Interleukin-8 promoter polymorphism -251A/T is a risk factor for age-related macular degeneration

Goverdhan, Srini; Ennis, Sarah; Hannan, Shabeeba R; Madhusudhana, Krishnappa C; Cree, Angela J.; Luff, A J; Lotery, Andrew

doi:10.1136/bjo.2007.123190

Cited by 69 publications

(50 citation statements)

References 26 publications

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“…We show that MDA adducts, similar to what has been shown following the ingestion of oxidized photoreceptors 23 , have the capacity to induce IL-8 secretion in RPE, which can be blocked by CFH. Increased IL-8 expression correlates with higher incidence of AMD, underlining its important pathogenic role 39 . Therefore, neutralization of MDA adducts by CFH has the potential to limit several pathogenic events in AMD.…”

Section: Discussionmentioning

confidence: 99%

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Weismann

Hartvigsen

Lauer

et al. 2011

Nature

464

453

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Oxidative stress and enhanced lipid peroxidation are linked to many chronic inflammatory diseases, including age-related macular degeneration (AMD). AMD is the leading cause of blindness in Western societies, but its aetiology remains largely unknown. Malondialdehyde (MDA) is a common lipid peroxidation product that accumulates in many pathophysiological processes, including AMD. Here we identify complement factor H (CFH) as a major MDA-binding protein that can block both the uptake of MDA-modified proteins by macrophages and MDA-induced proinflammatory effects in vivo in mice. The CFH polymorphism H402, which is strongly associated with AMD, markedly reduces the ability of CFH to bind MDA, indicating a causal link to disease aetiology. Our findings provide important mechanistic insights into innate immune responses to oxidative stress, which may be exploited in the prevention of and therapy for AMD and other chronic inflammatory diseases.

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Section: Discussionmentioning

confidence: 99%

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Weismann

Hartvigsen

Lauer

et al. 2011

Nature

464

453

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“…A study found that only the presence of the IL-8+781T allele was significantly associated with wet-AMD, disagreeing with another study that only found association for the –251A allele 108 113. Hull et al showed that the functional allele of IL-8 may lie on chromosomes of the −251A/+781T haplotype, and −251A may not be functional 114.…”

Section: Cytokine Gene Polymorphisms In Neovascular Amdmentioning

confidence: 94%

Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy

Dias¹,

Rodrigues

Maia

et al. 2011

British Journal of Ophthalmology

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The neovascular form of age-related macular degeneration (AMD), called wet-AMD or choroidal neovascularisation, begins with damage to the outer retinal cells and retinal pigment epithelium (RPE), which elicits a cascade of inflammatory and angiogenic responses leading to neovascularisation under the macula. Studies showed that oxidative damage, chronic inflammation of the RPE and complement misregulation work at different steps of this disease. After established neovascularisation, several pro- and antiangiogenic agents start to play an important role. Vascular endothelial growth factors (VEGFs) are the most specific and potent regulators of angiogenesis, which are inhibited by intravitreal injections of ranibizumab, bevacizumab, VEGF Trap, pegaptanib sodium and other agents under investigation. Pigment epithelium-derived factor, on the other hand, shows neuroprotective and antiangiogenic activities. Hepatocyte growth factor (HGF) has a mitogenic effect on a wide range of epithelial and endothelial cells, and it is inhibited by an anti-HGF monoclonal antibody. Platelet-derived growth factor is a potent chemoattractant and mitogen for both fibroblasts and retinal RPE cells, which has been inhibited experimentally by VEGF Trap and human anti-platelet-derived growth factor-D monoclonal antibody. Fibroblast growth factor-2 has pleiotropic effects in different cell and organ systems, and it is blocked by anti-FGF antibodies, with a greater benefit regarding antiangiogenesis when combined treatment with anti-VEGF is performed. Tumour necrosis factor alpha is expressed in the retina and the choroid, and its blockade in choroidal neovascularisation includes the use of monoclonals such as infliximab. This paper reviews the most important cytokines involved in the pathogenesis of wet-AMD, with emphasis on potential combined therapies for disease control.

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“…27, 28 However, not all studies have confirmed this association 29, 30 and different studies have identified distinct polymorphisms that may be associated with AMD. 31 Polymorphisms in the genes encoding the chemokine receptor CCR3 32 and chemokine CXCL8 (also known as IL-8), 33, 34 which have been implicated in angiogenesis, 35, 36 have also been associated with AMD. Therefore, AMD has been associated with genetic variants of various inflammatory molecules perhaps suggesting that several inflammatory pathways can lead to the same clinical disease.…”

Section: Immunogenetics Of Amdmentioning

confidence: 99%

Inflammatory Mechanisms of Age-related Macular Degeneration

Knickelbein

Chan

Sen

et al. 2015

International Ophthalmology Clinics

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Interleukin-8 promoter polymorphism -251A/T is a risk factor for age-related macular degeneration

Abstract: The pro-inflammatory homozygous IL8 -251AA genotype is an important risk factor for AMD. This may have implications for future therapy with biological agents that could target this cytokine.

Cited by 69 publications

References 26 publications

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Complement factor H binds malondialdehyde epitopes and protects from oxidative stress

Cytokines in neovascular age-related macular degeneration: fundamentals of targeted combination therapy

Inflammatory Mechanisms of Age-related Macular Degeneration

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