Joint effects of smoking history and APOE genotypes in age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of severe visual impairment in older adults worldwide. Cigarette smoking is one of the most consistently identified environmental risk factors for the disease. Several studies have implicated the apolipoprotein E (APOE) gene as modulating AMD risk. The purpose of this study was to investigate whether APOE genotypes modify the smoking-associated risk of AMD.

Patients with early- and late-stage AMD (n=377) and a group of unrelated ethnically matched controls of similar age (n=198) were ascertained at two sites in the southeastern United States. Smoking history and APOE genotype distribution in cases and controls were compared by multivariable logistic regression.

All measures of smoking history showed a highly significant association with AMD, and odds ratio estimates were consistently higher when only patients with exudative AMD were compared to controls. Main effects of APOE genotypes in the overall analysis did not reach statistical significance. The analysis of exudative AMD patients suggested that the risk increase due to smoking was greatest in carriers of the APOE-2 allele, with genotype-specific odds ratios increasing from 1.9 for APOE-4 carriers (p=0.11) to 2.2 for APOE-3/3 homozygotes (p=0.007) to 4.6 (p=0.001) for APOE-2 carriers, compared to nonsmoking APOE-3/3 individuals. Measures of statistical interaction indicated more than additive, and possibly more than multiplicative, joint effects of APOE and smoking history, however, the interaction was not statistically significant on either scale.

We hypothesize that a history of smoking is a stronger risk factor for exudative AMD in carriers of the APOE-2 allele, compared to carriers of APOE-4 and the most common APOE-3/3 genotype. To further clarify the association of AMD with APOE and smoking history, future studies should consider both factors simultaneously.