Genetic Determinants Highlight the Existence of Shared Etiopathogenetic Mechanisms Characterizing Age-Related Macular Degeneration and Neurodegenerative Disorders

Claudia Strafella; Valerio Caputo; Andrea Termine; Carlo Fabrizio; Paola Ruffo; Saverio Potenza; Andrea Cusumano; Federico Ricci; Carlo Caltagirone; Emiliano Giardina; Raffaella Cascella

doi:10.3389/fneur.2021.626066

Genetic Determinants Highlight the Existence of Shared Etiopathogenetic Mechanisms Characterizing Age-Related Macular Degeneration and Neurodegenerative Disorders

Front Neurol. 2021 May 31:12:626066. doi: 10.3389/fneur.2021.626066. eCollection 2021.

Authors

Claudia Strafella^{1

2}, Valerio Caputo^{1

2}, Andrea Termine¹, Carlo Fabrizio¹, Paola Ruffo¹, Saverio Potenza³, Andrea Cusumano⁴, Federico Ricci⁵, Carlo Caltagirone⁶, Emiliano Giardina^{1

2}, Raffaella Cascella^{2

7}

Affiliations

¹ Genomic Medicine Laboratory UILDM, IRCCS Santa Lucia Foundation, Rome, Italy.
² Medical Genetics Laboratory, Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
³ Department of Biomedicine and Prevention, Tor Vergata University, Rome, Italy.
⁴ UOSD of Ophthalmology PTV Foundation "Policlinico Tor Vergata", Rome, Italy.
⁵ UNIT Retinal Diseases PTV Foundation "Policlinico Tor Vergata", Rome, Italy.
⁶ Department of Clinical and Behavioral Neurology, IRCCS Fondazione Santa Lucia, Rome, Italy.
⁷ Department of Biomedical Sciences, Catholic University Our Lady of Good Counsel, Tirana, Albania.

Abstract

Age-related macular degeneration (AMD) showed several processes and risk factors in common with neurodegenerative disorders (NDDs). The present work explored the existence of genetic determinants associated with AMD, which may provide insightful clues concerning its relationship with NDDs and their possible application into the clinical practice. In this study, 400 AMD patients were subjected to the genotyping analysis of 120 genetic variants by OpenArray technology. As the reference group, 503 samples representative of the European general population were utilized. Statistical analysis revealed the association of 23 single-nucleotide polymorphisms (SNPs) with AMD risk. The analysis of epistatic effects revealed that ARMS2, IL6, APOE, and IL2RA could contribute to AMD and neurodegenerative processes by synergistic modulation of the expression of disease-relevant genes. In addition, the bioinformatic analysis of the associated miRNA variants highlighted miR-196a, miR-6796, miR-6499, miR-6810, miR-499, and miR-7854 as potential candidates for counteracting AMD and neurodegenerative processes. Finally, this work highlighted the existence of shared disease mechanisms (oxidative stress, immune-inflammatory response, mitochondrial dysfunction, axonal guidance pathway, and synaptogenesis) between AMD and NDDs and described the associated SNPs as candidate biomarkers for developing novel strategies for early diagnosis, monitoring, and treatment of such disorders in a progressive aging population.

Keywords: age-related macular degeneration; etiopathogenesis; genetic network; miRNAs; neurodegenerative disorders; susceptibility.