Abstract
Age-related macular degeneration (AMD) is a late onset vision disorder. Recent studies demonstrate that alterations in complement cascade genes are associated with AMD. Of the three identified complement loci, variants in complement factor H (CFH) have the highest impact as does an independent locus at 10q26. Our matched case–control study using the Age-Related Eye Disease Study (AREDS) cohort confirms and extends the associations in these loci. Subjects were genotyped for single nucleotide polymorphisms (SNPs) from CFH, complement component 2 (C2), complement component 3 (C3), complement factor B (CFB), age-related maculopathy susceptibility (ARMS2), HtrA serine peptidase 1 (HTRA1), and apolipoprotein E (APOE). Individual SNPs, and haplotypes showed risk trends consistent with those seen in other population studies for CFH, C3, C2, and CFB. SNP rs10490924 on chromosome 10 in exon 1 of the ARMS2 gene showed a highly significant association with an odds ratio (OR) of 3.2 (95% CI 2.4–4.2) for the risk allele and rs11200638 located in the proximal promoter region of HTRA1 showed a higher significant association with an OR of 3.4 (95% CI 2.5–4.6) with our AMD cases. We found that APOE haplotypes were not significantly associated with disease status. Adjustments for other risk factors did not significantly alter the observed associations. This study validates the complement pathway's involvement in AMD and suggests that allelic variants in complement genes have a direct role in disease. These results also support previous findings that variants in the region of 10q26 exert an independent risk for AMD.
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References
Seddon JM, Ajani UA, Mitchell BD : Familial aggregation of age-related maculopathy. Am J Ophthalmol 1997; 123: 199–206.
Meyers SM : A twin study on age-related macular degeneration. Trans Am Ophthalmol Soc 1994; 92: 775–843.
Jakobsdottir J, Conley YP, Weeks DE, Mah TS, Ferrell RE, Gorin MB : Susceptibility genes for age-related maculopathy on chromosome 10q26. Am J Hum Genet 2005; 77: 389–407.
Fisher SA, Abecasis GR, Yashar BM et al: Meta-analysis of genome scans of age-related macular degeneration. Hum Mol Genet 2005; 14: 2257–2264.
Bansback N, Czoski-Murray C, Carlton J et al: Determinants of health related quality of life and health state utility in patients with age related macular degeneration: the association of contrast sensitivity and visual acuity. Qual Life Res 2007; 16: 533–543.
Hughes AE, 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: 1173–1177.
Edwards AO, Ritter III R, Abel KJ, Manning A, Panhuysen C, Farrer LA : Complement factor H polymorphism and age-related macular degeneration. Science 2005; 308: 421–424.
Klein RJ, Zeiss C, Chew EY et al: Complement factor H polymorphism in age-related macular degeneration. Science 2005; 308: 385–389.
Hageman GS, Anderson DH, Johnson LV 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.
Haines JL, Hauser MA, Schmidt S et al: Complement factor H variant increases the risk of age-related macular degeneration. Science 2005; 308: 419–421.
Gold B, Merriam JE, Zernant J et al: Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006; 38: 458–462.
Rivera A, Fisher SA, Fritsche LG et al: 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 2005; 14: 3227–3236.
Hageman GS, Hancox LS, Taiber AJ et al: 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 2006; 38: 592–604.
Age-Related Eye Disease Study Research Group: The Age-Related Eye Disease Study (AREDS): design implications. AREDS report no. 1. Control Clin Trials 1999; 20: 573–600.
Jacques PF : The potential preventive effects of vitamins for cataract and age-related macular degeneration. Int J Vitam Nutr Res 1999; 69: 198–205.
Age-Related Eye Disease Study Research Group: A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol 2001; 119: 1439–1452.
Mitchell P, Foran S : Age-Related Eye Disease Study severity scale and simplified severity scale for age-related macular degeneration. Arch Ophthalmol 2005; 123: 1598–1599.
Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM : Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet 2007; 39: 1200–1201.
Allikmets R, Dean M : Bringing age-related macular degeneration into focus. Nat Genet 2008; 40: 820–821.
Hughes AE, Orr N, Patterson C et al: Neovascular age-related macular degeneration risk based on CFH, LOC387715/HTRA1, and smoking. PLoS Med 2007; 4: e355.
Schmidt S, Haines JL, Postel EA et al: Joint effects of smoking history and APOE genotypes in age-related macular degeneration. Mol Vis 2005; 11: 941–949.
Prosser BE, Johnson S, Roversi P et al: Structural basis for complement factor H linked age-related macular degeneration. J Exp Med 2007; 204: 2277–2283.
Fritsche LG, Loenhardt T, Janssen A et al: Age-related macular degeneration is associated with an unstable ARMS2 (LOC387715) mRNA. Nat Genet 2008; 40: 892–896.
Schultz DW, Klein ML, Humpert A et al: Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol 2003; 121: 679–683.
DeAngelis MM, Ji F, Kim IK et al: Cigarette smoking, CFH, APOE, ELOVL4, and risk of neovascular age-related macular degeneration. Arch Ophthalmol 2007; 125: 49–54.
Schmidt S, Klaver C, Saunders A et al: A pooled case–control study of the apolipoprotein E (APOE) gene in age-related maculopathy. Ophthalmic Genet 2002; 23: 209–223.
Yang Z, Stratton C, Francis PJ et al: Toll-like receptor 3 and geographic atrophy in age-related macular degeneration. N Engl J Med 2008; 359: 1456–1463.
Edwards AO, Chen D, Fridley BL et al: Toll-like receptor polymorphisms and age-related macular degeneration. Invest Ophthalmol Vis Sci 2008; 49: 1652–1659.
Allikmets A, Bergen AA, Dean M et al, the International AMD Genetics Consortium: Toll-like receptor 3 gene is not associated with geographic atrophy in age-related macular degeneration. NEJM 2009; (in press).
Cong R, Zhou B, Sun Q, Gu H, Tang N, Wang B : Smoking and the risk of age-related macular degeneration: a meta-analysis. Ann Epidemiol 2008; 18: 647–656.
Acknowledgements
This study was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research, and SAIC-Frederick under contract no. NO1-CO-12400 and with grants from the National Eye Institute EY13435 and EY017404 (RA); the Macula Vision Research Foundation; Wallach Foundation (RA); Elyachar Foundation (RA); Kaplen Foundation (RA); Wigdeon Point Charitable Foundation (RA); and an unrestricted grant to the Department of Ophthalmology, Columbia University, from Research to Prevent Blindness. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be marked as an advertisement in accordance with 18 USC Section 1734 solely to indicate this fact.
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Bergeron-Sawitzke, J., Gold, B., Olsh, A. et al. Multilocus analysis of age-related macular degeneration. Eur J Hum Genet 17, 1190–1199 (2009). https://doi.org/10.1038/ejhg.2009.23
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DOI: https://doi.org/10.1038/ejhg.2009.23
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