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L. J. Kopplin, B. E. K. Klein, R. Klein, D. V. Leontiev, K. E. Lee, S. K. Iyengar; Association of NGF1-A Binding Protein 1 With Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):2089.
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Age-related macular degeneration (AMD) is a progressive disease that can lead to loss of central vision and in severe cases, blindness. Multiple linkage studies have identified genomic regions that may contain susceptibility loci for AMD. Within one of these regions, chromosome 2q, is an interesting positional candidate gene NGF1-A binding protein 1 (NAB1). NAB1 is a known repressor of members of the NGFI-A family of zinc finger transcription factors. The NAB proteins play a key role in appropriate Drosophila eye development, are essential for Schwann cell differentiation, and NAB1 has recently been implicated in photoprotection in C. reinhardtii.
We performed a family based association study in samples from the Family Age Related Maculopathy Study (FARMS) to test for the association of NAB1 with AMD. In all, we genotyped 293 individuals from 34 extended pedigrees. Six tag SNPs, chosen using the Tagger program in HapMap (r2≥0.8, MAF≥0.1) and covering the gene, were tested for association with a power transformed AMD phenotype, calculated from a fifteen point quantitative severity scale. The 15-step AMD scale was derived from stereoscopic fundus photographs of both eyes taken on all available family members. For each SNP, we tested dominant, recessive and additive models of inheritance using the ASSOC program in S.A.G.E. The p-values from the likelihood ratio test are reported.
Using a variance component family-based association analysis model that included sibling effects, 3 SNPs were significantly (p<0.05) associated with the AMD phenotype and 1 SNP approached significance: rs958770 (p=0.002, recessive), rs2293765 (p=0.004, dominant), rs483515 (p=0.04, additive), rs2293765 (p=0.06, additive). Including polygenic effects in the model, SNPs rs958770 (p=0.002) and rs2293765 (p=0.04) remained significant. rs958770 and rs2483515 also showed significance under different models of inheritance (additive and recessive respectively). The significant SNPs are all located within intronic regions of NAB1; rs2293765 is located in an untranslated 5’ region of the gene.
Our analysis indicates that NAB1 shows some association with the AMD phenotype and may contribute to the pathogenesis of AMD. Replication of these findings in additional study groups and the accumulation of further biological lines of evidence is still necessary to confirm our work.
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