Assessing Susceptibility to Age-Related Macular Degeneration With Genetic Markers and Environmental Factors

Chen, Yuhong; Zeng, Junjie; Zhao, Chao; Wang, Kevin; Trood, Elizabeth; Buehler, Jeanette; Weed, Matthew C.; Kasuga, Daniel; Bernstein, Paul S.; Hughes, Guy; Fu, Victoria; Chin, Jessica; Lee, Clara; Crocker, Maureen; Bedell, Matthew; Salasar, Francesca; Yang, Zhenglin; Goldbaum, Michael H.; Ferreyra, Henry; Freeman, William R.; Kozák, Igor; Zhang, Kang

doi:10.1001/archophthalmol.2011.10

Cited by 72 publications

(58 citation statements)

References 32 publications

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“…Previous studies have found that at-risk alleles for AMD are more common in bilaterally affected individuals with AMD, compared with the unilaterally affected group. 18 However, in our analysis of patients with both CNV and GA simultaneously, we have found no statistical significance between GA only and CNV only and patients with concomitant CNV and GA. Therefore, it can be assumed that, based on these known genes analysed, that GA and CNV may fit on a continuum, in that patients with GA will at some point potentially develop CNV and that they are not separate diseases after all.…”

Section: Discussioncontrasting

confidence: 64%

“…17 It has also been demonstrated that CFH confers more risk to the bilaterality of GA whereas HTRA1/LOC387715 contributes more to the bilaterality of CNV. 18 Another subgroup analysis showed a highly significant association with C3 and CNV in both casecontrol groups in the population, whereas the association with C3 and GA was only significant in one group. 13 Therefore, with family history as a significant risk factor for AMD and the discovery of the relation of genetic variants to AMD, it is convincing that genetics has a strong role in the development, type, and prognosis of AMD.…”

Section: Genetics and Amdmentioning

confidence: 90%

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Genetic analysis of simultaneous geographic atrophy and choroidal neovascularization

Grob

Luo

Hughes

et al. 2012

Eye

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Section: Discussioncontrasting

confidence: 64%

Section: Genetics and Amdmentioning

confidence: 90%

Genetic analysis of simultaneous geographic atrophy and choroidal neovascularization

Grob

Luo

Hughes

et al. 2012

Eye

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“…Genetic testing for seven single-nucleotide polymorphisms (SNPs) was performed in all patients as previously described, 36 and the prevalence of the following [alleles] was assessed: CFH-rs1061170…”

Section: Genetic Analysismentioning

confidence: 99%

Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

Filho¹,

Yehoshua²,

Gregori³

et al. 2014

Ophthalmic Surg Lasers Imaging Retina

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BACKGROUND AND OBJECTIVE:To evaluate the change in drusen volume following treatment with eculizumab, a systemic inhibitor of complement component 5. PATIENTS AND METHODS:Single-center, prospective, randomized, double-masked clinical trial. Patients were randomized 2:1 to receive intravenous eculizumab or placebo over 26 weeks. Main outcome measure: decrease in drusen volume of at least 50% at 26-week follow-up. RESULTS:Mean drusen cube root volumes were 0.49 mm and 0.47 mm (P = .64) at baseline and 0.51 mm and 0.42 mm (P = .17) at 26 weeks in the eculizumab and placebo groups, respectively. In the placebo group, one eye had a decrease in drusen volume of at least 50% and two eyes developed neovascularization through 26 weeks. CONCLUSION:Systemic complement inhibition with eculizumab did not significantly reduce drusen volume. Drusen growth was dependent on the number of complement at-risk alleles. Future trials should consider the use of a composite clinical trial endpoint in which efficacy is defined by the treatment's ability to prevent drusen growth, neovascularization, and the formation of geographic atrophy over 1 year.

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“…Advanced age also compromises the endogenous antioxidant capacity of cells, increasing the amount of reactive oxygen species (ROS) (16,17). Thus, even though heterogeneous risk factors have been implicated in photoreceptor degeneration, it is possible that they result in a final common pathway of oxidative stress.A complex interaction between genetic susceptibility and environmental influences governs the onset and severity of photoreceptor disease (18,19). Identifying the mechanism(s) linking these risk factors might help early detection of disease and should aid in future design of efficient and early therapeutic interventions.…”

mentioning

confidence: 99%

“…A complex interaction between genetic susceptibility and environmental influences governs the onset and severity of photoreceptor disease (18,19). Identifying the mechanism(s) linking these risk factors might help early detection of disease and should aid in future design of efficient and early therapeutic interventions.…”

mentioning

confidence: 99%

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

Nagar

Noveral

Trudler

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Gaining mechanistic insight into interaction between causative factors of complex multifactorial diseases involving photoreceptor damage might aid in devising effective therapies. Oxidative stress is one of the potential unifying mechanisms for interplay between genetic and environmental factors that contribute to photoreceptor pathology. Interestingly, the transcription factor myocyte enhancer factor 2d (MEF2D) is known to be important in photoreceptor survival, as knockout of this transcription factor results in loss of photoreceptors in mice. Here, using a mild light-induced retinal degeneration model, we show that the diminished MEF2D transcriptional activity in Mef2d +/− retina is further reduced under photostimulation-induced oxidative stress. Reactive oxygen species cause an aberrant redox modification on MEF2D, consequently inhibiting transcription of its downstream target, nuclear factor (erythroid-derived 2)-like 2 (NRF2). NRF2 is a master regulator of phase II antiinflammatory and antioxidant gene expression. In the Mef2d heterozygous mouse retina, NRF2 is not up-regulated to a normal degree in the face of lightinduced oxidative stress, contributing to accelerated photoreceptor cell death. Furthermore, to combat this injury, we found that activation of the endogenous NRF2 pathway using proelectrophilic drugs rescues photoreceptors from photo-induced oxidative stress and may therefore represent a viable treatment for oxidative stress-induced photoreceptor degeneration, which is thought to contribute to some forms of retinitis pigmentosa and age-related macular degeneration.B lindness due to photoreceptor loss from a number of diseases is a prevalent and devastating condition in the human population. Genetic predisposition and environmental stress play major roles in the incidence and progression of the retinal degeneration. Understanding disease mechanisms and interactions of causative factors should help in the design of treatment strategies. Recent evidence indicates that oxidative stress, contributing to photoreceptor cell death, plays a significant role in the pathophysiology of nonsyndromic retinitis pigmentosa (RP) and possibly age-related macular degeneration (AMD) (1-3). Moreover, light-induced oxidative stress is known to potentiate photoreceptor loss in genetic models mimicking a number of human retinal degenerations (4-11).The oxidizing microenvironment of the retinal pigment epithelium (RPE)-photoreceptor complex has been predominantly attributed to high oxygen demand, abundant polyunsaturated fatty acids, and direct exposure to light, coupled with the adjacent choroidal hemodynamics (12). Light exposure compounded over many years in the presence of photosensitizers may prime photoreceptors and RPE for free radical/oxidative damage (12-14). In some animal models of photoreceptor degeneration, including RP and Leber congenital amaurosis, disease progression is accelerated by exposure to light and slowed by rearing in darkness (3, 15). Advanced age also compromises the endogenous antioxidant ...

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Assessing Susceptibility to Age-Related Macular Degeneration With Genetic Markers and Environmental Factors

Cited by 72 publications

References 32 publications

Genetic analysis of simultaneous geographic atrophy and choroidal neovascularization

Genetic analysis of simultaneous geographic atrophy and choroidal neovascularization

Change in Drusen Volume as a Novel Clinical Trial Endpoint for the Study of Complement Inhibition in Age-related Macular Degeneration

MEF2D haploinsufficiency downregulates the NRF2 pathway and renders photoreceptors susceptible to light-induced oxidative stress

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