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

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.

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Modern view on the etiopathogenesis of age-related macular degeneration and the role of molecular genetic determinants in it

Archive of Ukrainian Ophthalmology ◽

10.22141/2309-8147.9.3.2021.247905 ◽

2021 ◽

Vol 9 (3) ◽

pp. 21-27

Author(s):

N.V. Malachkova ◽

Mohammad Mashhour Mohammad Masa’deh ◽

Osama Mohammad Miteb Al-Jarrah ◽

H.P. Liudkevych ◽

D.S. Sukhan

Keyword(s):

Macular Degeneration ◽

Vision Loss ◽

Molecular Genetic ◽

Genetic Diagnosis ◽

High Specificity ◽

Age Related Macular Degeneration ◽

Nucleotide Polymorphisms ◽

Genetic Determinants ◽

Age Related

Age-related macular degeneration mainly affects the elderly and is one of the most common causes of rapidly progressive vision loss. Over more than 150 years of research, the scientific community has gone from understanding the macroscopic picture of the lesion, presumable identification of drusen as the main morphological manifestation of nosology, to detailed classifications and determine the role of genetic determinants in the etiopathogenesis of the disease — high specificity, the possibility of preventive analysis, and much unclear in the field of genetic diagnosis of eye diseases determine the accurate attention of specialized research groups to the early diagnosis using genetic analysis. The review article was aimed to systematize the information about possible links in the pathogenesis of age-related macular degeneration and identify potential polymorphisms that can initiate and modulate the activity of these links. During the study, we could find out five main mechanisms of damage to the vascular membrane of the eye itself, which are affected by single nucleotide polymorphisms. The highest affinity was shown by genetic variants of separate sites of CFH (rs1061170), HTRA1 (rs11200638), TNF (rs1800629), VEGFA (rs2010963). Literature data obtained from foreign and national sources indexed by Scopus, Web of Science databases, in particular for the last 5 years, pay special attention to these areas as potential predictors or modifiers of pathological processes involved in the process of macular degeneration. Despite the large number of studies examining the predisposition, pathogenesis, diagnosis, and treatment of age-related macular degeneration to stop the spread of vision loss, only a few issues are understood thoroughly. Considering the successful cases of application of biological and gene therapy for the management of such patients, we see new horizons in the detailed study of molecular interactions that underlie the pathology. The review confirms the active role of polymorphisms in one of the most relevant pathological processes of the human eye.

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The Interplay between miRNA-Related Variants and Age-Related Macular Degeneration: EVIDENCE of Association of MIR146A and MIR27A

International Journal of Molecular Sciences ◽

10.3390/ijms20071578 ◽

2019 ◽

Vol 20 (7) ◽

pp. 1578 ◽

Cited By ~ 5

Author(s):

Claudia Strafella ◽

Valeria Errichiello ◽

Valerio Caputo ◽

Gianluca Aloe ◽

Federico Ricci ◽

...

Keyword(s):

Macular Degeneration ◽

Direct Sequencing ◽

Bioinformatic Analysis ◽

Age Related Macular Degeneration ◽

Italian Population ◽

Nucleotide Polymorphisms ◽

Complex Interplay ◽

Single Nucleotide ◽

Age Related ◽

The Impact

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.

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Genetic risk factors for late age-related macular degeneration in India

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2017-311384 ◽

2017 ◽

Vol 102 (9) ◽

pp. 1213-1217 ◽

Cited By ~ 4

Author(s):

Anand Rajendran ◽

Pankaja Dhoble ◽

Periasamy Sundaresan ◽

Vijayan Saravanan ◽

Praveen Vashist ◽

...

Keyword(s):

Macular Degeneration ◽

Population Based ◽

Geographic Atrophy ◽

Age Related Macular Degeneration ◽

Nucleotide Polymorphisms ◽

Limited Data ◽

Genetic Determinants ◽

Single Nucleotide ◽

Age Related ◽

Disease Study

Background/AimsThere are limited data from India on genetic variants influencing late age-related macular degeneration (AMD). We have previously reported associations from a population-based study in India (the India age-related eye disease study (INDEYE)) of early AMD and single nucleotide polymorphisms (SNPs) in ARMS2/HTRA1 and no association with CFH, C2 or CFB. Late AMD cases were too few for meaningful analyses. We aimed to investigate SNPs for late AMD through case enrichment and extend the loci for early AMD.MethodsFundus images of late AMD hospital cases were independently graded by the modified Wisconsin AMD grading scheme. In total 510 cases with late AMD (14 geographic atrophy and 496 neovascular AMD (nvAMD)), 1876 with early AMD and 1176 with no signs of AMD underwent genotyping for selected SNPs. We investigated genotype and per-allele additive associations (OR and 95% CIs) with nvAMD or early AMD. Bonferroni adjusted P values are presented.ResultsWe found associations with nvAMD for CFHY402H variant (rs1061170) (OR=1.99, 95% CI 1.67 to 2.37, P=10−6), ARMS2 (rs10490924) (OR=2.94, 95% CI 2.45 to 3.52, P=10−9), C2 (rs547154) (OR=0.67, 95% CI 0.53 to 0.85, P=0.01), ABCA1 (rs1883025) (OR=0.77, 95% CI 0.65 to 0.92, P=0.04) and an SNP near VEGFA (rs4711751) (OR=0.64, 95% CI 0.54 to 0.77, P=10−3). We found no associations of TLR3 (rs3775291), CFD (rs3826945), FRK (rs1999930) or LIPC (rs10468017) or APOE ε4 alleles with nvAMD or early AMD, nor between early AMD and rs1883025 or rs4711751.ConclusionsThe major genetic determinants of nvAMD risk in India are similar to those in other ancestries, while findings for early AMD suggest potential differences in the pathophysiology of AMD development.

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Gene polymorphisms associated with an increased risk of exudative age-related macular degeneration in a Spanish population

European Journal of Ophthalmology ◽

10.1177/11206721211002698 ◽

2021 ◽

pp. 112067212110026

Author(s):

Pablo Gili ◽

Leyre Lloreda Martín ◽

José-Carlos Martín-Rodrigo ◽

Naon Kim-Yeon ◽

Laura Modamio-Gardeta ◽

...

Keyword(s):

Macular Degeneration ◽

Gene Polymorphisms ◽

Age Related Macular Degeneration ◽

Spanish Population ◽

Healthy Controls ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Exudative Amd ◽

Age Related ◽

Increased Risk

Purpose: To identify the association between single-nucleotide polymorphisms (SNPs) in CFH, ARMS2, HTRA1, CFB, C2, and C3 genes and exudative age-related macular degeneration (AMD) in a Spanish population. Methods: In 187 exudative AMD patients and 196 healthy controls (61% women, mean age 75 years), 12 SNPs as risk factors for AMD in CFH (rs1410996, rs1061170, r380390), ARMS2 (rs10490924, rs10490923), HTRA1 (rs11200638), CFB (rs641153), C2 (rs547154, rs9332739), and C3 (rs147859257, rs2230199, rs1047286) genes were analyzed. Results: The G allele was the most frequent in CFH gene (rs1410996) with a 7-fold increased risk of AMD (OR 7.69, 95% CI 3.17–18.69), whereas carriers of C allele in CFH (rs1061170) showed a 3-fold increased risk for AMD (OR 3.22, 95% CI 1.93–5.40). In CFH (rs380390), the presence of G allele increased the risk for AMD by 2-fold (OR 2.52, 95% CI 1.47–4.30). In ARMS2 (rs10490924), the T-allele was associated with an almost 5-fold increased risk (OR 5.49, 95% CI 3.23–9.31). The A allele in HTRA1 (rs11200638) was more prevalent in AMD versus controls (OR 6.44, 95% CI 3.62–11.47). In C2 gene (rs9332739) the presence of C increased risk for AMD by 3-fold (OR 3.10, 95% CI 1.06–9.06). Conclusion: SNPs in CFH, ARMS2, HTRA1, and C2 genes were associated in our study with an increased risk for exudative AMD in Spanish patients.

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Single Nucleotide Polymorphisms in MCP-1 and Its Receptor Are Associated with the Risk of Age Related Macular Degeneration

PLoS ONE ◽

10.1371/journal.pone.0049905 ◽

2012 ◽

Vol 7 (11) ◽

pp. e49905 ◽

Cited By ~ 20

Author(s):

Akshay Anand ◽

Neel Kamal Sharma ◽

Amod Gupta ◽

Sudesh Prabhakar ◽

Suresh Kumar Sharma ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Age Related

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Single-Nucleotide Polymorphisms Associated with the Senescence-Accelerated Phenotype of OXYS Rats: A Focus on Alzheimer’s Disease-Like and Age-Related-Macular-Degeneration-Like Pathologies

Journal of Alzheimer s Disease ◽

10.3233/jad-190956 ◽

2020 ◽

Vol 73 (3) ◽

pp. 1167-1183 ◽

Cited By ~ 2

Author(s):

Vasiliy A. Devyatkin ◽

Olga E. Redina ◽

Nataliya G. Kolosova ◽

Natalia A. Muraleva

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Single Nucleotide Polymorphisms ◽

Macular Degeneration ◽

Age Related Macular Degeneration ◽

Oxys Rats ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Age Related

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Major Predictive Factors for Progression of Early to Late Age-Related Macular Degeneration

Ophthalmologica ◽

10.1159/000507196 ◽

2020 ◽

Vol 243 (6) ◽

pp. 444-452 ◽

Cited By ~ 1

Author(s):

Vasilena Sitnilska ◽

Eveline Kersten ◽

Lebriz Altay ◽

Tina Schick ◽

Philip Enders ◽

...

Keyword(s):

Prediction Model ◽

Macular Degeneration ◽

Area Under The Curve ◽

Age Related Macular Degeneration ◽

Advanced Age ◽

Fundus Photography ◽

Imaging Biomarkers ◽

Nucleotide Polymorphisms ◽

Phenotypic Profile ◽

Age Related

Introduction: We present a prediction model for progression from early/intermediate to advanced age-related macular degeneration (AMD) within 5.9 years. Objectives: To evaluate the combined role of genetic, nongenetic, and phenotypic risk factors for conversion from early to late AMD over ≥5 years. Methods: Baseline phenotypic characteristics were evaluated based on color fundus photography, spectral-domain optical coherence tomography, and infrared images. Genotyping for 36 single-nucleotide polymorphisms as well as systemic lipid and complement measurements were performed. Multivariable backward logistic regression resulted in a final prediction model. Results and Conclusions: During a mean of 5.9 years of follow-up, 22.4% (n = 52) of the patients (n = 232) showed progression to late AMD. The multivariable prediction model included age, CFH variant rs1061170, pigment abnormalities, drusenoid pigment epithelial detachment (DPED), and hyperreflective foci (HRF). The model showed an area under the curve of 0.969 (95% confidence interval 0.948–0.990) and adequate calibration (Hosmer-Lemeshow test, p = 0.797). In addition to advanced age and carrying a CFH variant, pigment abnormalities, DPED, and HRF are relevant imaging biomarkers for conversion to late AMD. In clinical routine, an intensified monitoring of patients with a high-risk phenotypic profile may be suitable for the early detection of conversion to late AMD.

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