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Madeleine K. Adams, Luba Robman, Julie Simpson, Robyn H. Guymer, Khin Zaw Aung, Galina Makeyeva, Paul N. Baird; APOE Gene-environment Interaction In AMD Risk. Invest. Ophthalmol. Vis. Sci. 2011;52(14):5236.
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To explore APOE e2, e3 and e4 allele frequencies and their association with AMD risk in a large age-matched case control study in Australia, and assess if associations are modified by environmental factors including age, sex and smoking.
4616 participants (2308 cases of early or late AMD and 2308 controls individually matched on sex, age and country of birth) were selected from the Melbourne Collaborative Cohort Study of 22287 participants. Fundus photographs were graded for AMD. APOE allele status was determined and genotypes were grouped into e3e3 (reference group), e2e2 e2e3 e2e4, and e4e4 e3e4. Estimates of the odds ratios (OR) were determined using conditional logistic regression.
We confirmed that APOE is an AMD risk gene, with the e2 risk allele strongly associated with disease. The associations were dependent on sex, age and smoking status. In men, age modified the association (P-value for interaction 0.03) with no association seen with the e2 allele below the median age of 72 (OR 1.11 95%CI 0.75-1.64 P=0.6) but in those above age 72, those with one or more e2 alleles were twice as likely to have AMD (2.01 95%CI 1.33-3.03 P<0.001). Significant effect modification in men was observed for smoking (P=0.04) where the direction of effect of e4 was positive in non smokers and negative in former smokers. For women with one or more e2 alleles a 25% increase risk of AMD was observed, independent of age, (OR 1.25 95%CI 1.01-1.56 P=0.04) whereas the e4 allele had a borderline significant protective association (OR 0.82 95%CI 0.68-1.0 P=0.06).
This is the first single study to be sufficiently powered to explore gene-environment interactions in APOE and AMD. We have demonstrated significant effect modification by age and smoking on the effect of APOE, which may explain contradictory results found in previous studies that did not stratify on these variables.
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