Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. Numerous genetic factors contribute to the development of the multifactorial disease. We performed a case-control study to assess the risk conferred by known and candidate genetic polymorphisms on the development of AMD. We searched for genetic interactions and for differences in dry and wet AMD etiology. We enrolled 213 patients with exudative, 67 patients with dry AMD and 106 age and ethnically matched controls. Altogether 12 polymorphisms in Apolipoprotein E, complement factor H, complement factor I, complement component 3, blood coagulation factor XIII, HTRA1, LOC387715, Gas6 and MerTK genes were tested. No association was found between either the exudative or the dry form and the polymorphisms in the Apolipoprotein E, complement factor I, FXIII and MerTK genes. Gas6 c.834+7G>A polymorphism was found to be significantly protective irrespective of other genotypes, reducing the odds of wet type AMD by a half (OR = 0.50, 95%CI: 0.26–0.97, p = 0.04). Multiple regression models revealed an interesting genetic interaction in the dry AMD subgroup. In the absence of C3 risk allele, mutant genotypes of both CFH and HTRA1 behaved as strongly significant risk factors (OR = 7.96, 95%CI: 2.39 = 26.50, p = 0.0007, and OR = 36.02, 95%CI: 3.30–393.02, p = 0.0033, respectively), but reduced to neutrality otherwise. The risk allele of C3 was observed to carry a significant risk in the simultaneous absence of homozygous CFH and HTRA1 polymorphisms only, in which case it was associated with a near-five-fold relative increase in the odds of dry type AMD (OR = 4.93, 95%CI: 1.98–12.25, p = 0.0006). Our results suggest a protective role of Gas6 c.834+7G>A polymorphism in exudative AMD development. In addition, novel genetic interactions were revealed between CFH, HTRA1 and C3 polymorphisms that might contribute to the pathogenesis of dry AMD.
References
[1]
Klein R, Peto T, Bird A, Vannewkirk MR (2004) The epidemiology of age-related macular degeneration. Am J Ophthalmol 137: 486–495.
[2]
Friedman DS, Katz J, Bressler NM, Rahmani B, Tielsch JM (1999) Racial differences in the prevalence of age-related macular degeneration: the Baltimore Eye Survey. Ophthalmology 106: 1049–1055.
[3]
Friedman DS, O'Colmain BJ, Munoz B, Tomany SC, McCarty C, et al. (2004) Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 122: 564–572.
[4]
Seddon JM, Sharma S, Adelman RA (2006) Evaluation of the clinical age-related maculopathy staging system. Ophthalmology 113: 260–266.
Chakravarthy U, Wong TY, Fletcher A, Piault E, Evans C, et al. (2010) Clinical risk factors for age-related macular degeneration: a systematic review and meta-analysis. BMC Ophthalmol 10: 31.
[7]
Ho L, Boekhoorn SS, Liana , van Duijn CM, Uitterlinden AG, et al. (2008) Cataract surgery and the risk of aging macula disorder: the rotterdam study. Invest Ophthalmol Vis Sci 49: 4795–4800.
[8]
Francis PJ, Klein ML (2011) Update on the role of genetics in the onset of age-related macular degeneration. Clin Ophthalmol 5: 1127–1133.
[9]
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, et al. (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308: 385–389.
[10]
Edwards AO, Ritter R 3rd, Abel KJ, Manning A, Panhuysen C, et al. (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308: 421–424.
[11]
Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, et al. (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308: 419–421.
[12]
Sofat R, Casas JP, Webster AR, Bird AC, Mann SS, et al. (2012) Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype. Int J Epidemiol 41: 250–262.
[13]
Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, et al. (2007) Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med 357: 553–561.
[14]
Despriet DD, van Duijn CM, Oostra BA, Uitterlinden AG, Hofman A, et al. (2009) Complement component C3 and risk of age-related macular degeneration. Ophthalmology 116: 474–480 e472.
[15]
Thakkinstian A, McKay GJ, McEvoy M, Chakravarthy U, Chakrabarti S, et al. (2011) Systematic review and meta-analysis of the association between complement component 3 and age-related macular degeneration: a HuGE review and meta-analysis. Am J Epidemiol 173: 1365–1379.
[16]
Fagerness JA, Maller JB, Neale BM, Reynolds RC, Daly MJ, et al. (2009) Variation near complement factor I is associated with risk of advanced AMD. Eur J Hum Genet 17: 100–104.
[17]
Ennis S, Gibson J, Cree AJ, Collins A, Lotery AJ (2010) Support for the involvement of complement factor I in age-related macular degeneration. Eur J Hum Genet 18: 15–16.
[18]
Cipriani V, Matharu BK, Khan JC, Shahid H, Hayward C, et al. (2012) No evidence of association between complement factor I genetic variant rs10033900 and age-related macular degeneration. Eur J Hum Genet 20: 1–2 author reply 3.
[19]
Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, et al. (2005) Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 77: 389–407.
[20]
Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, et al. (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14: 3227–3236.
[21]
Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, et al. (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314: 992–993.
[22]
Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, et al. (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314: 989–992.
[23]
Yoshida T, DeWan A, Zhang H, Sakamoto R, Okamoto H, et al. (2007) HTRA1 promoter polymorphism predisposes Japanese to age-related macular degeneration. Mol Vis 13: 545–548.
[24]
Cameron DJ, Yang Z, Gibbs D, Chen H, Kaminoh Y, et al. (2007) HTRA1 variant confers similar risks to geographic atrophy and neovascular age-related macular degeneration. Cell Cycle 6: 1122–1125.
[25]
Wang L, Clark ME, Crossman DK, Kojima K, Messinger JD, et al. (2010) Abundant lipid and protein components of drusen. PLoS One 5: e10329.
[26]
Souied EH, Benlian P, Amouyel P, Feingold J, Lagarde JP, et al. (1998) The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 125: 353–359.
[27]
Baird PN, Guida E, Chu DT, Vu HT, Guymer RH (2004) The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 45: 1311–1315.
[28]
Baird PN, Richardson AJ, Robman LD, Dimitrov PN, Tikellis G, et al. (2006) Apolipoprotein (APOE) gene is associated with progression of age-related macular degeneration (AMD). Hum Mutat 27: 337–342.
[29]
Francis PJ, Hamon SC, Ott J, Weleber RG, Klein ML (2009) Polymorphisms in C2, CFB and C3 are associated with progression to advanced age related macular degeneration associated with visual loss. J Med Genet 46: 300–307.
[30]
Yu Y, Reynolds R, Fagerness J, Rosner B, Daly MJ, et al. (2011) Association of variants in the LIPC and ABCA1 genes with intermediate and large drusen and advanced age-related macular degeneration. Invest Ophthalmol Vis Sci 52: 4663–4670.
[31]
Asensio-Sanchez VM, Rodriguez-Martin T, Gala-Molina I, Rodriguez-Fernandez I (2006) [Age-related macular degeneration: its association with the epsilon4 allele of the apolipoprotein E gene]. Arch Soc Esp Oftalmol 81: 9–12.
[32]
Losonczy G, Fekete A, Voko Z, Takacs L, Kaldi I, et al. (2011) Analysis of complement factor H Y402H, LOC387715, HTRA1 polymorphisms and ApoE alleles with susceptibility to age-related macular degeneration in Hungarian patients. Acta Ophthalmol 89: 255–262.
[33]
McKay GJ, Patterson CC, Chakravarthy U, Dasari S, Klaver CC, et al. (2011) Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies. Hum Mutat 32: 1407–1416.
[34]
Adams MK, Simpson JA, Richardson AJ, English DR, Aung KZ, et al. (2012) Apolipoprotein E gene associations in age-related macular degeneration: the Melbourne Collaborative Cohort Study. Am J Epidemiol 175: 511–518.
[35]
Fernandez-Fernandez L, Bellido-Martin L, Garcia de Frutos P (2008) Growth arrest-specific gene 6 (GAS6). An outline of its role in haemostasis and inflammation. Thromb Haemost 100: 604–610.
[36]
Jiang L, Liu CY, Yang QF, Wang P, Zhang W (2009) Plasma level of growth arrest-specific 6 (GAS6) protein and genetic variations in the GAS6 gene in patients with acute coronary syndrome. Am J Clin Pathol 131: 738–743.
[37]
Lutgens E, Tjwa M, Garcia de Frutos P, Wijnands E, Beckers L, et al. (2008) Genetic loss of Gas6 induces plaque stability in experimental atherosclerosis. J Pathol 216: 55–63.
[38]
Gallicchio M, Mitola S, Valdembri D, Fantozzi R, Varnum B, et al. (2005) Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood 105: 1970–1976.
[39]
Balogh I, Hafizi S, Stenhoff J, Hansson K, Dahlback B (2005) Analysis of Gas6 in human platelets and plasma. Arterioscler Thromb Vasc Biol 25: 1280–1286.
[40]
Munoz X, Obach V, Hurtado B, de Frutos PG, Chamorro A, et al. (2007) Association of specific haplotypes of GAS6 gene with stroke. Thromb Haemost 98: 406–412.
[41]
Lee CH, Chu NF, Shieh YS, Hung YJ (2012) The growth arrest-specific 6 (Gas6) gene polymorphism c.834+7G>A is associated with type 2 diabetes. Diabetes Res Clin Pract 95: 201–206.
[42]
Rothlin CV, Lemke G (2010) TAM receptor signaling and autoimmune disease. Curr Opin Immunol 22: 740–746.
[43]
Duncan JL, LaVail MM, Yasumura D, Matthes MT, Yang H, et al. (2003) An RCS-like retinal dystrophy phenotype in mer knockout mice. Invest Ophthalmol Vis Sci 44: 826–838.
[44]
Hall MO, Obin MS, Heeb MJ, Burgess BL, Abrams TA (2005) Both protein S and Gas6 stimulate outer segment phagocytosis by cultured rat retinal pigment epithelial cells. Exp Eye Res 81: 581–591.
[45]
Chen YY, Lu QJ, Lu QX, Wang NL (2011) Gene expression profile changes caused by the dysfunction of Mer during retinal pigment epithelium phagocytosis. Chin Med J (Engl) 124: 1145–1155.
[46]
Hurtado B, Abasolo N, Munoz X, Garcia N, Benavente Y, et al. (2010) Association study between polymorphisms in GAS6-TAM genes and carotid atherosclerosis. Thromb Haemost 104: 592–598.
[47]
Shemirani AH, Muszbek L (2004) Rapid detection of the factor XIII Val34Leu (163 G→T) polymorphism by real-time PCR using fluorescence resonance energy transfer detection and melting curve analysis. Clin Chem Lab Med 42: 877–879.
[48]
Rudnicka AR, Jarrar Z, Wormald R, Cook DG, Fletcher A, et al. (2012) Age and gender variations in age-related macular degeneration prevalence in populations of European ancestry: a meta-analysis. Ophthalmology 119: 571–580.
[49]
Spencer KL, Olson LM, Anderson BM, Schnetz-Boutaud N, Scott WK, et al. (2008) C3 R102G polymorphism increases risk of age-related macular degeneration. Hum Mol Genet 17: 1821–1824.
[50]
Mullins RF, Russell SR, Anderson DH, Hageman GS (2000) 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 14: 835–846.
[51]
Johnson LV, Ozaki S, Staples MK, Erickson PA, Anderson DH (2000) A potential role for immune complex pathogenesis in drusen formation. Exp Eye Res 70: 441–449.
[52]
Anderson DH, Mullins RF, Hageman GS, Johnson LV (2002) A role for local inflammation in the formation of drusen in the aging eye. Am J Ophthalmol 134: 411–431.
[53]
Johnson LV, Leitner WP, Staples MK, Anderson DH (2001) Complement activation and inflammatory processes in Drusen formation and age related macular degeneration. Exp Eye Res 73: 887–896.
[54]
Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, et al. (2006) Drusen complement components C3a and C5a promote choroidal neovascularization. Proc Natl Acad Sci U S A 103: 2328–2333.
[55]
Chi ZL, Yoshida T, Lambris JD, Iwata T (2010) Suppression of drusen formation by compstatin, a peptide inhibitor of complement C3 activation, on cynomolgus monkey with early-onset macular degeneration. Adv Exp Med Biol 703: 127–135.
[56]
An E, Sen S, Park SK, Gordish-Dressman H, Hathout Y (2010) Identification of novel substrates for the serine protease HTRA1 in the human RPE secretome. Invest Ophthalmol Vis Sci 51: 3379–3386.
[57]
Chen W, Stambolian D, Edwards AO, Branham KE, Othman M, et al. (2010) Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration. Proc Natl Acad Sci U S A 107: 7401–7406.
[58]
Seddon JM, Reynolds R, Rosner B (2010) Associations of smoking, body mass index, dietary lutein, and the LIPC gene variant rs10468017 with advanced age-related macular degeneration. Mol Vis 16: 2412–2424.
[59]
Kondo N, Bessho H, Honda S, Negi A (2010) Additional evidence to support the role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration. Eur J Hum Genet 18: 634–635.
[60]
Dardik R, Loscalzo J, Inbal A (2006) Factor XIII (FXIII) and angiogenesis. J Thromb Haemost 4: 19–25.
[61]
Kovar FM, Marsik CL, Jilma B, Mannhalter C, Joukhadar C, et al. (2009) The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model. Wien Klin Wochenschr 121: 515–519.
[62]
Balogh I, Szoke G, Karpati L, Wartiovaara U, Katona E, et al. (2000) Val34Leu polymorphism of plasma factor XIII: biochemistry and epidemiology in familial thrombophilia. Blood 96: 2479–2486.
[63]
Ariens RA, Philippou H, Nagaswami C, Weisel JW, Lane DA, et al. (2000) The factor XIII V34L polymorphism accelerates thrombin activation of factor XIII and affects cross-linked fibrin structure. Blood 96: 988–995.
[64]
Png KJ, Halberg N, Yoshida M, Tavazoie SF (2011) A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature 481: 190–194.
