Evidence of association of APOE with age-related macular degeneration: a pooled analysis of 15 studies

Abstract

Age-related macular degeneration (AMD) is the most common cause of incurable visual impairment in high-income countries. Previous studies report inconsistent associations between AMD and apolipoprotein E (APOE), a lipid transport protein involved in low-density cholesterol modulation. Potential interaction between APOE and sex, and smoking status has been reported. We present a pooled analysis (n = 21,160) demonstrating associations between late AMD and APOε4 (odds ratio [OR] = 0.72 per haplotype; confidence interval [CI]: 0.65-0.74; P = 4.41×10(-11) ) and APOε2 (OR = 1.83 for homozygote carriers; CI: 1.04-3.23; P = 0.04), following adjustment for age group and sex within each study and smoking status. No evidence of interaction between APOE and sex or smoking was found. Ever smokers had significant increased risk relative to never smokers for both neovascular (OR = 1.54; CI: 1.38-1.72; P = 2.8×10(-15) ) and atrophic (OR = 1.38; CI: 1.18-1.61; P = 3.37×10(-5) ) AMD but not early AMD (OR = 0.94; CI: 0.86-1.03; P = 0.16), implicating smoking as a major contributing factor to disease progression from early signs to the visually disabling late forms. Extended haplotype analysis incorporating rs405509 did not identify additional risks beyond ε2 and ε4 haplotypes. Our expanded analysis substantially improves our understanding of the association between the APOE locus and AMD. It further provides evidence supporting the role of cholesterol modulation, and low-density cholesterol specifically, in AMD disease etiology.

Figure 1

Analysis of APOE diplotype and late AMD. Late AMD includes categories GA, NV and GANV. Odds ratios against the reference (ε3ε3), 95% confidence intervals and P values were adjusted for age-group and gender within each study and for smoking status (ever versus never smoker).

Figure 2

Odds ratios and confidence intervals for late AMD calculated for one copy of ε4 by study (additive model with adjustment for age-group and gender within each study and for smoking status). Meta-analyses tests for heterogeneity of ε4 effects between studies were not significant either for late AMD (χ²=15.0, df=14, P=0.38) or for any AMD sub-phenotype (NV:χ²=12.0, df=14, P=0.61; GA: χ²=9.90, df=14, P=0.77; GANV: χ²=15.2, df=14, P=0.37; eAMD:χ²=19.4, df=14, P=0.15).

Figure 3

Odds ratio associated with (a)ε2 diplotype (recessive model) and (b) ε4 haplotype and late AMD (GA, NV and GANV samples combined) were estimated after adjustment for age-group and gender within each study and smoking status. (a) ε2 diplotype (recessive model): OR=1.83; CI: 1.04–3.23; P=0.04 (Table 2). (b) ε4 per haplotype (additive model): OR=0.72; CI: 0.65–0.79; P=4.41 × 10⁻¹¹ (Table 2). No significant heterogeneity in associated risk was detected between each late AMD sub-phenotype (ε2ε2: χ²=0.35, df=2, P=0.84; ε4: χ²=4.33, df=2, P=0.11) or between all late AMD and eAMD ((ε2ε2: χ²=0.01, df=1, P=0.91; ε4: χ²=2.52, df=1, P=0.11).

Figure 3

Odds ratio associated with (a)ε2 diplotype (recessive model) and (b) ε4 haplotype and late AMD (GA, NV and GANV samples combined) were estimated after adjustment for age-group and gender within each study and smoking status. (a) ε2 diplotype (recessive model): OR=1.83; CI: 1.04–3.23; P=0.04 (Table 2). (b) ε4 per haplotype (additive model): OR=0.72; CI: 0.65–0.79; P=4.41 × 10⁻¹¹ (Table 2). No significant heterogeneity in associated risk was detected between each late AMD sub-phenotype (ε2ε2: χ²=0.35, df=2, P=0.84; ε4: χ²=4.33, df=2, P=0.11) or between all late AMD and eAMD ((ε2ε2: χ²=0.01, df=1, P=0.91; ε4: χ²=2.52, df=1, P=0.11).

Figure 4

Odds ratios and confidence intervals for smoking status by (a) AMD phenotype and by (b) study for late AMD only. Late AMD is composed of all GA, NV and GANV samples combined. Smoking status was categorized as ever smoker versus never smoker. ORs were estimated and adjusted for age-group and gender within each study, for smoking status and APOE diplotype (late AMD OR: 1.50; CI: 1.36–1.65: P=7.92 × 10⁻¹⁷). Smoking status was not significantly associated with increased risk of eAMD (OR=0.94; CI: 0.86–1.03; P=0.16). Tests for heterogeneity in smoking effect between each late AMD sub-phenotype were not significant, but a difference in the effect of smoking was detected between all late AMD and eAMD. Significant heterogeneity in smoking effect between studies was detected for late AMD, NV, but not for GA.

Figure 4

Odds ratios and confidence intervals for smoking status by (a) AMD phenotype and by (b) study for late AMD only. Late AMD is composed of all GA, NV and GANV samples combined. Smoking status was categorized as ever smoker versus never smoker. ORs were estimated and adjusted for age-group and gender within each study, for smoking status and APOE diplotype (late AMD OR: 1.50; CI: 1.36–1.65: P=7.92 × 10⁻¹⁷). Smoking status was not significantly associated with increased risk of eAMD (OR=0.94; CI: 0.86–1.03; P=0.16). Tests for heterogeneity in smoking effect between each late AMD sub-phenotype were not significant, but a difference in the effect of smoking was detected between all late AMD and eAMD. Significant heterogeneity in smoking effect between studies was detected for late AMD, NV, but not for GA.