Apolipoprotein E Gene and Early Age-Related Maculopathy: The Atherosclerosis Risk in Communities Study

doi:10.1016/j.ophtha.2005.10.048

Ophthalmology

Volume 113, Issue 2, February 2006, Pages 255-259

https://doi.org/10.1016/j.ophtha.2005.10.048 Get rights and content

Objective

To examine the association between the apolipoprotein E (APOE) gene and early age-related maculopathy (ARM) in middle-aged persons.

Design

Population-based cross-sectional study.

Participants

Participants from the Atherosclerosis Risk in Communities Study (n = 10 139; age range, 49–73 years).

Methods

Retinal photography was performed on 1 randomly selected eye, and grading for presence of ARM was carried out using a modification of the Wisconsin ARM Grading System. Early ARM was defined as the presence of either soft drusen alone, retinal pigment epithelial depigmentation alone, or a combination of soft drusen with increased retinal pigment and/or depigmentation. DNA extracted from blood samples of participants were analyzed for common allelic variants of the APOE gene (ϵ2, ϵ3, and ϵ4).

Main Outcome Measures

Presence of early ARM on retinal photographs.

Results

The prevalence of early ARM was similar in participants with different APOE genotypes: ϵ2/ϵ2 (5.9%), ϵ2/ϵ3 (5.2%), ϵ2/ϵ4 (3.2%), ϵ3/ϵ3 (5.2%), ϵ3/ϵ4 (4.9%), and ϵ4/ϵ4 (4.1%). After controlling for age, gender, race, cigarette smoking, and other factors, early ARM was not associated with APOE genotypes, with an odds ratio (OR) of 1.35 (95% confidence interval [CI], 0.54–3.38) for ϵ2/ϵ2 genotype, an OR of 1.06 (95% CI, 0.80–1.40) for ϵ2/ϵ3 genotype, an OR of 0.63 (95% CI, 0.32–1.24) for ϵ2/ϵ4 genotype, an OR of 0.99 (95% CI, 0.80–1.24) for ϵ3/ϵ4 genotype, and an OR of 0.88 (95% CI, 0.47–1.63) for ϵ4/ϵ4 genotype, as compared with ϵ3/ϵ3 genotype (reference). No associations were found for specific early ARM signs or in analyses stratified by age, gender, race, or cigarette smoking status.

Conclusions

These data provide no evidence of a strong association between the APOE gene and early ARM in middle-aged persons. This suggests that APOE is not likely a major determinant of the early stages of ARM in younger people. However, our study does not exclude the possibility of a weaker association or that APOE may influence only the development of late ARM in older populations, as reported in other studies.

Section snippets

Study Population

The Atherosclerosis Risk in Communities (ARIC) study is a population-based cohort study that included 15 792 women and men 45 to 64 years of age at recruitment in 1987 through 1989.¹⁸ The study population was selected by probability sampling from 4 U.S. communities: Forsyth County, NC; Jackson, MS; the suburbs of Minneapolis, MN; and Washington County, MD. The Jackson sample included black persons only; in the other field centers, samples were representative of the populations in these

Results

Characteristics between persons with (n = 531) and without (n = 9608) any ARM are presented in Table 1. In general, persons with any ARM were significantly older, less likely to be black, to have hypertension, and to have higher systolic blood pressure than persons without ARM. Other characteristics were not associated with any ARM status. Because of the small number of persons with late ARM in this middle-aged population (n = 15), subsequent analysis was confined to early ARM signs only.

The

Discussion

The APOE gene has been shown to influence lipoprotein metabolism and has been linked to a variety of neurodegenerative disorders, most notably Alzheimer’s disease.4, 5, 6 Previous studies that have examined a possible relationship between APOE and ARM have focused on late stages of ARM (exudative macular degeneration and geographic atrophy) and on elderly populations.9, 10, 11, 12, 13, 14, 15, 16, 17 Few have been population based.⁹ In general, most of these studies suggest that ϵ4 is

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Earlier studies reported that the presence of the ε4 allele of APOE was inversely associated with late AMD, whereas the ε2 allele may be associated with an increased risk of AMD. Wong et al. (2006) examined the association between the APOE gene and early AMD in the participants of the Atherosclerosis Risk Communities Study and showed that the prevalence of early AMD was not significantly different in participants with different APOE genotypes. So far, it appears that the results of earlier studies using GWAS have not identified genetic loci common to AD and AMD.
Age is a common risk factor for Alzheimer’s disease (AD) and age-related macular degeneration (AMD). Because of the increasing age of the population, these two age-related diseases have recently received a great deal of attention. In addition to age as a risk factor, AD and AMD have many characteristics in common. An important characteristic common to both diseases is the presence of amyloid β (Aβ) in the senile plaques of the AD brain and in the drusen of AMD patients. We have focused on the role of Aβ as a key regulator of the progression from drusen to AMD, and our results have shown that Aβ causes an imbalance of angiogenesis-related factors in the retinal pigment epithelial (RPE) cells. Mice that lack the Aβ-degrading enzyme neprilysin develop RPE degeneration, and the sub-RPE deposits that are formed have features similar to those of AMD in humans. These data suggest that a common pathogenic mechanism might exist between AMD and AD. Thus, therapeutic approaches that have targeted Aβ in patients with AD can also be applied to AMD. In this review, we summarise recent findings on the shared characteristics and perspectives between AMD and AD, beginning with the mechanism of Aβ deposition and including a discussion of Aβ-targeted therapeutic approaches for both AD and AMD.
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Based on the role of ApoE in recycling of cholesterol and lipids for cell-membrane biosynthesis after neuronal injury, these polymorphisms have been speculated to impact retinal membrane renewal and affect macular integrity. Several studies later confirmed a role for ApoE SNP in AMD (Baird et al., 2006; Jun et al., 2005; Kovacs et al., 2007; Schmidt et al., 2002; Souied et al., 1998; Zareparsi et al., 2004), while others found no effect (Kaur et al., 2006; Schmidt et al., 2005; Schultz et al., 2003; Wong et al., 2006). We have also found the association between ApoE112R (E4) and a decreased risk of AMD development, and the underlying mechanisms might involve differential regulation of both CCL2 and VEGF by the ApoE isoforms (Bojanowski et al., 2006).
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Review of the literature related to ARMD and ApoE, using OVID as our main database, led to the development of several theories regarding ApoE ε4’s behavior compared to ε3 and potential explanation of its protective characteristics.
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Manuscript no. 2005-449.

The authors have no proprietary interests.

Carried out as a collaborative study supported by the National Heart, Lung, and Blood Institute, Bethesda, Maryland (contract nos.: N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022); National Institutes of Health, Bethesda, Maryland (grant nos.: HL073366, UR6/CCU617218 [MSB], EYO13939 [TYW, RK]); and Sylvia and Charles Viertel Clinical Investigator Award (TYW).

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Original ArticleApolipoprotein E Gene and Early Age-Related Maculopathy: The Atherosclerosis Risk in Communities Study

Objective

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Study Population

Results

Discussion

Am J Hum Genet

Am J Ophthalmol

J Clin Epidemiol

Ophthalmology

Ophthalmology

Prevalence of age-related macular degeneration in the United States

Arch Ophthalmol

Complement factor H polymorphism in age-related macular degeneration

Science

Complement factor H polymorphism and age-related macular degeneration

Science

Apolipoprotein Echolesterol transport protein with expanding role in cell biology

Science

Apolipoprotein E epsilon4 and incidence of Alzheimer disease in a community population of older persons

JAMA

Apolipoprotein E epsilon4 and the risk of dementia with stroke. A population-based investigation

JAMA

The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics

JAMA

Original Article
Apolipoprotein E Gene and Early Age-Related Maculopathy: The Atherosclerosis Risk in Communities Study