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Toll-like Receptor Polymorphisms and Age-Related Macular Degeneration

¹From the Department of Ophthalmology, the ²Division of Biostatistics, and the ³Advanced Genomics Technology Center, Mayo Clinic, Rochester, Minnesota; the ⁴Departments of Biostatistics, ⁵Ophthalmology and Visual Sciences, and ⁶Human Genetics, University of Michigan, Ann Arbor, Michigan; the ⁸Departments of Epidemiology and Biostatistics, ⁹Genetics, and ¹⁰Ophthalmology, Case Western Reserve University, Cleveland, Ohio; and the ¹¹Department of Ophthalmology and Visual Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.

PURPOSE. Evidence from genetic-association studies in conjunction with the demonstration of complement deposition in the retina and choroid implicates noncellular pathways of innate immunity in the pathogenesis of age-related macular degeneration (AMD). The purpose of this study was to determine whether common variation in the 10 human toll-like receptors (TLRs) alters the risk of AMD.

METHODS. Sixty-eight SNPs were iteratively genotyped across the TLR genes in a cohort of 577 subjects, with and without AMD. Two additional cohorts were used for replication studies. Standard genetic-association methods were used to analyze the results for association with disease and interaction with other loci.

RESULTS. Coding SNPs in TLR3 (rs3775291) and TLR7 (rs179008) showed association with AMD in one group (P = 0.01 and P = 0.02, respectively) before correction for multiple testing. For both SNPs, the association with AMD arose due to an excess of heterozygotes compared with homozygotes for the major allele. The two coding SNPs were not associated with AMD in another case–control cohort or an extended-family cohort. Although an intronic SNP in TLR4 was associated marginally with AMD (P = 0.03), it was not possible to replicate a previous association with the rare coding SNP D299G in this gene (P = 0.6).

CONCLUSIONS. Although borderline support for association between polymorphisms in TLR genes and AMD was reported for some cohorts, these initial observations of coding SNPs in TLR3, TLR4, and TLR7 were not replicated. TLR variants are unlikely to have a major impact on overall AMD risk, and the common variants studied were not associated with AMD.

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