079080, located in the 3ʹ-UTR and binding site for miRNA-4470. Both miRNA-4470 and <i>SUCNR1</i> were found to be expressed in human retina. Moreover, using a luciferase reporter assay, a 60% decrease in activity was observed when miRNA-4470 was co-expressed with the C allele compared to the T allele of rs13079080. Finally, genotyping rs13079080 in an AMD case-control cohort revealed a protective effect of the TT genotype on AMD compared to the CC genotype (p = 0.007, odds ratio = 0.66). However, the association was not confirmed in the case-control study of the International AMD Genomics Consortium. Our study demonstrates that the T allele of rs13079080 in <i>SUCNR1</i> disrupts a binding site for miRNA-4470, potentially increasing <i>SUCNR1</i> expression and consequently increasing the capacity of sensing and dealing with oxidative stress. Therefore, it would be worthwhile assessing the relevance of rs13079080 in other oxidative stress-associated diseases in future studies.