Extremely Discordant Sibpair Multivariate Analyses of Apoe Alleles, Smoking, Hypertension and Hypercholesterolemia Shows That Smoking Is the Strongest Risk Factor Associated With Neovascular Age–Related Macular Degneration

Abstract

Abstract: : Purpose: To examine the interaction between alleles of the apolipoprotein E (apoE) gene and other reported factors that may be associated with risk for neovascular age–related macular degeneration (AMD). Methods: We ascertained extremely discordant sibpairs in which one member (the index patient) had the neovascular form of AMD and another member (the unaffected sib) had no sign of AMD at the same age or older. If more than one unaffected sib were available, the oldest one was chosen for this study. To date, we have epidemiological and DNA results from 57 such sibpairs, with average age of index patients = 71.6, SD = 7.2, and the average unaffected sib age = 76.0, SD 7.0. Disease status was confirmed by fundus photography of every participant except in 4 cases where a home visit was conducted. apoE genotypes were determined through agarose gel electrophoresis of DNA fragments resulting from HhaI digestion and or through direct sequencing. Logistic regression analysis was used to search for interactions between the E2, E3, and E4 alleles of the apoE gene and hypertension status, hypercholesterolemia status, gender, and pack years of smoking (measured continuously). Subjects were recorded as having hypertension or hypercholesterolemia if they reportedly took medication for one or both of these conditions for at least 6 months prior to time of diagnosis of AMD in the index patient. Results: We found a statistically significant association between the E4 allele of apoE gene and the neovascular form of AMD (n = 11 informative pairs, p =0.02, using McNemar’s test). However, when we used a multivariate model to control for hypertension status, hypercholesterolemia status, gender, and pack years of smoking, the E4 allele was no longer significantly associated with decreased risk of neovascular AMD, although the association was nearly significant (p=0.08). By multivariate analysis, smoking was the only risk factor found to be significantly associated with increased risk of neovascular AMD (by almost 2% per pack year, p = 0.04). Conclusions: Multivariate analysis showed that smoking appears to be a risk factor for neovascular AMD not apoE geneotype, hypertension or hypercholesterolemia.

Keywords: age-related macular degeneration • neovascularization • gene modifiers