Abstract
The complex interplay among genetic, epigenetic, and environmental variables is the basis for the multifactorial origin of age-related macular degeneration (AMD). Previous results highlighted that single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 were significantly associated with the risk of AMD in the Italian population. Given these data, this study aimed to investigate the impact of SNPs in genes coding for MIR146A, MIR31, MIR23A, MIR27A, MIR20A, and MIR150 on their susceptibility to AMD. Nine-hundred and seventy-six patients with exudative AMD and 1000 controls were subjected to an epigenotyping analysis through real-time PCR and direct sequencing. Biostatistical and bioinformatic analysis was performed to evaluate the association with susceptibility to AMD. These analyses reported that the SNPs rs11671784 (MIR27A, G/A) and rs2910164 (MIR146A, C/G) were significantly associated with AMD risk. Interestingly, the bioinformatic analysis showed that MIR27A and MIR146A take part in the angiogenic and inflammatory pathways underlying AMD etiopathogenesis. Thus, polymorphisms within the pre-miRNA sequences are likely to affect their functional activity, especially the interaction with specific targets. Therefore, our study represents a step forward in the comprehension of the mechanisms leading to AMD onset and progression, which certainly include the involvement of epigenetic modifications.
Highlights
The network of interactions between genetic and non-genetic factors has been so far investigated in several multifactorial disorders, including neurodegenerative, cardiovascular, and retinal diseases [1]
Single nucleotide polymorphisms (SNPs) of CFH, ARMS2, IL-8, TIMP3, SLC16A8, RAD51B, VEGFA, and COL8A1 are significantly associated with a higher risk of age-related macular degeneration (AMD) in the Italian cohort, accounting for the 23% of disease susceptibility, in contrast to the 46–71% observed across global populations [8,12]
The present study aimed to investigate the variability of a set of genes coding for candidate miRNAs involved in molecular pathways leading to AMD etiopathogenesis
Summary
The network of interactions between genetic and non-genetic factors has been so far investigated in several multifactorial disorders, including neurodegenerative, cardiovascular, and retinal diseases [1]. The prevalence of these pathologies is directly correlated to the progressive ageing of populations, which represents a common triggering factor associated with the onset and evolution of complex disorders [1,2,3] In this context, the advancement of biomedical research and the application of artificial intelligence systems have been crucial to elucidate the impact of genes, epigenetic modifications, aging, nutrition, drugs, microbiomes, and other environmental factors on health and disease [2]. The analysis of gene–gene and gene–environment interactions revealed that AMD-associated genes may be involved in the induction of angiogenesis; alteration of extra-cellular matrix (ECM) remodeling mechanisms and of Bruch’s Membrane (BrM) integrity and permeability; modification of retinal pigment epithelium (RPE) and photoreceptor cell activities; and over-activation of inflammatory and immune responses [1,5,8,13] The alteration of these mechanisms helps exacerbate the damage caused by aging and environmental factors, leading thereby to the onset and the advancement of AMD. These miRNAs were selected on the basis of literature data concerning their role of in AMD etiopathogenesis, especially those involved in angiogenic, inflammatory, and cell survival processes in response to external stimuli (oxidative stress, ageing, and nutrient intake) [13,15]
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