Association of Apolipoprotein E Alleles with Susceptibility to Age-Related Macular Degeneration in a Large Cohort from a Single Center

Zareparsi, Sepideh; Reddick, Adam C.; Branham, Kari; Moore, Kathryn B.; Jessup, Laurie; Thoms, Susan; Smith-Wheelock, Michael; Yashar, Beverly M.; Swaroop, Anand

doi:10.1167/iovs.03-1253

Cited by 132 publications

(87 citation statements)

References 35 publications

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“…Interestingly, the E4 allele has been reported by several independent groups as being significantly less prevalent among AMD cases when compared with the corresponding control populations [Klaver et al, 1998a;Souied et al, 1998;Simonelli et al, 2001;Baird et al, 2004;Zareparsi et al, 2004]. The E4 polymorphism is associated with a protective effect against AMD, while the E2 allele is weakly associated with a slightly increased risk for developing late AMD (see our meta-analysis).…”

Section: Introductionsupporting

confidence: 49%

“…Investigators have attempted to determine the role of ApoE in AMD development and pathogenesis [Klaver et al, 1998a;Souied et al, 1998;Baird et al, 2004;Zareparsi et al, 2004]. Interestingly, the E4 allele has been reported by several independent groups as being significantly less prevalent among AMD cases when compared with the corresponding control populations [Klaver et al, 1998a;Souied et al, 1998;Simonelli et al, 2001;Baird et al, 2004;Zareparsi et al, 2004].…”

Section: Introductionmentioning

confidence: 99%

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An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Bojanowski

Shen

Chew

et al. 2006

Environ and Mol Mutagen

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Age-related macular degeneration (AMD) is the leading cause of visual impairment and blindness among the elderly in Western countries. Genetic factors, age, cigarette smoking, nutrition, and exposure to light have been identified as AMD risk factors. In this study, we investigated the association between ApoE C112R/R158C single nucleotide polymorphisms (which determine the E2, E3, and E4 isoforms) and age-related macular degeneration (AMD), and the mechanism underlying the association. Genomic DNA was extracted from 133 clinically screened controls, 94 volunteers with a younger mean age, 120 patients with advanced AMD, and 40 archived ocular AMD slides for single nucleotide polymorphism typing. The effects of recombinant ApoE isoforms on CCL2 (a chemokine), CX3CR1 (a chemokine receptor), and VEGF (a cytokine) expression in cultured human retinal pigment epithelium (RPE) cells were tested and serum cholesterol profiles of the clinically screened subjects were analyzed. ApoE112R (E4) distribution differed significantly between AMD patients and controls. ApoE112R allele frequency was 10.9% in the AMD group when compared with 16.5% in the younger controls and 18.8% in the clinically screened controls. The pathologically diagnosed archived AMD cases had the lowest allele frequency of 5%. No significant differences in ApoE158C (E2) distribution were observed among the groups. A meta-analysis of 8 cohorts including 4,289 subjects showed a strong association between AMD and 112R, but not 158C. In vitro studies found that recombinant ApoE suppresses CCL2 and VEGF expression in RPE cells. However, the E4 isoform showed more suppression than E3 in both cases. These results further confirm the association between ApoE112R and a decreased risk of AMD development. The underlying mechanisms may involve differential regulation of both CCL2 and VEGF by the ApoE isoforms.

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Section: Introductionsupporting

confidence: 49%

Section: Introductionmentioning

confidence: 99%

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Bojanowski

Shen

Chew

et al. 2006

Environ and Mol Mutagen

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“…In particular, several investigators have suggested an association between ApoE and various diseases, including Alzheimer disease (AD), atherosclerosis, and AMD. 22,23,100 Abalain et al investigated the association between AMD and serum levels of lipoproteins and lipoparticles. 1 They found that there was no difference in serum ApoA-I and ApoB levels between AMD patients and controls.…”

Section: Apolipoproteinsmentioning

confidence: 99%

“…A study by Zareparsi et al in 2004 demonstrated a significant association between the 34 allele and AMD in a large cohort of subjects, where this allele was found to be protective against AMD. 100 This particular study examined the 34 allelic distribution in sporadic and familial cases of AMD (632 affected patients versus 206 control subjects). The frequency of the 34 allele was found to be significantly lower in subjects with AMD.…”

Section: Apo 34 Allele Status and Amdmentioning

confidence: 99%

“…74 We have referred to the growing body of evidence suggesting that the 34 allele protects against AMD, reflected in the significantly reduced prevalence of this allele among sufferers of AMD. 4,47,79,84,100 It is possible, therefore, that the putative protective effect of the 34 allele against AMD is attributable, at least in part, to the role its phenotypic expression (ApoE4) plays in the transport and delivery of the macular carotenoids to the retina, and to their stabilization within the retina.…”

Section: Simonelli Et Al 2001 79mentioning

confidence: 99%

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Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

Loane

Nolan

O'Donovan

et al. 2008

Survey of Ophthalmology

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Abstract. Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population in the western world. The etiology and pathogenesis of this disease remain unclear. However, there is an increasing body of evidence supporting the hypothesis that the macular pigment carotenoids, lutein and zeaxanthin, play an important role in protection against AMD, by filtering out blue light at a pre-receptoral level, or by quenching free radicals. Lutein and zeaxanthin are dietary xanthophyll carotenoids, which are delivered to the retina via plasma lipoproteins. The biological mechanisms governing retinal capture and accumulation of lutein and zeaxanthin, to the exclusion of other carotenoids, are still poorly understood. Although these mechanisms remain unclear, it is possible that selective capture of these carotenoids is related to lipoprotein, or apolipoprotein, function and profile. Xanthophyll-binding proteins appear to play an important role in the retinal capture of the xanthophyll carotenoids. The Pi isoform of GSTP1 has been isolated as a specific binding protein for zeaxanthin. The binding protein responsible for retinal uptake of lutein remains elusive. This article reviews the literature germane to the mechanisms involved in the capture, accumulation and stabilization of lutein and zeaxanthin by the retina, and the processes involved in their transport in serum. (Surv Ophthalmol 53:68--81, 2008 The central retina, known as the macula, is responsible for central and color vision because of its high concentration of cone photoreceptors. The macula is characterized by a yellow color, attributable to the presence of macular pigment. 81 Macular pigment (MP) is composed of lutein and zeaxanthin, two hydroxycarotenoids, which are entirely of dietary origin. 17 The concentration of MP peaks at the center of the macula, known as the fovea, where zeaxanthin is the dominant carotenoid. In contrast, lutein dominates in the parafoveal region. 16,82 Dietary sources 68

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A Clinician's View of the Molecular Genetics of Age-Related Maculopathy

Gorin¹

2007

Arch Ophthalmol

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Association of Apolipoprotein E Alleles with Susceptibility to Age-Related Macular Degeneration in a Large Cohort from a Single Center

Abstract: The association between the APOE-epsilon4 allele and a reduced risk of AMD was established in a large cohort with sufficient statistical power. How distinct APOE alleles affect AMD susceptibility warrants further investigation.

Cited by 132 publications

References 35 publications

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

A Clinician's View of the Molecular Genetics of Age-Related Maculopathy

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