Genetic Mechanisms and Age-related Macular Degeneration: Common Variants, Rare Variants, Copy Number Variations, Epigenetics, and Mitochondrial Genetics

Overview

Journal Hum Genomics

Publisher Biomed Central

Specialty Genetics

Date 2012 Dec 19

PMID 23244519

Citations 38

Authors

Melissa M Liu

Chi-Chao Chan

Jingsheng Tuo

Affiliations

Soon will be listed here.

Abstract

Age-related macular degeneration (AMD) is a complex and multifaceted disease involving contributions from both genetic and environmental influences. Previous work exploring the genetic contributions of AMD has implicated numerous genomic regions and a variety of candidate genes as modulators of AMD susceptibility. Nevertheless, much of this work has revolved around single-nucleotide polymorphisms (SNPs), and it is apparent that a significant portion of the heritability of AMD cannot be explained through these mechanisms. In this review, we consider the role of common variants, rare variants, copy number variations, epigenetics, microRNAs, and mitochondrial genetics in AMD. Copy number variations in regulators of complement activation genes (CFHR1 and CFHR3) and glutathione S transferase genes (GSTM1 and GSTT1) have been associated with AMD, and several additional loci have been identified as regions of potential interest but require further evaluation. MicroRNA dysregulation has been linked to the retinal pigment epithelium degeneration in geographic atrophy, ocular neovascularization, and oxidative stress, all of which are hallmarks in the pathogenesis of AMD. Certain mitochondrial DNA haplogroups and SNPs in mitochondrially encoded NADH dehydrogenase genes have also been associated with AMD. The role of these additional mechanisms remains only partly understood, but the importance of their further investigation is clear to elucidate more completely the genetic basis of AMD.

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References

Lukiw W, Surjyadipta B, Dua P, Alexandrov P . Common micro RNAs (miRNAs) target complement factor H (CFH) regulation in Alzheimer's disease (AD) and in age-related macular degeneration (AMD). Int J Biochem Mol Biol. 2012; 3(1):105-16. PMC: 3325769. View

Hageman G, Hancox L, Taiber A, Gehrs K, Anderson D, Johnson L . Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications. Ann Med. 2007; 38(8):592-604. PMC: 1905836. View

Sawitzke J, Im K, Kostiha B, Dean M, Gold B . Association assessment of copy number polymorphism and risk of age-related macular degeneration. Ophthalmology. 2011; 118(12):2442-6. PMC: 3223559. DOI: 10.1016/j.ophtha.2011.05.027. View

Baird P, Islam F, Richardson A, Cain M, Hunt N, Guymer R . Analysis of the Y402H variant of the complement factor H gene in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006; 47(10):4194-8. DOI: 10.1167/iovs.05-1285. View

Liu M, Agron E, Chew E, Meyerle C, Ferris 3rd F, Chan C . Copy number variations in candidate genes in neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci. 2011; 52(6):3129-35. PMC: 3109020. DOI: 10.1167/iovs.10-6735. View

Liang F, Godley B . Oxidative stress-induced mitochondrial DNA damage in human retinal pigment epithelial cells: a possible mechanism for RPE aging and age-related macular degeneration. Exp Eye Res. 2003; 76(4):397-403. DOI: 10.1016/s0014-4835(03)00023-x. View

Baird P, Guida E, Chu D, Vu H, Guymer R . The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2004; 45(5):1311-5. DOI: 10.1167/iovs.03-1121. View

Tuo J, Smith B, Bojanowski C, Meleth A, Gery I, Csaky K . The involvement of sequence variation and expression of CX3CR1 in the pathogenesis of age-related macular degeneration. FASEB J. 2004; 18(11):1297-9. PMC: 1971128. DOI: 10.1096/fj.04-1862fje. View

Brasch-Andersen C, Christiansen L, Tan Q, Haagerup A, Vestbo J, Kruse T . Possible gene dosage effect of glutathione-S-transferases on atopic asthma: using real-time PCR for quantification of GSTM1 and GSTT1 gene copy numbers. Hum Mutat. 2004; 24(3):208-14. DOI: 10.1002/humu.20074. View

10.

Zareparsi S, Buraczynska M, Branham K, Shah S, Eng D, Li M . Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. Hum Mol Genet. 2005; 14(11):1449-55. DOI: 10.1093/hmg/ddi154. View

11.

Chan C, Tuo J, Bojanowski C, Csaky K, Green W . Detection of CX3CR1 single nucleotide polymorphism and expression on archived eyes with age-related macular degeneration. Histol Histopathol. 2005; 20(3):857-63. PMC: 1930145. DOI: 10.14670/HH-20.857. View

12.

Patel N, Adewoyin T, Chong N . Age-related macular degeneration: a perspective on genetic studies. Eye (Lond). 2007; 22(6):768-76. DOI: 10.1038/sj.eye.6702844. View

13.

Garzon R, Marcucci G, Croce C . Targeting microRNAs in cancer: rationale, strategies and challenges. Nat Rev Drug Discov. 2010; 9(10):775-89. PMC: 3904431. DOI: 10.1038/nrd3179. View

14.

Fritsche L, Loenhardt T, Janssen A, Fisher S, Rivera A, N Keilhauer C . Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet. 2008; 40(7):892-6. DOI: 10.1038/ng.170. View

15.

Haines J, Hauser M, Schmidt S, Scott W, Olson L, Gallins P . Complement factor H variant increases the risk of age-related macular degeneration. Science. 2005; 308(5720):419-21. DOI: 10.1126/science.1110359. View

16.

Robertson K . DNA methylation and human disease. Nat Rev Genet. 2005; 6(8):597-610. DOI: 10.1038/nrg1655. View

17.

Hughes A, Orr N, Esfandiary H, Diaz-Torres M, Goodship T, Chakravarthy U . A common CFH haplotype, with deletion of CFHR1 and CFHR3, is associated with lower risk of age-related macular degeneration. Nat Genet. 2006; 38(10):1173-7. DOI: 10.1038/ng1890. View

18.

Sobrin L, Maller J, Neale B, Reynolds R, Fagerness J, Daly M . Genetic profile for five common variants associated with age-related macular degeneration in densely affected families: a novel analytic approach. Eur J Hum Genet. 2009; 18(4):496-501. PMC: 2911949. DOI: 10.1038/ejhg.2009.185. View

19.

Klein R, Zeiss C, Chew E, Tsai J, Sackler R, Haynes C . Complement factor H polymorphism in age-related macular degeneration. Science. 2005; 308(5720):385-9. PMC: 1512523. DOI: 10.1126/science.1109557. View

20.

Ding X, Patel M, Chan C . Molecular pathology of age-related macular degeneration. Prog Retin Eye Res. 2008; 28(1):1-18. PMC: 2715284. DOI: 10.1016/j.preteyeres.2008.10.001. View