DNA Methylation Is Associated with Altered Gene Expression in AMD

Hunter, Allan A.; Spechler, Paul; Cwanger, Alyssa; Song, Ying; Zhang, Zhe; Ying, Gui Shuang; Hunter, Anna K.; deZoeten, Edwin F.; Dunaief, Joshua L.

doi:10.1167/iovs.11-8449

Cited by 115 publications

(97 citation statements)

References 67 publications

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“…Likewise, relatively small methylation differences have be linked to changes in gene expression, which hint at potential functional effects of our observed methylation differences. 16 This is one of the first studies to show a relationship between DNAm and AMD, [38][39][40] but many questions remain. Did the disease-associated differential methylation observed in the blood and retina arise prior to the onset of AMD and contribute to the disease phenotype or was it a secondary effect of the disease process or treatment?…”

Section: Discussionmentioning

confidence: 99%

“…meQTL analysis in Illumina 450K samples Observed high-quality genotypes on 290 subjects with Illumina 450k data (out of 298, 97.3%) were obtained from dbGaP (accession: phs000182.v2.p1). SNPs on chromosome 10 were phased using ShapeIT, 37 and the 6 megabase area flanking the AMD risk SNP (chr10:121214448-127214448) was imputed up to the latest 1000 Genomes Phase 3 reference panel using Impute2 38 to obtain genotype calls for rs10490924 and rs72631113. Using the previously calculated surrogate variables (SVs, see above), we performed meQTL analyses separately within AMD patients (NV and GA together) and controls, at both SNPs, using the linear model of the form: Meth j D a C bSNP j C zSV j C e j for person j.…”

Section: Gwas Enrichment Analysismentioning

confidence: 99%

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Differential DNA methylation identified in the blood and retina of AMD patients

Oliver¹,

Jaffe

Song

et al. 2015

Epigenetics

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Age-related macular degeneration (AMD) is a major cause of blindness in the western world. While genetic studies have linked both common and rare variants in genes involved in regulation of the complement system to increased risk of development of AMD, environmental factors, such as smoking and nutrition, can also significantly affect the risk of developing the disease and the rate of disease progression. Since epigenetics has been implicated in mediating, in part, the disease risk associated with some environmental factors, we investigated a possible epigenetic contribution to AMD. We performed genome-wide DNA methylation profiling of blood from AMD patients and controls. No differential methylation site reached genome-wide significance; however, when epigenetic changes in and around known GWASdefined AMD risk loci were explored, we found small but significant DNA methylation differences in the blood of neovascular AMD patients near age-related maculopathy susceptibility 2 (ARMS2), a top-ranked GWAS locus preferentially associated with neovascular AMD. The methylation level of one of the CpG sites significantly correlated with the genotype of the risk SNP rs10490924, suggesting a possible epigenetic mechanism of risk. Integrating genome-wide DNA methylation analysis of retina samples with and without AMD together with blood samples, we further identified a consistent, replicable change in DNA methylation in the promoter region of protease serine 50 (PRSS50). These methylation changes may identify sites in novel genes that are susceptible to non-genetic factors known to contribute to AMD development and progression.

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Section: Discussionmentioning

confidence: 99%

Section: Gwas Enrichment Analysismentioning

confidence: 99%

Differential DNA methylation identified in the blood and retina of AMD patients

Oliver¹,

Jaffe

Song

et al. 2015

Epigenetics

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“…(2012) [128] GSTP1 Glutathione S-transferase P Codes for an enzyme that has an important role to play in the prevention of oxidative damage. …”

Section: Computational Models Of the Dna Methylation Cyclementioning

confidence: 99%

Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

2016

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Dietary folates have a key role to play in health, as deficiencies in the intake of these B vitamins have been implicated in a wide variety of clinical conditions. The reason for this is folates function as single carbon donors in the synthesis of methionine and nucleotides. Moreover, folates have a vital role to play in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Intriguingly, a growing body of experimental evidence suggests that DNA methylation status could be a central modulator of the ageing process. This has important health implications because the methylation status of the human genome could be used to infer age-related disease risk. Thus, it is imperative we further our understanding of the processes which underpin DNA methylation and how these intersect with folate metabolism and ageing. The biochemical and molecular mechanisms, which underpin these processes, are complex. However, computational modelling offers an ideal framework for handling this complexity. A number of computational models have been assembled over the years, but to date, no model has represented the full scope of the interaction between the folate cycle and the reactions, which governs the DNA methylation cycle. In this review, we will discuss several of the models, which have been developed to represent these systems. In addition, we will present a rationale for developing a combined model of folate metabolism and the DNA methylation cycle.

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“…Glutathione S-transferase PI (GSTP1) is a scavenger of reactive oxygen species (ROS) and its absence could reduce protection from genome-damaging oxidants, resulting in increased vulnerability to further oxidative insults. Hunter et al 28 found that mRNA levels of glutathione S-transferase isoforms mu1 (GSTM1) and mu5 (GSTM5) were significantly reduced in AMD patients vs age-matched controls in retinal pigment epithelium (RPE)/choroid and neurosensory retina. This corresponded to hypermethylation of the GSTM5 promoter.…”

Section: Dna Methylation Changes Affect Antioxidant Gene Expression Imentioning

confidence: 99%

The role of epigenetics in age-related macular degeneration

Gemenetzi

Lotery

2014

Eye

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It is becoming increasingly evident that epigenetic mechanisms influence gene expression and can explain how interactions between genetics and the environment result in particular phenotypes during development. The extent to which this epigenetic effect contributes to phenotype heritability in age-related macular degeneration (AMD) is currently ill defined. However, emerging evidence suggests that epigenetic changes are relevant to AMD and as such provide an exciting new avenue of research for AMD. This review addresses information on the impact of posttranslational modification of the genome on the pathogenesis of AMD, such as DNA methylation changes affecting antioxidant gene expression, hypoxia-regulated alterations in chromatin structure, and histone acetylation status in relation to angiogenesis and inflammation. It also contains information on the role of non-coding RNA-mediated gene regulation in AMD at a posttranscriptional (before translation) level. Our aim was to review the epigenetic mechanisms that cause heritable changes in gene activity without changing the DNA sequence. We also describe some long-term alterations in the transcrip-

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DNA Methylation Is Associated with Altered Gene Expression in AMD

Cited by 115 publications

References 67 publications

Differential DNA methylation identified in the blood and retina of AMD patients

Differential DNA methylation identified in the blood and retina of AMD patients

Computational modelling folate metabolism and DNA methylation: implications for understanding health and ageing

The role of epigenetics in age-related macular degeneration

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