Human Molecular Genetics Advance Access published online on June 1, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi204
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Health Promotion and Development, School of Nursing, University of Pittsburgh, Pittsburgh, PA 15261; Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261
* To whom correspondence should be addressed. Age-related maculopathy (ARM) is a leading cause of visual impairment in elderly Americans and is a complex genetic disorder. Hypothesized pathways for the etiology of ARM include cholesterol and lipoprotein metabolism and transport, extracellular matrix integrity, oxidative stress and inflammatory/immunologic processes. This study investigates 21 polymorphisms within 15 candidate genes whose products function within these pathways by performing family and case-control genetic association studies using clearly affected familial cases (n=338 families, 796 individuals), clearly affected, unrelated sporadic cases (n=196) and clearly unaffected, unrelated controls (n=120). Two genes demonstrated significant association with ARM status. A Met299Val variant in the elongation of very long chain fatty acids-like 4 (ELOVL4) gene was significantly associated with ARM in the case-control allele (p=0.001), case-control genotype (p=0.001) and case-control family (p<0.0001) tests. A Tyr402His variant in exon 9 in the complement factor H (CFH) gene was also significantly association with ARM in the case-control allele (p<0.0001), case-control genotype (p<0.0001) and case-control family (p<0.0001) tests. All of these results remain significant after adjusting for false discovery rates to control for the impact of multiple testing. Additionally, the CFH variant appears to play a role in exudative and atrophic disease, while the ELOVL4 variant may play a greater role in exudative disease in our population. These results support a potential role for multiple pathways in the etiology of ARM, including pathways involved with fatty acid biosynthesis and the complement system.
Received March 11, 2005
Revised May 12, 2005
Accepted May 23, 2005
Article
Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy
2 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261
3 Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, PA 15261
4 Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, PA 15261; Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, PA 15261
5 Department of Ophthalmology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261
6 Departments of Ophthalmology and Human Genetics, University of Pittsburgh School of Medicine and Graduate School of Public Health, The Eye and Ear Institute Building, 203 Lothrop Street, Pittsburgh, PA 15213
Michael B. Gorin, E-mail: gorinmb{at}upmc.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  G. Wang, K. L. Spencer, B. L. Court, L. M. Olson, W. K. Scott, J. L. Haines, and M. A. Pericak-Vance Localization of Age-Related Macular Degeneration-Associated ARMS2 in Cytosol, Not Mitochondria Invest. Ophthalmol. Vis. Sci., July 1, 2009; 50(7): 3084 - 3090. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Udar, S. R. Atilano, M. Memarzadeh, D. S. Boyer, M. Chwa, S. Lu, B. Maguen, J. Langberg, P. Coskun, D. C. Wallace, et al. Mitochondrial DNA Haplogroups Associated with Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., June 1, 2009; 50(6): 2966 - 2974. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Zhou, S. R. Kim, B. S. Westlund, and J. R. Sparrow Complement Activation by Bisretinoid Constituents of RPE Lipofuscin Invest. Ophthalmol. Vis. Sci., March 1, 2009; 50(3): 1392 - 1399. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Kim, J. H. Kang, O. W. Kwon, S. J. Lee, J. H. Oh, and H. S. Chin Association between Complement Factor H Gene Polymorphisms and Neovascular Age-Related Macular Degeneration in Koreans Invest. Ophthalmol. Vis. Sci., May 1, 2008; 49(5): 2071 - 2076. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Cui, G. Kang, K. Sun, M. Qian, R. Romero, and W. Fu Gene-Centric Genomewide Association Study via Entropy Genetics, May 1, 2008; 179(1): 637 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Fu, D. Garland, Z. Yang, D. Shukla, A. Rajendran, E. Pearson, E. M. Stone, K. Zhang, and E. A. Pierce The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice Hum. Mol. Genet., October 15, 2007; 16(20): 2411 - 2422. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kanda, W. Chen, M. Othman, K. E. H. Branham, M. Brooks, R. Khanna, S. He, R. Lyons, G. R. Abecasis, and A. Swaroop A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration PNAS, October 9, 2007; 104(41): 16227 - 16232. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Spencer, M. A. Hauser, L. M. Olson, N. Schnetz-Boutaud, W. K. Scott, S. Schmidt, P. Gallins, A. Agarwal, E. A. Postel, M. A. Pericak-Vance, et al. Haplotypes Spanning the Complement Factor H Gene Are Protective against Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., September 1, 2007; 48(9): 4277 - 4283. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tuo, C. M. Bojanowski, M. Zhou, D. Shen, R. J. Ross, K. I. Rosenberg, D. J. Cameron, C. Yin, J. A. Kowalak, Z. Zhuang, et al. Murine Ccl2/Cx3cr1 Deficiency Results in Retinal Lesions Mimicking Human Age-Related Macular Degeneration Invest. Ophthalmol. Vis. Sci., August 1, 2007; 48(8): 3827 - 3836. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Thomas, M. A. Grassi, J. R. Lee, A. O. Edwards, M. B. Gorin, R. Klein, T. L. Casavant, T. E. Scheetz, E. M. Stone, and A. B. Williams IDOCS: Intelligent Distributed Ontology Consensus System--The Use of Machine Learning in Retinal Drusen Phenotyping Invest. Ophthalmol. Vis. Sci., May 1, 2007; 48(5): 2278 - 2284. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Schaumberg, W. G. Christen, J. E. Buring, R. J. Glynn, N. Rifai, and P. M. Ridker High-Sensitivity C-Reactive Protein, Other Markers of Inflammation, and the Incidence of Macular Degeneration in Women Arch Ophthalmol, March 1, 2007; 125(3): 300 - 305. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shankar, P. Mitchell, E. Rochtchina, J. Tan, and J. J. Wang Association between Circulating White Blood Cell Count and Long-Term Incidence of Age-related Macular Degeneration: The Blue Mountains Eye Study Am. J. Epidemiol., February 15, 2007; 165(4): 375 - 382. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. B. Gorin A Clinician's View of the Molecular Genetics of Age-Related Maculopathy Arch Ophthalmol, January 1, 2007; 125(1): 21 - 29. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. M. DeAngelis, F. Ji, I. K. Kim, S. Adams, A. Capone Jr, J. Ott, J. W. Miller, and T. P. Dryja Cigarette Smoking, CFH, APOE, ELOVL4, and Risk of Neovascular Age-Related Macular Degeneration Arch Ophthalmol, January 1, 2007; 125(1): 49 - 54. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Schaumberg, S. E. Hankinson, Q. Guo, E. Rimm, and D. J. Hunter A Prospective Study of 2 Major Age-Related Macular Degeneration Susceptibility Alleles and Interactions With Modifiable Risk Factors Arch Ophthalmol, January 1, 2007; 125(1): 55 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. P. Conley, J. Jakobsdottir, T. Mah, D. E. Weeks, R. Klein, L. Kuller, R. E. Ferrell, and M. B. Gorin CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses Hum. Mol. Genet., November 1, 2006; 15(21): 3206 - 3218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. N. Baird, F. M. A. Islam, A. J. Richardson, M. Cain, N. Hunt, and R. Guymer Analysis of the Y402H Variant of the Complement Factor H Gene in Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci., October 1, 2006; 47(10): 4194 - 4198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Thakkinstian, P. Han, M. McEvoy, W. Smith, J. Hoh, K. Magnusson, K. Zhang, and J. Attia Systematic review and meta-analysis of the association between complementary factor H Y402H polymorphisms and age-related macular degeneration Hum. Mol. Genet., September 15, 2006; 15(18): 2784 - 2790. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G Malek and S W Cousins Is our current clinical classification of AMD up to the job? Br J Ophthalmol, September 1, 2006; 90(9): 1080 - 1081. [Full Text] [PDF]
|
|
|
|
|
|
F Simonelli, G Frisso, F Testa, R di Fiore, D F Vitale, M P Manitto, R Brancato, E Rinaldi, and L Sacchetti Polymorphism p.402Y>H in the complement factor H protein is a risk factor for age related macular degeneration in an Italian population Br J Ophthalmol, September 1, 2006; 90(9): 1142 - 1145. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L.-I. Lau, S.-J. Chen, C.-Y. Cheng, M.-Y. Yen, F.-L. Lee, M.-W. Lin, W.-M. Hsu, and Y.-H. Wei Association of the Y402H Polymorphism in Complement Factor H Gene and Neovascular Age-Related Macular Degeneration in Chinese Patients. Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3242 - 3246. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N Dashti, G McGwin, C Owsley, and C A Curcio Plasma apolipoproteins and risk for age related maculopathy Br J Ophthalmol, August 1, 2006; 90(8): 1028 - 1033. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Tuo, B. Ning, C. M. Bojanowski, Z.-N. Lin, R. J. Ross, G. F. Reed, D. Shen, X. Jiao, M. Zhou, E. Y. Chew, et al. Synergic effect of polymorphisms in ERCC6 5' flanking region and complement factor H on age-related macular degeneration predisposition PNAS, June 13, 2006; 103(24): 9256 - 9261. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Schaumberg, W. G. Christen, P. Kozlowski, D. T. Miller, P. M. Ridker, and R. Y. L. Zee A Prospective Assessment of the Y402H Variant in Complement Factor H, Genetic Variants in C-Reactive Protein, and Risk of Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci., June 1, 2006; 47(6): 2336 - 2340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Wiggs Complement factor h and macular degeneration: the genome yields an important clue. Arch Ophthalmol, April 1, 2006; 124(4): 577 - 578. [Full Text] [PDF]
|
|
|
|
|
|
A. Rivera, S. A. Fisher, L. G. Fritsche, C. N. Keilhauer, P. Lichtner, T. Meitinger, and B. H.F. Weber 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., November 1, 2005; 14(21): 3227 - 3236. [Abstract] [Full Text] [PDF]
|
|