Complement C3 variant and the risk of age-related macular degeneration

被引:668
作者
Yates, John R. W.
Sepp, Tiina
Matharu, Baljinder K.
Khan, Jane C.
Thurlby, Deborah A.
Shahid, Humma
Clayton, David G.
Hayward, Caroline
Morgan, Joanne
Wright, Alan F.
Armbrecht, Ana Maria
Dhillon, Baljean
Deary, Ian J.
Redmond, Elizabeth
Bird, Alan C.
Moore, Anthony T.
机构
[1] Univ Cambridge, Cambridge Inst Med Res, Wellcome Trust, Dept Med Genet,Addenbrookes Hosp, Cambridge CB2 0XY, England
[2] Med Res Council Human Genet Unit, Edinburgh, Midlothian, Scotland
[3] Univ Edinburgh, Edinburgh, Midlothian, Scotland
[4] UCL, London, England
[5] Moorfields Eye Hosp, London, England
基金
英国医学研究理事会; 英国惠康基金;
关键词
D O I
10.1056/NEJMoa072618
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Age-related macular degeneration is the most common cause of blindness in Western populations. Susceptibility is influenced by age and by genetic and environmental factors. Complement activation is implicated in the pathogenesis. Methods: We tested for an association between age-related macular degeneration and 13 single-nucleotide polymorphisms (SNPs) spanning the complement genes C3 and C5 in case subjects and control subjects from the southeastern region of England. All subjects were examined by an ophthalmologist and had independent grading of fundus photographs to confirm their disease status. To test for replication of the most significant findings, we genotyped a set of Scottish cases and controls. Results: The common functional polymorphism rs2230199 (Arg80Gly) in the C3 gene, corresponding to the electrophoretic variants C3S (slow) and C3F (fast), was strongly associated with age-related macular degeneration in both the English group (603 cases and 350 controls, P=5.9 x 10(sup -5)) and the Scottish group (244 cases and 351 controls, P=5.0 x 10(sup -5)). The odds ratio for age-related macular degeneration in C3 S/F heterozygotes as compared with S/S homozygotes was 1.7 (95% confidence interval [CI], 1.3 to 2.1); for F/F homozygotes, the odds ratio was 2.6 (95% CI, 1.6 to 4.1). The estimated population attributable risk for C3F was 22%. Conclusions: Complement C3 is important in the pathogenesis of age-related macular degeneration. This finding further underscores the influence of the complement pathway in the pathogenesis of this disease.
引用
收藏
页码:553 / 561
页数:9
相关论文
共 41 条
[1]   Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease) [J].
Abrera-Abeleda, M. A. ;
Nishimura, C. ;
Smith, J. L. H. ;
Sethi, S. ;
McRae, J. L. ;
Murphy, B. F. ;
Silvestri, G. ;
Skerka, C. ;
Jozsi, M. ;
Zipfel, P. F. ;
Hageman, G. S. ;
Smith, R. J. H. .
JOURNAL OF MEDICAL GENETICS, 2006, 43 (07) :582-589
[2]   Membranoproliferative glomerulonephritis type II (dense deposit disease):: An update [J].
Appel, GB ;
Cook, HT ;
Hageman, G ;
Jennette, JC ;
Kashgarian, M ;
Kirschfink, M ;
Lambris, JD ;
Lanning, L ;
Lutz, HU ;
Meri, S ;
Rose, NR ;
Salant, DJ ;
Sethi, S ;
Smith, RJH ;
Smoyer, W ;
Tully, HF ;
Tully, SP ;
Walker, P ;
Welsh, M ;
Würzner, R ;
Zipfel, PF .
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY, 2005, 16 (05) :1392-1403
[3]   CAPACITY OF COMPLEMENT C3 PHENOTYPES TO BIND ON TO MONONUCLEAR-CELLS IN MAN [J].
ARVILOMMI, H .
NATURE, 1974, 251 (5477) :740-741
[4]   GENETIC POLYMORPHISM OF C'3(BETA1C-GLOBULIN) IN HUMAN SERUM [J].
AZEN, EA ;
SMITHIES, O .
SCIENCE, 1968, 162 (3856) :905-&
[5]  
BARTOK I, 1995, J IMMUNOL, V154, P5367
[6]   AN INTERNATIONAL CLASSIFICATION AND GRADING SYSTEM FOR AGE-RELATED MACULOPATHY AND AGE-RELATED MACULAR DEGENERATION [J].
BIRD, AEC ;
BRESSLER, NM ;
BRESSLER, SB ;
CHISHOLM, IH ;
COSCAS, G ;
DAVIS, MD ;
DEJONG, PTVM ;
KLAVER, CCW ;
KLEIN, BEK ;
KLEIN, R ;
MITCHELL, P ;
SARKS, JP ;
SARKS, SH ;
SOURBANE, G ;
TAYLOR, HR ;
VINGERLING, JR .
SURVEY OF OPHTHALMOLOGY, 1995, 39 (05) :367-374
[7]   Immunotherapy for choroidal neovascularization in a laser-induced mouse model simulating exudative (wet) macular degeneration [J].
Bora, PS ;
Hu, ZW ;
Tezel, TH ;
Sohn, JH ;
Kang, SG ;
Cruz, JMC ;
Bora, NS ;
Garen, A ;
Kaplan, HJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (05) :2679-2684
[8]   MOLECULAR-BASIS OF POLYMORPHISMS OF HUMAN-COMPLEMENT COMPONENT-C3 [J].
BOTTO, M ;
FONG, KY ;
SO, AK ;
KOCH, C ;
WALPORT, MJ .
JOURNAL OF EXPERIMENTAL MEDICINE, 1990, 172 (04) :1011-1017
[9]   Influence of donor C3 allotype on late renal-transplantation outcome [J].
Brown, KM ;
Kondeatis, E ;
Vaughan, RW ;
Kon, SP ;
Farmer, CKT ;
Taylor, JD ;
He, X ;
Johnston, A ;
Horsfield, C ;
Janssen, BJC ;
Gros, P ;
Zhou, WD ;
Sacks, SH ;
Sheerin, NS .
NEW ENGLAND JOURNAL OF MEDICINE, 2006, 354 (19) :2014-2023
[10]   Visual impairment caused by retinal abnormalities in mesangiocapillary (membranoproliferative) glomerulonephritis type II ("dense deposit disease") [J].
Colville, D ;
Guymer, R ;
Sinclair, RA ;
Savige, J .
AMERICAN JOURNAL OF KIDNEY DISEASES, 2003, 42 (02)