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 Table of Contents  
Year : 2014  |  Volume : 4  |  Issue : 4  |  Page : 152-155

Role of genetic factors in the pathogenesis of exudative age-related macular degeneration

1 Key Laboratory of Vision Loss and Restoration, Ministry of Education of China, Beijing; Department of Ophthalmology, Parkway Health Hong Qiao Medical Center, Shanghai, People's Republic of China
2 Key Laboratory of Vision Loss and Restoration, Ministry of Education of China; Department of Ophthalmology, Peking University People's Hospital, Beijing, People's Republic of China

Date of Web Publication1-Oct-2014

Correspondence Address:
Xiao-Xin Li
Department of Ophthalmology, Peking University People's Hospital, Number 11, South Avenue of Xizhimen, Xicheng District, Beijing 100044
People's Republic of China
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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.tjo.2014.03.007

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Exudative age-related macular degeneration (AMD) is one of the leading causes of irreversible blindness worldwide. Many recent genetic association studies on large case–control cohorts have helped in drawing an outline of the pathogenesis of AMD. The majority of the associations observed in oxidative stress and lipid peroxidation (complement factor H or CFH), complement (CFH, C3, complement factor I, C2, complement factor B), and neovascularization (vascular endothelial growth factor A, high-temperature requirement factor A1) genes have been replicated in diverse populations worldwide. In this review, we have provided an overview on the genetic factors in the pathogenesis of AMD, and highlight their underlying molecular genetic mechanisms. Further comprehensive research is needed to verify this outline, to explore the treatment target, and to develop the effective primary and secondary prevention of AMD.

Keywords: age-related macular degeneration, complement, lipid peroxidation, neovascularization, oxidative stress

How to cite this article:
Zhou P, Li XX. Role of genetic factors in the pathogenesis of exudative age-related macular degeneration. Taiwan J Ophthalmol 2014;4:152-5

How to cite this URL:
Zhou P, Li XX. Role of genetic factors in the pathogenesis of exudative age-related macular degeneration. Taiwan J Ophthalmol [serial online] 2014 [cited 2022 Nov 29];4:152-5. Available from: https://www.e-tjo.org/text.asp?2014/4/4/152/204131

  1. Introduction Top

1.1. Age-related macular degeneration

Age-related macular degeneration (AMD) is the leading cause of visual impairment in elderly individuals and is the most common cause of blindness in Western countries.[1],[2] Advanced AMD has two major subtypes, namely, geographic atrophy (also called advanced “dry” AMD) and choroidal neovascularization (CNV; also called exudative AMD or “wet” AMD). Exudative AMD affects 10–15% of patients with AMD and rapidly progresses to blindness if left untreated.[3]

1.2. Hypothesis of AMD pathogenesis

In the early stages of AMD, the abnormal oxidative stress in retinal pigment epithelium (RPE) triggers the dysfunction or changes in the composition or permeability of Bruch’s membrane, leading to the formation of drusen. Drusen are small, yellowish extracellular deposits of cellular debris, protein, lipid, carbohydrate, complement components, and anaphylatoxins. Local inflammatory and immune-mediated events play an important role in the development of drusen.[4],[5],[6],[7],[8] In turn, the inflammation becomes chronic and increasingly amplified over decades as the outer macula becomes even more hypoxic. The complement system may play a central role in chronic inflammation. The inflammation triggers the production of vascular endothelial growth factor (VEGF), which was identified to play a major role in CNV in 1996.[9],[10] A previous study demonstrated that VEGF plays a role in the progression of CNV and enhancement of vascular permeability, both of which result in loss of vision.[11] It stimulates dissociation of tight junction components, promotes vascular permeability, and endothelial cell growth.[12],[13] In the late stages of AMD, there is excessive recruitment of scar tissue that leads to irreversible destruction of photoreceptors [Figure 1].
Figure 1: Hypothesis of age-related macular degeneration pathogenesis. APOE = apolipoprotein E; ARMS2 = age-related maculopathy susceptibility protein 2; CFB = complement factor B; CFH = complement factor H; CFI = complement factor I; HTRA1 = high-temperature requirement factor A1; VEGFA = vascular endothelial growth factor A.

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  2. Role of genetic factors in the pathogenesis of AMD Top

Recent large-sample genome-wide association studies (GWASs) confirmed previously reported AMD-associated genes, including complement factor H (CFH),[14] high-temperature requirement factor A1 (HTRA1),[14] age-related maculopathy susceptibility protein 2 (ARMS2),[14] C3,[14],[15] VEGFA,[14] etc. In this paper, the role of these genes in the pathogenesis of AMD is reviewed.

2.1. Role of genetic factors in oxidative stress/lipid peroxidation stage

Increased oxidative stress has been implicated in the pathogenesis of AMD.[16],[17] Owing to oxidative stress, proteins, lipids, and DNA can be damaged. When phospholipids in cell membranes undergo lipid peroxidation, malondialdehyde (MDA) and other reactive decomposition products are generated.[18] Previous studies have reported that oxidative stress and lipid peroxidation-related genes–CFH and apolipoprotein E (APOE)–are associated with AMD.

2.1.1. CFH protects from oxidative stress.

The CFH is one of the first genes reported to be associated with AMD.[19] Individuals with a CFH variant that substitutes a tyrosine for a histidine at position 402 have an increased likelihood of developing AMD by 4.6-folds if the variation is present on one allele and by 7.4-folds if it is present on both alleles.[19] Further CFH studies found that the CFH haplotype significantly increased the risk for AMD with odds ratios (ORs) between 2.45 and 5.57 and that a common variant likely explains approximately 43% of AMD in older adults.[20],[21],[22],[23],[24],[25]

Recent research found that CFH is an innate defense protein against oxidative stress.[17] Results from animal models lacking immunoglobulins showed that over 55% of peptides that bind to MDA could be attributed to CFH. Mapping of the binding site for MDA on CFH showed that it crossed the amino acid position 402, highlighted in the original genetic association studies and, most importantly, the H402 variant of CFH showed reduced MDA binding by up to 23% in the plasma of heterozygotes and up to 52% in homozygotes. Normal CFH then appears to protect against inflammation by inhibiting the complement pathway; however, once mutated, the CFH’s ability to control the inflammation associated with AMD appears to be lost. Functioning CFH is able to suppress the inflammatory response by mopping up the MDA adducts.[17]

2.1.2. APOE suppresses lipid peroxidation

APOE is a lipid transport protein that acts as a ligand for the low-density lipoprotein (LDL) receptor, which is involved in the maintenance and repair of neuronal cell membranes. Variation at two single-nucleotide polymorphisms (SNPs) within the coding sequence of the APOE gene, rs429358 and rs7412, results in different isoforms reported to attenuate binding affinity to the LDL receptor. Three allelic variants derived from these SNPs commonly referred to as ε2, ε3, and ε4 are differentiated based on cysteine (Cys) and arginine (Arg) residue interchanges at positions 112 (rs429358) and 158 (rs7412) in the amino acid. APOε2 has a much reduced binding affinity leading to lower total cholesterol levels with respect to APOε3 and APOε4, which reveal a higher binding affinity with higher total cholesterol levels.[26] The APOE has been found to be associated with AMD. A pooled analysis of 15 studies demonstrated the associations between late AMD and APOε4 (OR = 0.72 per haplotype) and APOε2 (OR = 1.83 for homozygote carriers).[27]

APOE plays an important role in suppressing the oxidative stress and lipid peroxidation. APOE binds directly to 4-hydroxynonenal and has a protective effect against lipid peroxidation.[28] A recent study found that lipid peroxidation is caused by a reduction of antioxidant activity with aging in APOE knockout mice.[29]

2.1.3. Role of genetic factors in chronic inflammation

Oxidatively modified proteins are known to induce inflammatory responses and are recognized by innate immunity.[30],[31] The oxidation-specific epitopes are recognized as danger signals by innate immune receptors.[32] Following a series of independent research papers in late 2005 suggesting a link between the body’s immune system and AMD, further investigations established the alternative complement system as a potentially critical player that may help scientists to join the dots between drusen, a fatty tissue characteristic of the disease, and the symptomatic degeneration of the macula. Understanding the links between the genetic susceptibility data and the clinical symptoms should provide a framework for a deeper understanding of AMD pathogenesis and consequently contribute to identifying new therapeutic targets to slow or halt vision loss associated with the disease.

2.1.4. CFH

We have previously discussed that CFH protects from oxidative stress. Moreover, CFH plays an important role in the regulation of the alternative pathway. CFH binds C3b, and accelerates the decay of the alternative C3 convertase (C3bBb). It also acts as a cofactor for the inactivation of C3b by complement factor I (CFI).[33],[34] CFH binds to cell surfaces to regulate amplification of the alternative complement pathway resulting from spontaneous C3b deposition, which occurs on any surface in contact with blood.[33],[34]

2.1.5. Complement C3

Complement C3 is the most abundant component of the complement pathway. Variations in the C3 gene are associated with AMD. A nonsynonymous C3 variation Arg80Gly (rs2230199) is associated with AMD.[35],[36],[37] Another C3 variant (rs1047286) is also associated with AMD.[20],[36] Furthermore, some rare variants, such as p.Arg1210-Cys[38] and p.Pro314Leu,[15] are associated with a high risk of AMD.

C3 may have an important role in the pathogenesis of AMD. C3 messenger RNA can be detected in the neural retina, choroids, and RPE.[7] Local C3a levels increase in the experimental model of wet AMD.[39] Eliminating the C3 gene protects from CNV development after exposure to laser in C3 gene knockout mice.[40] Furthermore, C3a may increase VEGF secretion[40] and recruitment of monocytes by intercellular adhesion molecule 1 production.

2.1.6. CFI

CFI is a serine protease that cleaves and inactivates C4b and C3b. AC>T transition (rs10033900) located downstream from the 3′-untranslated region of the CFI gene has been shown to be associated with AMD.[41],[42] Recently, some rare variants in CFI, such as p.Gly119Arg[43] and p.Pro50Ala,[44] are associated with a high risk of advanced AMD.

The effect of CFI variations on AMD formation may be due to a reduction in the degradation of C3b. A recent study found that plasma and sera from cases carrying the p.Gly119Arg substitution mediated the degradation of C3b to a lesser extent than those from controls.[43]

2.1.7. Complement C2/complement factor B

Complement component 2 (C2) and complement factor B (CFB) are described together because of similarities in structure, function, and genetic characteristics.[34] The C2 gene, located on 6p21.33, encodes a serum glycoprotein that functions as part of the classical complement pathway, which is involved in innate immunity and inflammation.[45] Two polymorphisms, rs9332739 G > C and rs547154 G > T, have been implicated in AMD. The C2 polymorphisms may be associated directly with AMD or indirectly through the high level of linkage disequilibrium that exists between C2 and CFB, which is located downstream on the same chromosome.[20],[46],[47]

The protective effect of C2/CFB variations may due to a reduction in formation of either classical or alternative pathway C3 convertase. Montes et al[48] found that the CFB 32Q variant had up to four times less C3b binding affinity than the nonrisk 32R protein, with consequent reduction in C3 convertase formation.

2.2. Role of genetic factors in neovascularization

2.2.1. VEGF

VEGF is a signal protein produced by cells and stimulates vasculogenesis and angiogenesis. VEGFA is the most important member of the VEGF family. VEGFA plays a particularly important role in the pathogenesis of wet AMD. Anti-VEGF therapies are the first-line treatment for AMD.[49],[50],[51] Previous studies found that VEGF polymorphisms are associated with neovascular AMD.

Previous studies on VEGF and AMD have yielded conflicting results. Some case–control studies reported significant associations for VEGF polymorphisms,[52],[53],[54] but the validity of these results remains unconfirmed.[55] A recent collaborative GWAS, including 17,100 advanced AMD cases and 60,000 controls, found that the rs943080 variant in VEGFA is associated with increased risk of AMD.[14]

2.2.2. High-temperature requirement factor A1 and ARMS2

Numerous genetic association studies have shown that chromosome 10q26 is a major candidate region associated with the susceptibility of AMD.[56] The linkage peak was refined to two neighboring genes, HTRA1[57],[58],[59] and ARMS2.[20],[60],[61]

HTRA1 is a multifunctional serine protease. Overexpression of human HTRA1 in mouse eyes leads to CNV and polypoidal choroidal vasculopathy in mice.[62] Further studies found that HTRA1 regulates angiogenesis through transforming growth factor-β family member growth differentiation factor 6.[63]

The function of ARMS2 has not yet been clearly demonstrated. Polymorphisms in ARMS2 and HTRA1 are strongly associated with AMD, whereas the strong linkage disequilibrium in the genomic region makes their effects indistinguishable in statistical analyses. Some experiments showed that ARMS2 localizes to the mitochondrial outer membrane.[60] Other studies claimed that ARMS2 is mainly distributed in the cytosol.[64]

  3. Conclusion Top

The growing genetic evidence draws an outline of the pathogenesis of AMD. Further comprehensive research is needed to verify this outline, to explore the treatment target, and to develop the effective primary and secondary prevention of AMD.


This study was supported by a grant (no. 2011CB510200) from the National Basic Research Program of China (973 Program).

Conflicts of interest: The authors declare no potential financial and nonfinancial conflicts of interest.

  References Top

de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355: 1474–1485.  Back to cited text no. 1
Lim LS, Mitchell P, Seddon JM, Holz FG, Wong TY. Age-related macular degeneration. Lancet. 2012;379:1728–1738.  Back to cited text no. 2
Wong TY, Chakravarthy U, Klein R, Mitchell P, Zlateva G, Buggage R, et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology.2008;115:116–126.  Back to cited text no. 3
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res. 2001;20:705–732.  Back to cited text no. 4
Dithmar S, Sharara NA, Curcio CA, Le NA, Zhang Y, Brown S, et al. Murine high-fat diet and laser photochemical model of basal deposits in Bruch membrane. Arch Ophthalmol. 2001;119:1643–1649.  Back to cited text no. 5
Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, et al. A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA. 2005;102:7227–7232.  Back to cited text no. 6
Mullins RF, Russell SR, Anderson DH, Hageman GS. Drusen associated with aging and age-related macular degeneration contain proteins common to extracellular deposits associated with atherosclerosis, elastosis, amyloidosis, and dense deposit disease. FASEB J. 2000;14:835–846.  Back to cited text no. 7
Mullins RF, Aptsiauri N, Hageman GS. Structure and composition of drusen associated with glomerulonephritis: implications for the role of complement activation in drusen biogenesis. Eye (Lond). 2001;15:390–395.  Back to cited text no. 8
Kvanta A, Algvere PV, Berglin L, Seregard S. Subfoveal fibrovascular membranes in age-related macular degeneration express vascular endothelial growth factor. Invest Ophthalmol Vis Sci. 1996;37:1929–1934.  Back to cited text no. 9
Wells JA, Murthy R, Chibber R, Nunn A, Molinatti PA, Kohner EM, et al. Levels of vascular endothelial growth factor are elevated in the vitreous of patients with subretinal neovascularisation. Br JOphthalmol. 1996;80:363–366.  Back to cited text no. 10
Ferrara N. Vascular endothelial growth factor and age-related macular degeneration: from basic science to therapy. Nat Med. 2010;16:1107–1111.  Back to cited text no. 11
Kajdaniuk D, Marek B, Borgiel-Marek H, Kos-Kudla B. Vascular endothelial growth factor (VEGF)–part 1: in physiology and pathophysiology. Endokrynol Pol. 2011;62:444–455.  Back to cited text no. 12
Zhang K, Zhang L, Weinreb RN. Ophthalmic drug discovery: novel targets and mechanisms for retinal diseases and glaucoma. Nat Rev Drug Discov. 2012;11:541–559.  Back to cited text no. 13
Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, et al. Seven new loci associated with age-related macular degeneration. Nat Genet. 2013;45:433–439, 439e1–e2.  Back to cited text no. 14
Helgason H, Sulem P, Duvvari MR, Luo H, Thorleifsson G, Stefansson H, et al. A rare nonsynonymous sequence variant in C3 is associated with high risk of age-related macular degeneration. Nat Genet. 2013;45:1371–1374.  Back to cited text no. 15
Chou MY, Hartvigsen K, Hansen LF, Fogelstrand L, Shaw PX, Boullier A, et al. Oxidation-specific epitopes are important targets of innate immunity. J Intern Med. 2008;263:479–488.  Back to cited text no. 16
Weismann D, Hartvigsen K, Lauer N, Bennett KL, Scholl HP, Charbel Issa P, et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature. 2011;478:76–81.  Back to cited text no. 17
Esterbauer H, Schaur RJ, Zollner H. Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes. Free Radic Biol Med.1991;11:81–128.  Back to cited text no. 18
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science.2005;308:385–389.  Back to cited text no. 19
Contreras AV, Zenteno JC, Fernandez-Lopez JC, Rodriguez-Corona U, Falfan-Valencia R, Sebastian L, et al. CFH haplotypes and ARMS2, C2, C3, and CFB alleles show association with susceptibility to age-related macular degenerationin Mexicans. Mol Vis. 2014;20:105–116.  Back to cited text no. 20
Awh CC, Lane AM, Hawken S, Zanke B, Kim IK. CFH and ARMS2 genetic polymorphisms predict response to antioxidants and zinc in patients with age-related macular degeneration. Ophthalmology. 2013;120:2317–2323.  Back to cited text no. 21
Ansari M, McKeigue PM, Skerka C, Hayward C, Rudan I, Vitart V, et al. Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration. Hum Mol Genet. 2013;22:4857–4869.  Back to cited text no. 22
Pei XT, Li XX, Bao YZ, Yu WZ, Yan Z, Qi HJ, et al. Association of c3 gene polymorphisms with neovascular age-related macular degeneration in a Chinese population. Curr Eye Res. 2009;34:615–622.  Back to cited text no. 23
Tian J, Yu W, Qin X, Fang K, Chen Q, Hou J, et al. Association of genetic polymorphisms and age-related macular degeneration in Chinese population. Invest Ophthalmol Vis Sci. 2012;53:4262–4269.  Back to cited text no. 24
Tian J, Qin X, Fang K, Chen Q, Hou J, Li J, et al. Association of genetic polymorphisms with response to bevacizumab for neovascular age-related macular degeneration in the Chinese population. Pharmacogenomics. 2012;13:779–787.  Back to cited text no. 25
Siest G, Pillot T, Regis-Bailly A, Leininger-Muller B, Steinmetz J, Galteau MM, et al. Apolipoprotein E: an important gene and protein to follow in laboratory medicine. Clin Chem. 1995;41:1068–1086.  Back to cited text no. 26
McKay GJ, Patterson CC, Chakravarthy U, Dasari S, Klaver CC, Vingerling JR, et al. Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies. Hum Mutat. 2011;32:1407–1416.  Back to cited text no. 27
Pedersen WA, Chan SL, Mattson MP. A mechanism for the neuroprotective effect of apolipoprotein E: isoform-specific modification by the lipid peroxi-dation product 4-hydroxynonenal. J Neurochem. 2000;74:1426–1433.  Back to cited text no. 28
Honma T, Tsuduki T, Sugawara S, Kitano Y, Ito J, Kijima R, et al. Aging decreases antioxidant effects and increases lipid peroxidation in the apolipoprotein E deficient mouse. J Clin Biochem Nutr. 2013;52:234–240.  Back to cited text no. 29
Thiele GM, Duryee MJ, Willis MS, Sorrell MF, Freeman TL, Tuma DJ, et al. Malondialdehyde-acetaldehyde (MAA) modified proteins induce pro-inflammatory and pro-fibrotic responses by liver endothelial cells. Comp Hepatol. 2004;3:S25.  Back to cited text no. 30
Shanmugam N, Figarola JL, Li Y, Swiderski PM, Rahbar S, Natarajan R. Proin-flammatory effects of advanced lipoxidation end products in monocytes. Diabetes. 2008;57:879–888.  Back to cited text no. 31
Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. Oxidation-specific epitopes are danger-associated molecular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. 2011;108:235–248.  Back to cited text no. 32
Pangburn MK. Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement. Immunopharmacology. 2000;49:149–157.  Back to cited text no. 33
Khandhadia S, Cipriani V, Yates JR, Lotery AJ. Age-related macular degeneration and the complement system. Immunobiology. 2012;217:127–146.  Back to cited text no. 34
Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, et al. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med.2007;357:553–561.  Back to cited text no. 35
Park KH, Fridley BL, Ryu E, Tosakulwong N, Edwards AO. Complement component 3 (C3) haplotypes and risk of advanced age-related macular degeneration. Invest Ophthalmol Vis Sci. 2009;50:3386–3393.  Back to cited text no. 36
Thakkinstian A, McKay GJ, McEvoy M, Chakravarthy U, Chakrabarti S, Silvestri G, et al. Systematic review and meta-analysis of the association between complement component 3 and age-related macular degeneration: a HuGE review and meta-analysis. Am JEpidemiol. 2011;173:1365–1379.  Back to cited text no. 37
Zhan X, Larson DE, Wang C, Koboldt DC, Sergeev YV, Fulton RS, et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Gen. 2013;45:1375–1379.  Back to cited text no. 38
Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A. 2006;103:2328–2333.  Back to cited text no. 39
Bora PS, SohnJH, Cruz JM, Jha P, Nishihori H, Wang Y, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neo-vascularization. J Immunol. 2005;174:491–497.  Back to cited text no. 40
Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, Seddon JM. Variation near complement factor I is associated with risk of advanced AMD. Eur J HumGenet. 2009;17:100–104.  Back to cited text no. 41
Ennis S, Gibson J, Cree AJ, Collins A, Lotery AJ. Support for the involvement of complement factor I in age-related macular degeneration. Eur J Hum Genet.2010;18:15–16.  Back to cited text no. 42
van de Ven JP, Nilsson SC, Tan PL, Buitendijk GH, Ristau T, Mohlin FC, et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet.2013;45:813–817.  Back to cited text no. 43
Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet.2013;45:1366–1370.  Back to cited text no. 44
Kim SJ, Lee SJ, Kim NR, Chin HS. Association of polymorphisms in C2, CFB and C3 with exudative age-related macular degeneration in a Korean population. Exp Eye Res. 2012;96:42–47.  Back to cited text no. 45
Jakobsdottir J, Conley YP, Weeks DE, Ferrell RE, Gorin MB. C2 and CFB genes in age-related maculopathy and joint action with CFH and LOC387715 genes. PLoS One. 2008;3:e2199.  Back to cited text no. 46
Spencer KL, Hauser MA, Olson LM, Schmidt S, Scott WK, Gallins P, et al. Protective effect of complement factor B and complement component 2 variants in age-related macular degeneration. Hum Mol Genet. 2007;16:1986–1992.  Back to cited text no. 47
Montes T, Tortajada A, Morgan BP, Rodriguez de Cordoba S, Harris CL. Functional basis of protection against age-related macular degeneration conferred by a common polymorphism in complement factor B. Proc Natl Acad Sci U S A. 2009;106:4366–4371.  Back to cited text no. 48
Kodjikian L, Souied EH, Mimoun G, Mauget-Faysse M, Behar-Cohen F, Decullier E, et al. Ranibizumab versus bevacizumab for neovascular age-related macular degeneration: results from the GEFAL noninferiority randomized trial. Ophthalmology. 2013;120:2300–2309.  Back to cited text no. 49
Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, et al. Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology. 2012;119:2537–2548.  Back to cited text no. 50
Li X, Hu Y, Sun X, Zhang J, Zhang M. Neovascular Age-Related Macular Degeneration Treatment Trial using Bevacizumab (NATTB). Bevacizumab for neovascular age-related macular degeneration in China. Ophthalmology.2012;119:2087–2093.  Back to cited text no. 51
Haines JL, Schnetz-Boutaud N, Schmidt S, Scott WK, Agarwal A, Postel EA, et al. Functional candidate genes in age-related macular degeneration: significant association with VEGF, VLDLR, and LRP6. Invest Ophthalmol Vis Sci. 2006;47:329–335.  Back to cited text no. 52
Churchill AJ, Carter JG, Lovell HC, Ramsden C, Turner SJ, Yeung A, et al. VEGF polymorphisms are associated with neovascular age-related macular degeneration. Hum Mol Genet. 2006;15:2955–2961.  Back to cited text no. 53
Lin JM, Wan L, Tsai YY, Lin HJ, Tsai Y, Lee CC, et al. Vascular endothelial growth factor gene polymorphisms in age-related macular degeneration. Am J Ophthalmol. 2008;145:1045–1051.  Back to cited text no. 54
Fang AM, Lee AY, Kulkarni M, Osborn MP, Brantley Jr MA. Polymorphisms in the VEGFA and VEGFR-2 genes and neovascular age-related macular degeneration. Mol Vis. 2009;15:2710–2719.  Back to cited text no. 55
Majewski J, Schultz DW, Weleber RG, Schain MB, Edwards AO, Matise TC, et al. Age-related macular degeneration–a genome scan in extended families. Am J Hum Genet. 2003;73:540–550.  Back to cited text no. 56
Jaouni T, Averbukh E, Burstyn-Cohen T, Grunin M, Banin E, Sharon D, et al. Association of pattern dystrophy with an HTRA1 single-nucleotide polymorphism. Arch Ophthalmol. 2012;130:987–991.  Back to cited text no. 57
Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, et al. A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science. 2006;314:992–993.  Back to cited text no. 58
Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, et al. HTRA1 promoter polymorphism in wet age-related macular degeneration. Science. 2006;314:989–992.  Back to cited text no. 59
Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, et al. A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A 2007;104:16227–16232.  Back to cited text no. 60
Hirata FE, Vasconcellos JP, Medina FM, Rim PH, Fulco EA, Melo MB. Association of LOC387715/ARMS2 (rs10490924) gene polymorphism with age-related macular degeneration in the Brazilian population. Ophthalmic Genet. 2014. in press.  Back to cited text no. 61
A1 Jones, Kumar S, Zhang N, Tong Z, Yang JH, Watt C, et al. Increased expression of multifunctional serine protease, HTRA1, in retinal pigment epithelium induces polypoidal choroidal vasculopathy in mice. Proc Natl Acad Sci U S A. 2011;108:14578–14583.  Back to cited text no. 62
Zhang L, Lim SL, Du H, Zhang M, Kozak I, Hannum G, et al. High temperature requirement factor A1 (HTRA1) gene regulates angiogenesis through transforming growth factor-β family member growth differentiation factor 6. J Biol Chem. 2012;287:1520–1526.  Back to cited text no. 63
Wang G, Spencer KL, Court BL, Olson LM, Scott WK, Haines JL, et al. Localization of age-related macular degeneration-associated ARMS2 in cytosol, not mitochondria. Invest Ophthalmol Vis Sci. 2009;50:3084–3090.  Back to cited text no. 64


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