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M. A. Sohrab, G. Barile, L. Xu, L. Perretta, R. Allikmets, J. E. Merriam, J. Zernant, B. Mirochnik, R. T. Smith; Association of Homozygous High-Risk Alleles in Complement Factor H and ARMS2 With Drusen Staging of Age-Related Macular Degeneration (AMD). Invest. Ophthalmol. Vis. Sci. 2009;50(13):3451.
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To determine the association of homozygous high-risk and protective alleles in both complement factor H (CFH) Y402H (rs1061170) and LOC387715/ARMS2 A69S (rs10490924) loci, along with other risk factors, with the staging of AMD.
629 patients enrolled in the Macular Genetics Study classified as having early or late stage AMD underwent genotyping to determine CFH Y402H and ARMS2 A69S status. History of smoking, hypertension, and sun exposure was obtained through questionnaires. From the initial set, 208 patients homozygous for either CFH high-risk (402H) or protective (402Y) and homozygous for ARMS2 high-risk (69S) or protective (69A) alleles (a total of four subgroups) were chosen for further analysis.
Of the 208 patients, 46% were graded early AMD (eAMD) and 54% were graded late AMD, including choroidal neovascularization (CNV) and/or geographic atrophy (GA). In patients with eAMD, those with homozygous ARMS2 risk allele compared to homozygous protective allele were much more likely to present with stage 3 AMD (indistinct soft drusen and pigmentary changes) versus stage 2A or 2B AMD (soft indistinct drusen or soft distinct drusen with pigmentary changes, respectively) (OR 3.9, 95% CI 1.2, 12; p=0.02), whereas those with homozygous CFH risk allele versus protective allele were not (OR 1.4, 95% CI 0.5, 3.6; p=0.5). In comparing eAMD to late AMD, patients homozygous for both CFH and ARMS2 risk alleles were most likely (OR 6.2, 95% CI 1.9, 20; p=0.02) to develop late AMD. Patients with hypertension were less likely to develop late AMD (OR 0.4, 95% CI 0.2, 1.01; p=0.051). Patients homozygous for ARMS2 risk allele versus protective allele had a lower mean age of presentation with AMD (75 years versus 80 years). CFH and ARMS2 genotypes were not significantly associated with a specific form (CNV vs. GA) of late stage disease.
Patients homozygous for ARMS2 risk allele, but not those homozygous for CFH risk allele, were more likely to present with the high-risk clinical stage of soft drusen and pigment than lower risk stages 2A or 2B, consistent with ARMS2 conferring risk for late AMD. Effects of ARMS2 and CFH risk on drusen load are under investigation. Homozygosity for both CFH and ARMS2 high-risk alleles conferred the greatest risk for late AMD, but the form of late disease was not influenced. Hypertension appeared protective, perhaps secondary to anti-hypertensive medication or statin use. Patients with homozygous ARMS2 risk allele had an earlier age of presentation with AMD than those homozygous for ARMS2 protective allele.
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