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M. Hayashi, J.C. Merriam, G. Barile, S. Chang, R. Allikmets, J.E. Merriam; Evaluation of Laminin Genes (LAMC1, LAMC2 and LAMB3) in Patients with Age-related Maculopathy . Invest. Ophthalmol. Vis. Sci. 2003;44(13):1753.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Our ARM/AMD Genetics Study utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, presence of laminins in the basal lamina of the RPE, Bruch's membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25-32 region, which overlaps with the previously mapped ARMD1 locus. Here, we present a comprehensive analysis of genetic variation in these 3 laminin genes in patients with ARM and matched unaffected controls. Methods: Extensive cohorts of ARM patients and age-matched controls were ascertained at the Harkness Eye Institute, Columbia University. Subjects were diagnosed according to a modified International Classification System and divided into five categories: normal (0), early ARM (E), neovascular (N), geographic atrophy (G), and mixed (N+G) AMD. The entire open reading frame of the 3 laminin genes was screened for variants by DHPLC and direct sequencing in at least 92, and up to 368 subjects. Results: Sixty nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Of these, 38 were in the coding region, including 9 amino acid-changing and 29 synonymous substitutions. Overall, we found no statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Several rare, non-synonymous, variants were detected in single cases of ARM patients. Allelic frequencies of common variants were equally distributed between cases and controls, confirming proper matching of the two cohorts. Conclusions: Our current data on limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out. The accumulated databases of genetic variation will be used for selection of informative markers for large case-control studies.
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