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I. K. Kim, F. Ji, M. A. Morrison, L. E. Patty, S. A. Adams, A. Capone, J. W. Miller, T. P. Dryja, J. Ott, M. M. DeAngelis; Analysis of the 1q24-q41 Region and the Candidate Gene RGS13 in Sibling Pairs Extremely Discordant for Neovascular Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4621.
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We sought to validate that the candidate gene region, 1q24-q41, is associated with neovascular AMD in our cohort. Additionally, we examined a candidate gene in this region, Regulator of G-Protein Signaling 13 (RGS13) , chosen from previous expression profiling studies identifying it as a potential contributor to the pathophysiology of neovascular AMD.
We ascertained 135 unrelated patients with neovascular AMD who had one sibling with normal maculae and was past the age at which the index patient was diagnosed with neovascular AMD, i.e., 135 extremely discordant sibpairs. CFH genotype (rs1061170) data was available for each member of a sibpair. We analyzed 14 highly heterozygous microsatellite markers spanning 1q24-1q41, including several that were tightly linked to CFH and RGS13. Identity-by-state (IBS) scores were calculated from the number of alleles shared between each member of a pair for each of the 14 markers. Using heterozygosities for each marker, observed and expected (null hypothesis of no linkage) IBS values were compared across all sibpairs using the chi-squared test. Genotyping of RGS13 was performed by direct sequencing of known SNPs from ENSEMBL that were located in the promoter/5’UTR, coding and 3’-UTR regions. Conditional logistic regression was used for statistical analysis. For each SNP, we tested the effect of the rare allele in the homozygous state and in the heterozygous state compared to the common allele in the homozygous state.
After adjusting for multiple comparisons using a Bonferroni correction, analysis of IBS scores revealed that only D1S3468 was significantly associated with neovascular AMD (p = .002). D1S3468 is located 1.4 cM from RGS13 and 6.8 cM from CFH. However, no significant association was observed between neovascular AMD and any of the 5 RGS13 SNPs analyzed.
Results from linkage analysis in the 1q24-q41 region indicates that there may be other genes, along with CFH, that influence risk of neovascular AMD.
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