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John Paul P. SanGiovanni, Jing Chen, Roberta J. Dennison, Traci E. Clemons, Przemyslaw Mike Sapieha, Lois E. Smith, Emily Y. Chew; Regulatory Elements in Noncoding DNA Contain AMD-Associated Sequence Variants. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3303.
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© ARVO (1962-2015); The Authors (2016-present)
Noncoding DNA contains nucleotide binding sequences (motifs) for regulatory elements manifesting capacity to impact transcriptional and translational regulation of protein-coding sequences. Novel physical maps of highly conserved mammalian regulatory motifs permitted us to expand our inferences on the biologic relevance of intergenic DNA variation as it may relate to age-related macular degeneration (AMD).
We examined age-, sex-, and smoking-adjusted distributions of 371 DNA sequence variants resident in 137 highly conserved regulatory motifs for their association with advanced AMD (AAMD) in 2222 people from 3 independent cohorts participating in a large-scale genotyping project on the genetics of AMD. Our analytic sample contained 1190 people with AAMD and 1032 people who were both AMD-free and ≥ 64-years-of-age. Homology and conservation of regulatory motifs were determined from sequence alignments on 18 mammalian genomes using a Bayesian method to distinguish phylogenetic relationships from those likely attributed to species proximity. We combined measures of motif-resident SNP-AMD associations across cohorts with meta-analytic techniques and computed exact P-values on the total population with maxT permutation tests (applying 10000 iterations on each sequence variant). Regulatory elements of AMD-associated loci were annotated to identify targeting transcription factors and proximal sites of histone modification or nucleosome access.
An AMD-associated sequence variant existed in a highly conserved intergenic region of chromosome 7 (P ≤ 2.2 x 10-5, Pexact = 0.004). This variant is resident in an area containing an active DNase hypersensitivity cluster and transcription factor binding sites for EBF1 and TCF12. Our inferences were strengthened by the observation that sequence variants in genes encoding these transcription factors also showed associations with AAMD (EBF1, P ≤ 0.005; TCF12, P ≤ 0.002).
Examination of noncoding DNA sequence variation in intergenic regions under strong selective pressure can yield meaningful insights on the pathogenesis, pathophysiology, and treatment options for AMD and other complex diseases. Data from large-scale genotyping projects may be used to efficiently examine SNPs in intergenic areas enriched with regulatory elements.
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