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

Abstract

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 SUCNR1 on its expression through differential micro-RNA (miRNA) binding to target mRNA, and investigated the relevance of altered SUCNR1 expression in AMD pathogenesis. We analysed common SUCNR1 SNPs for potential miRNA binding sites and identified rs13079080, located in the 3ʹ-UTR and binding site for miRNA-4470. Both miRNA-4470 and SUCNR1 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 SUCNR1 disrupts a binding site for miRNA-4470, potentially increasing SUCNR1 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.

The metabolite receptor SUCNR1 in oxidative stress-induced age-related macular degeneration

“…A genome-wide association study (GWAS) using over 16,000 AMD patients and 17,000 controls have linked AMD to several genes involved in lipid metabolism and the complement system 25 . Favret et al described several genetic variants in the SUCNR1 gene to be associated with dry AMD 17 and in a recent study we also identified a genetic variant in the SUCNR1 gene to be associated with AMD 18 . Furthermore, we showed a possible mechanism of SUCNR1 mRNA downregulation as a result of this variant.…”

“…It was shown that deficiency of Sucnr1 in mice led to outer retinal lesions and accumulation of oxidative LDL (oxLDL), a lipid-protein complex found in drusen. Moreover, we recently described a single nucleotide polymorphism in the 3'-UTR of the SUCNR1 gene, which is enriched in the EUGENDA AMD cohort, and reduces the SUCNR1 expression levels in vitro 18 .…”

RNA sequencing‑based identification of potential targets in acute myeloid leukemia: A case report

“…To the best of our knowledge, the role of SUCNR1 in AML has not yet been explored. SUCNR1 is a sensor of oxidative stress, which may assist in the cells ability to sense and manage excessive oxidative stress (27). In this regard, succinate is considered an oncometabolite, which promotes tumorigenesis by promoting angiogenesis in experimental models as well as a transgenic zebrafish cancer model (28).…”

Comparative miRNA expression profile analysis of porcine ovarian follicles: new insights into the initiation mechanism of follicular atresia

“…MicroRNAs (miRNAs) are a kind of short non-coding RNA molecule (∼22 nucleotides; nt) that suppress gene expression post-transcriptionally by binding to the 3ʹ-UTR region to mediate mRNA degradation or translational repression ( Li et al, 2018 ; Bofill-De Ros et al, 2019 ; Louer et al, 2019 ). It has been estimated that nearly all mRNA transcripts contain miRNA response elements (MREs), and more than 60% of human genes have been identified as regulated by miRNA ( Friedman et al, 2009 ; Zhang et al, 2019a ).…”