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K. Nakai, M. S. Rogers, T. Baba, T. Funakoshi, A. E. Birsner, D. S. Luyindula, R. J. D’Amato; Genetic Loci That Control the Size of Laser-Induced Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1604.
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A major cause of legal blindness is Age-Related Macular Degeneration (ARMD). Blindness results from choroidal neovascularization (CNV), when abnormal blood vessels grow under the retina. Previously, we mapped the genetic loci for corneal angiogenesis induced by VEGF or FGF2 in BXD recombinant inbred mice. The purpose of this study was to investigate the loci that control the size of laser-induced choroidal neovascularization.
Laser photocoagulation was used to induce CNV in mice. The CNV area was measured using choroidal flatmount FITC-dextran perfusion method after 14 days. To investigate the genetic contribution to CNV, we have undertaken an interval mapping approach to identify QTLs that influence laser-induced CNV in the BXD mice.
Interval mapping identified 3 areas exhibiting highly significant linkages (Chr. 2, 13, 19; P<0.001). We concluded that there are laser response-modifying polymorphisms between C57BL/6J and DBA/2J mice on chromosome 2 near 124 Mbp (95% CI from interval mapping, 117.9-148.7 Mbp), on chromosome 13 proximal to 33.8 Mbp and on chromosome 19 distal to 54.9 Mbp. In addition, we observed regions on chromosomes 9 and 10 that exhibited near-significant linkage. The locus on chromosome 9 corresponds to the dilute locus, and may be explained by reduced pigmentation and thus altered laser energy absorption. The locus observed on chromosome 10 is consistent with the VEGF-response locus AngVq1 previously mapped by our group. Similarly, the highly significant region on chromosome 13 between 0 and 32 Mbp coincides with AngFq2. We have designated the new regions on chromosomes 2 and 19 AngCNVq1 and AngCNVq2 respectively for angiogenesis due to laser-induced choroidal neovascularization QTL. The newly mapped regions contain several candidate genes involved in the angiogenic process including thrombospondin 1, delta-like 4, Bcl2 modifying factor, phospholipase C, beta 2, adrenergic receptor, beta 1, actin-binding LIM protein 1 and colony stimulating factor 2 receptor, alpha.
Differences in these regions may control individual susceptibility to CNV. We expect that the identification of the specific genes that underlie responsiveness to laser-induced CNV in mice will have prognostic value for ARMD as the functional relevance of individual polymorphisms is determined.
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