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J. M. Seddon, R. Reynolds, J. Fagerness, L. Sobrin, E. H. Souied, P. Bernstein, M. Brantley, Jr., N. Katsanis, R. Allikmets, M. Daly; Genome-Wide Association Study of Advanced Age-Related Macular Degeneration Identifies a New Susceptibility Locus in the Lipid Metabolism Pathway, Hepatic Lipase (LIPC). Invest. Ophthalmol. Vis. Sci. 2010;51(13):2475.
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We conducted a large genome-wide association study (GWAS) of advanced age-related macular degeneration (AMD) to identify new genetic pathways contributing to the development of this complex disease.
The GWAS included 979 cases of geographic atrophy and neovascular AMD and 1709 controls all of whom were Caucasian and unrelated, and used the Affymetrix 6.0 platform (906,000 single nucleotide polymorphisms (SNPs) and 946,000 genotyped copy number variations. Replication genotyping was performed using 4337 advanced cases and 2077 controls from six independent samples with similar phenotypes and ethnicity.
Our discovery scan implicated a strong association between AMD and the hepatic lipase gene LIPC with P=4.5 x 10 -5. We conducted several stages of replication of this and other significant findings (P < 10-4). The association with LIPC remained our most significant finding and was genome-wide significant with replication P= 3.3 x 10-7 for the discovery SNP and P= 1.2 x 10-8 for the functional variant in this gene. The odds ratio for the minor T allele (which raises HDL) was 0.76 (95% confidence interval 0.69-0.87) suggesting a decreased risk of AMD related to each copy of this allele, with consistent effects for geographic atrophy and neovascular disease. We also found strong associations between advanced AMD and other SNPs in the same lipid pathway including CETP and ABCA1, but these were not genome-wide significant and the direction of effect was not consistent among the lipid SNPs. We confirmed reported loci including two CFH loci, ARMS2/HTRA1, CFB/C2, CFI, and C3. No new copy number variations were shown to have genome-wide significant associations with AMD.
LIPC, encoding hepatic lipase, a critical enzyme in HDL metabolism, is a new gene associated with AMD. Several related mechanisms are plausible. This locus provides a new pathway for consideration in the pathogenesis of AMD, and may lead to new avenues for prevention and treatment.
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