APOE Variants Associated With a High Risk of Age-Related Macular Degeneration

Ruth Frikke-Schmidt, MD, DMSc

New research published in JAMA Ophthalmology suggests structural genetic variations in apolipoprotein E (APOE) may be associated with a risk of age-related macular degeneration (AMD).

Although previously reported to have a protective effect against Alzheimer disease, the APOE ε2/ ε3/ε4 variant led to a significant linearly increasing trend for risk of AMD from ε4 to ε2. Rare variations associated with low plasma apolipoprotein E (apoE) were associated with reduced risk (ε4) and rare variations associated with high plasma apoE were associated with increased risk (ε2) of AMD.

“These findings highlight that structural variation in APOE beyond the ε2 and ε4 alleles are important for risk of AMD in a general population setting of White individuals of European ancestry,” wrote study author Ruth Frikke-Schmidt, MD, DMSc, Department of Clinical Biochemistry, Rigshospitalet.

High-income countries are shown to struggle with AMD as the leading cause of irreversible-late onset blindness. The association of the spectrum of rare and common variation in the APOE gene with risk of AMD in the general population remains unknown, further cementing it as an important area of study.

Frikke-Schmidt and colleagues addressed the association in White individuals of European ancestry using 2 large general populations in the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS). They performed population-based sequencing in 10,369 individuals from the CCHS and genotyped 9 variants with a frequency of at least 2 per 10,369 in 95,177 individuals from the CGPS. Individuals were followed from inclusion at the time of blood sampling to occurrence of event, death, emigration, or on the last update of the registries (December 7, 2018).

In order to test whether genetic variants in APOE were associated with risk of AMD, investigators used Cox regression models multifactorially adjusted for known biologically relevant risk factors and markers of lifestyle. The study exposure was APOE status and the direct gene product in plasma, apoE, was measured in all participants.

Among the individuals in the CCHS, 164 developed any AMD, including 123 with neovascular AMD and 164 with non neovascular AMD during follow-up. For the individuals in the CGPS, 1575 developed any AMD, including 1109 with neovascular AMD and 911 with non neovascular AMD.

When sequencing the APOE gene in the CCHS, investigators identified 27 rare variants. The 9 amino acid–changing variants with frequencies of at least 2 per 10,369 were genotyped in the CGPS. The allele frequencies for the 9 rare variants ranged from 0.01% to 0.4%.

Data show geometric mean values of plasma apoE levels for the 6 common APOE ε2/ε3/ε4 genotypes decreased from 8.6 mg/dL for ε22, to 5.5 mg/dL for ε32, to 5.1 mg/dL for ε42, to 4.0 mg/dL for ε33, to 3.6 mg/dL for ε43, and to 2.9 mg/dL for ε44 (P for trend < .001).

Compared with the common ε33 variant, the risk of any AMD was lower in participants with ε44 (adjusted hazard ratio [aHR], 0.66; 95% CI, 0.45 - 0.96) and ε43 (aHR, 0.80; 95% CI, 0.71 - 0.90) genotypes and higher in the ε32 (aHR, 1.15; 95% CI, 1.00 - 1.31) genotype.

Individuals heterozygous for Gly145Asp had increased risk of any AMD (aHR, 3.53; 95% CI, 1.14 - 10.96) compared to noncarriers. The same was observed for participants heterozygous for Arg154Cys (aHR, 4.52; 95% CI, 1.13 - 18.13).

Investigators noted the findings were similar after further adjustments for lipids, lipoproteins, and apolipoproteins, as well as adjustment for the APOE ε2/ε3/ε4 variant. When combining all common and rare structural variants in a weighted allele score, the risk of all AMD and non-neovascular AMD increased with genetically higher plasma apoE.

The risk for any AMD per 1-mg/dL genetic increase of plasma apoE were similar after multifactorial adjustment (aHR, 1.12; 95% CI, 1.05 - 1.19), further adjustment for APOE ε2/ε3/ε4 (aHR, 1.82; 95% CI, 1.20 - 2.76), and in a model for individuals with ε33 only (aHR, 1.77; 95% CI, 1.14 - 2.75).

The study, “The Associations of Alzheimer Disease-Protective APOE Variants With Age-Related Macular Degeneration,” was published in JAMA Ophthalmology.