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E.N. Wandel, C.C. Klaver, J.E. Merriam, R.T. Smith, L.A. Yannuzzi, I.A. Barbazetto, R. Allikmets; Comprehensive Genetic Analysis of Nuclear Receptor Genes in Age-related Maculopathy . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1505.
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Purpose: Candidate gene analysis in case-control studies is an established methodology for discovery of the genetic component of complex traits, e.g., age-related maculopathy (ARM). Genes encoding nuclear receptors, which regulate the biological effects of retinoids through retinoic acid-mediated gene activation, are plausible candidates for involvement in the etiology of ARM. This study aimed to generate a comprehensive database of genetic variation in the nuclear receptor genes RXRA, RXRG, RARA, RGR, and RX by screening a population of subjects with and without ARM. Methods: All subjects were ascertained at two ophthalmology clinics, and diagnosed according to a modification of the International Classification System for early and end stages of ARM. The entire open reading frame of all 5 genes, included in 31 amplicons, was screened in at least 92, and up to 439 subjects. Sequence variants were detected by denaturing high performance liquid chromatography and confirmed by direct sequencing. Results: We detected a total of 27 variants in the 5 genes, of which 18 were located in the coding region. Most changes had not been described earlier, nor were present in public databases. 7/27 variants represented non-synonymous changes, of which 5 were rare variants. Three variants in the 3' UTR of RXRA were significantly less frequent in 251 cases compared to 145 age-matched controls (1.6% vs. 4.8%, p<0.05). Differences in other rare variants did not reach statistical significance. Allelic frequencies of common variants appeared to be equally distributed between cases and controls. Conclusions: Our preliminary data suggest that the RXRA gene may be involved in ARM. Comprehensive screening of candidate genes for genetic variation in ARM, as presented, enables the selection of informative markers for evaluation in large populations of ARM cases and controls.
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