Two genetic pathways for age-related macular degeneration.
ABSTRACT 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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ABSTRACT: To evaluate whether complement Factor P (properdin) was present in surgically removed choroidal neovascular membranes of patients with age-related macular degeneration (AMD) and to investigate whether associated pre- and postoperative clinical characteristics can be correlated. The study population consisted of 26 AMD patients (26 eyes) with the exclusion criterion of prior treatment of the choroidal neovascular membranes. Factor P was detected immunocytochemically on paraffin sections (7 microm) by a polyclonal rabbit antihuman antibody. Eleven of 22 assessable membranes showed a positive reaction for Factor P. The average percentage of Factor P-positive cells per membrane ranged from 0.65% to 4.09%. The duration of visual loss was significantly longer (8.6 +/- 2.7 vs. 3.9 +/- 0.8 months), and the size of postoperative measured area of atrophic retinal pigment epithelium was larger (27.6 +/- 7.6 vs. 15.0 +/- 6.9 mm2) in patients with Factor P-positive membranes compared with Factor P-negative ones. Factor P was expressed in 50% of choroidal neovascular membranes of patients with AMD. The group with Factor P-positive membranes differed significantly from the Factor P-negative group in key clinical outcomes. Additional studies need to investigate the role of Factor P in the development of AMD for potential therapeutic intervention.Retina (Philadelphia, Pa.) 01/2009; 29(7):966-73. DOI:10.1097/IAE.0b013e3181a2f40f
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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.Investigative ophthalmology & visual science 04/2008; 49(8):3312-7. DOI:10.1167/iovs.07-1517