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D. Cameron, Z. Yang, D. Gibbs, H. Chen, A. Jorgensen, L. Luo, G. Brinton, N. A. Zabriskie, Z. Tong, K. Zhang; Genetic Analysis of HTRA1 in Dry Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2099. doi: https://doi.org/.
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Age-related macular degeneration (AMD) is the most common cause of irreversible visual impairment in the developed world. The two forms of advanced AMD, geographic atrophy (GA) and choroidal neovascularization (wet AMD), represent two degenerative processes in the macula that lead to loss of central vision. Soft confluent drusen, characterized by deposits in macula without visual loss, are considered a precursor of advanced AMD. Recently, We have shown that a common variant, rs11200638 in the promoter of HTRA1 increases the risk for wet AMD. However, its impact on soft confluent drusen and GA or the relationship between them is unclear.
We genotyped 250 patients with dry AMD (138 GA and 112 soft confluent drusen) and 294 controls. We performed chi square analysis for an additive allelic model to investigate dissease association. We also examined other variants in region 10q26 conditioned on rs11200638 using stepwise logistical regression.
The HTRA1 rs11200638 has a highly significant association with GA (p=9.9 × 10-9 for an additive allele-dosage model, ORhet=2.06 (1.32, 3.22), ORhom=9.29 (4.14, 20.84)) and confers an estimated population attributable risk of 47.9%. We found that soft confluent drusen is also associated with HTRA1 rs11200638 risk allele (p=3.6 x 10-5 for an additive allele-dosage model, ORhet=1.12 (0.70, 1.79), ORhom=5.73 (2.48, 13.23)). Furthermore, among the variants examined, none remained significant after conditioning to rs11200638.
We show that the rs11200638 confers similar risks for GA as was demonstrated for wet AMD. It also confers risk to soft confluent drusen, although to a lesser extent. Our results suggest that HTRA1 is a major risk factor for GA and wet AMD. Further genetic and functional investigations will provide important insight in AMD pathogenesis and therapy.
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