Two genetic pathways for age-related macular degeneration

Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, CT 06520, USA.
Current Opinion in Genetics & Development (Impact Factor: 7.57). 07/2007; 17(3):228-33. DOI: 10.1016/j.gde.2007.04.004
Source: PubMed


The discovery of strong associations of the His402 variant of complement factor H (CFH) and the change in the promoter region of HtrA serine peptidase 1 (HTRA1) with age-related macular degeneration (AMD) have altered our conception of the pathophysiology of this disease. The complement system has been placed at the center of a flurry of research interest, and a similar growth in attention to the serine proteases is not far behind. The specific role of these variants in causing AMD is unknown, but they will undoubtedly lead to a deeper understanding of the biological mechanisms and will point to new avenues for pharmacologic management. Furthermore, these variants will enable clinicians and investigators to identify people at high risk for this condition, thereby establishing the preconditions for preventing the disease.

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    • "The discovery of the strongest associations of AMD with the variants of complement factor H (CFH; OMIM 134370) [10-13] and ARMS2/HTRA1 (age-related maculopathy susceptibility 2, OMIM 611313; the high temperature requirement factor A1, OMIM: 602194) [14-17] has led to new hypotheses regarding the pathogenesis of this disease. CFH is primarily associated with the formation of drusen that often characterizes both types of advanced AMD in Caucasian populations, whereas ARMS2/HTRA1 is mainly associated with wet AMD [18]. Other than these two major loci, three other members of the complement system, complement component 2 (C2; OMIM 217000), complement component 3 (C3; OMIM 120700), and complement factor B (CFB; OMIM 138470), were also found to be associated with AMD [10,19-21]. "
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    ABSTRACT: Age-related macular degeneration (AMD) is the most common cause of irreversible central vision loss worldwide. Research has linked AMD susceptibility with dysregulation of the complement cascade. Typically, complement factor H (CFH), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3) are associated with AMD. In this paper, we investigated the association between complement factor D (CFD), another factor of the complement system, and advanced AMD in a Caucasian population. Six single nucleotide polymorphisms (SNPs), rs1683564, rs35186399, rs1683563, rs3826945, rs34337649, and rs1651896, across the region covering CFD, were chosen for this study. One hundred and seventy-eight patients with advanced AMD and 161 age-matched normal controls were genotyped. Potential positive signals were further tested in another independent 445 advanced AMD patients and 190 controls. χ2 tests were performed to compare the allele frequencies between case and control groups. None of the six SNPs of CFD was found to be significantly associated with advanced AMD in our study. Our findings suggest that CFD may not play a major role in the genetic susceptibility to AMD because no association was found between the six SNPs analyzed in the CFD region and advanced AMD.
    Full-text · Article · Nov 2010 · Molecular vision
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    ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in elderly patients. The more aggressive exudative form is characterized by abnormal blood-vessel development that occurs beneath the retina as a result of choroidal neovascularization (CNV). Vascular endothelial growth factor (VEGF) has emerged as the key mediator of CNV formation; this has led to intensive research on VEGF and the recent approval of anti-VEGF compounds by the US Food and Drug Administration. Despite this successful introduction of anti-angiogenic therapies into the clinical setting, there is still a lack of treatments that definitively reverse damaged vision. Here, we consider the importance of putative molecular targets other than VEGF that might have been underestimated. Emerging cellular mechanisms offer additional opportunities for innovative therapeutic approaches.
    Full-text · Article · Sep 2007 · Trends in Molecular Medicine
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    ABSTRACT: Variants in the complement factor H (CFH) gene have been shown to be strongly associated with age-related macular degeneration (AMD). In this study, sequence alterations in CFH were investigated in 163 Chinese patients with exudative AMD and 155 unrelated Chinese control subjects. All the 22 CFH exons, intron-exon boundaries, and promoter sequences were screened by polymerase chain reaction and DNA sequencing. Fifty-eight sequence changes, 42 of them novel, were identified. Six SNPs with an allele frequency >30% were significantly associated with exudative AMD. SNP rs3753396 was novel; the rest had been reported: rs3753394, rs551397, rs800292, rs2274700, and rs1329428. Two haplotype blocks were constructed. The TG haplotype for rs551397 and rs800292 was the major haplotype that conferred a significantly increased susceptibility to exudative AMD (P(corr) = 0.0001, OR = 1.91, 95% CI = 1.36-2.68). The findings support prior evidence that the CFH gene is one of the AMD-associated genes. There is a different distribution pattern of CFH variants in the Chinese compared with other populations. Individual SNP and haplotype analyses revealed that the ancient alleles at the 5' end of CFH contribute to an increased susceptibility to exudative AMD.
    Full-text · Article · Apr 2008 · Investigative ophthalmology & visual science
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