Structural variation in APOE beyond ε2/ε3/ε4 variants may be important for risk of AMD: JAMA

ApoE plays a central role in plasma clearance of lipoprotein particles by serving as a ligand for members of the low-density lipoprotein (LDL) receptor family. Not only plasma levels of apoE, but also levels of other lipids and lipoproteins are affected by the well-known APOE variant, which is a combination of 2 genetic variants giving rise to 6 common APOE genotypes: ε22, ε32, ε33, ε42, ε43, and ε44.

apoE is an essential apolipoprotein in cerebral cholesterol metabolism: the ε4 allele is a well-known genetic risk factor for Alzheimer disease and ε4 also plays a role in vascular dementia and cerebrovascular disease and appears important for immune responses and longevity. Interestingly, the APOEε2/ε3/ε4 variant has been reported to be associated with risk of AMD, whereas the ε4 allele has been suggested to be associated with reduced risk and the ε2 allele with increased risk in a few small studies. The APOE region has also been identified as a genomic signal in genome-wide association studies of AMD.

The association of the entire spectrum of rare and common variation in the APOE gene with risk of AMD in the general population is not known. To address this question in White individuals of European ancestry, authors Katrine L. Rasmussen and team used 2 large general population cohorts, the Copenhagen City Heart Study (CCHS) and the Copenhagen General Population Study (CGPS), and performed population-based sequencing in 10369 individuals from the CCHS and further genotyped 9 variants with a frequency of at least 2 per 10369 in 95 177 individuals from the CGPS.

Participants were followed from study inclusion at the time of blood sampling to occurrence of event, death, emigration, or December 7, 2018, whichever came first. For participants in CCHS, the APOE gene was sequenced, and 9 variants with a heterozygote frequency of at least 0.0002 were genotyped in the CGPS. Observers were masked to patient groupings. Data were analyzed from March to September 2021. The exposure was APOE status, and the direct gene product in plasma, apoE levels, was measured in all participants.

A total of 1,05,546 participants were included. Compared with participants with the common ε33 genotype, risk of AMD was lower in participants with ε44 (multifactorially adjusted hazard ratio [aHR], 0.66) and ε43 (aHR, 0.80) genotypes and higher in the ε32 (aHR, 1.15) genotype. Compared with non carriers, risk of AMD was higher for participants with Gly145Asp (aHR, 3.53) and Arg154Cys (aHR, 4.52) heterozygotes.

Results were similar after further adjustment for lipid traits and after adjustment for the APOE ε2/ε3/ε4 variant. Combining all common and rare structural variants in a weighted allele score, risk of AMD per 1-mg/dL genetically higher plasma apoE was increased in the adjusted model (aHR, 1.12), the adjusted model plus APOE ε2/ε3/ε4 status (aHR, 1.82), and the adjusted model in individuals with the ε33 genotype only (aHR, 1.77).

This large, prospective cohort study including gene sequencing of 10,369 individuals and genotyping of 9 selected variants in 95,177 additional individuals found that the APOE ε2/ ε3/ε4 variant was associated with a significant linearly increasing trend for risk of AMD from ε4 to ε3 to ε2, and that rare variations associated with low plasma apoE, like ε4, were associated with a reduced risk, while rare variations associated with high plasma apoE, like ε2, were associated with increased risk 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. This study demonstrated a clear protective association of ε4 against AMD, in line with previous studies reporting a reduced risk for the ε4 allele and a decreased frequency of ε4 in individuals with AMD vs control individuals. Authors also found an increased risk of AMD for ε32 carriers, supporting previous observations of an increased frequency of the ε2 allele in individuals with AMD vs control individuals.

Source: Katrine L. Rasmussen, MD, PhD; Anne Tybjærg-Hansen, MD, DMSc; Børge G. Nordestgaard, MD, DMS; JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2022.4602