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J. P. SanGiovanni, T. E. Clemons, E. Agron, A. Vora, E. Y. Chew; Advanced AMD and Variants in Elements of Omega-3 Lipid-Associated Signaling Pathways. Invest. Ophthalmol. Vis. Sci. 2009;50(13):3096.
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© ARVO (1962-2015); The Authors (2016-present)
To determine if common variants in genes encoding elements of the LCPUFA-asociated Akt/PI3K, cytochrome P450 (CYP), and peroxisome proliferator-activated (PPAR)/retinoid X (RXR) pathways are jointly associated with risk of developing advanced AMD.
We used NCBI, Ensembl, and LIPIDMAPS resources to develop catalogs of genes encoding structures impacted by or impacting LCPUFA-associated enzymatic activity, metabolic processes, and signaling pathways. We identified 2274 Akt/PI3K, 448 CYP, 586 PPAR/RXR variants in regions of these genes in a genome-wide association dataset from The Age-Related Eye Disease Study (AREDS). Our final sample contained 367 people with advanced AMD and 141 healthy elderly AMD-free people. Professional graders ascertained AMD annually from stereoscopic fundus photographs with a validated method from this multicenter 12-year natural history study. Gene variants with at least 95% complete data, in Hardy-Weinberg equilibrium, and associated with advanced AMD at P-values ≤ 0.01 in age-, sex-, and smoking-adjusted logistic regression models were entered into joint action models and reduced to parsimony through a stepwise selection procedure. We computed predicted probabilities of sight-treating AMD from these models.
All three gene set pathways showed strong predictive utility for identifying approximately 8-of-10 people with advanced AMD on the basis of genomic data alone. The final model for Akt/PI3K was based on 11 SNPs from 11 genes distributed across the genome (odds ratio [OR] = 3.5, 95% CI = 2.8-4.7, P ≤ 3.1x10-21). The model for CYPs was based on 9 SNPs from 9 genes (OR = 3.2, 95% CI = 2.5-4.2, P ≤ 6.8x10-18). The PPAR/RXR model was based on 14 SNPs from 13 genes (OR = 4.2, 95% CI = 3.2-5.5, P ≤ 6.8x10-24). The lowest P-value from 1500 simulations on randomly selected sets of SNPs from our complete 100K array panel was 1.2x10-9, suggesting these results were unlikely due to random sampling error.
The joint effects of genomic variants encoding elements of Akt/PI3K, CYP450, and PPAR/RXR pathways had predictive utility in identifying people with advanced AMD in AREDS. Our findings offer novel insights on the relationship of dietary ω-3 LCPUFA intake with advanced AMD as all 3 signaling pathways are impacted by these lipids.
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