Autophagy Genes for Wet Age-Related Macular Degeneration in a Finnish Case-Control Study.

Jussi J. Paterno,Ewelina Synowiec,Elina Vattulainen,Raimo Tuuminen,Kai Kaarniranta,Cezary Watala,Ali Koskela,Juha M.T. Hyttinen,Janusz Blasiak

doi:10.3390/genes11111318

Abstract

Age-related macular degeneration is an eye disease that is the main cause of legal blindness in the elderly in developed countries. Despite this, its pathogenesis is not completely known, and many genetic, epigenetic, environmental and lifestyle factors may be involved. Vision loss in age-related macular degeneration (AMD) is usually consequence of the occurrence of its wet (neovascular) form that is targeted in the clinic by anti-VEGF (vascular endothelial growth factor) treatment. The wet form of AMD is associated with the accumulation of cellular waste in the retinal pigment epithelium, which is removed by autophagy and the proteosomal degradation system. In the present work, we searched for the association between genotypes and alleles of single nucleotide polymorphisms (SNPs) of autophagy-related genes and wet AMD occurrence in a cohort of Finnish patients undergoing anti-VEGF therapy and controls. Additionally, the correlation between treatment efficacy and genotypes was investigated. Overall, 225 wet AMD patients and 161 controls were enrolled in this study. Ten SNPs (rs2295080, rs11121704, rs1057079, rs1064261, rs573775, rs11246867, rs3088051, rs10902469, rs73105013, rs10277) in the mTOR (Mechanistic Target of Rapamycin), ATG5 (Autophagy Related 5), ULK1 (Unc-51-Like Autophagy Activating Kinase 1), MAP1LC3A (Microtubule Associated Protein 1 Light Chain 3 α), SQSTM1 (Sequestosome 1) were analyzed with RT-PCR-based genotyping. The genotype/alleles rs2295080-G, rs11121704-C, rs1057079-C and rs73105013-T associated with an increased, whereas rs2295080-TT, rs2295080-T, rs11121704-TT, rs1057079-TT, rs1057079-T, rs573775-AA and rs73105013-C with a decreased occurrence of wet AMD. In addition, the rs2295080-GG, rs2295080-GT, rs1057079-TT, rs11246867-AG, rs3088051-CC and rs10277-CC genotypes were a positively correlated cumulative number of anti-VEGF injections in 2 years. Therefore, variability in autophagy genes may have an impact on the risk of wet AMD occurrence and the efficacy of anti-VEGF treatment.

Highlights

Age-related macular degeneration (AMD) is the most common cause of permanent sharp and color vision loss in the elderly which has a significant socioeconomic burden on patients and theirGenes 2020, 11, 1318; doi:10.3390/genes11111318 www.mdpi.com/journal/genesGenes 2020, 11, 1318 caregivers and societies [1]
Differences were detected in genes that showed agreement with Hardy–Weinberg equilibrium (HWE)
Our results showed that the rs2295080-GG, rs2295080-GT, rs1057079-TT, rs11246867-AG, rs3088051-CC and rs10277-CC genotypes were associated with two years of a cumulative number of injections (0.13 < R < 0.14 Spearman’s correlation coefficient) for two years in wet AMD patients and genotypes of polymorphisms in autophagy-related genes

Summary

Introduction

Age-related macular degeneration (AMD) is the most common cause of permanent sharp and color vision loss in the elderly which has a significant socioeconomic burden on patients and theirGenes 2020, 11, 1318; doi:10.3390/genes11111318 www.mdpi.com/journal/genesGenes 2020, 11, 1318 caregivers and societies [1]. AMD starts in its dry form, which may progress to wet (exudative) AMD in. Exudative AMD is a rapidly progressive sight-threatening condition and should be treated aggressively with intravitreal anti-vascular epithelial growth factor (anti-VEGF) injections [9,10]. Despite this often-effective treatment, 10% of wet AMD patients present a low visual outcome within two-year follow-up [11,12]. The varying anti-VEGF treatment responses have been explained by genetic factors, the timing of the initiation of treatment, and the choice of drug used [9,13,14,15]

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Results

Conclusion