Association of genetic variants at CETP, AGER, and CYP4F2 locus with the risk of atrophic age‐related macular degeneration

Liutkevičienė, Rasa; Vilkeviciute, Alvita; Kriauciuniene, Loresa; Banevičius, Mantas; Būdienė, Brigita; Stanislovaitienė, Daiva; Žemaitienė, Reda; Deltuva, Vytenis Pranas

doi:10.1002/mgg3.1357

Cited by 5 publications

(6 citation statements)

References 62 publications

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“…Besides, cytochrome P450 (CitP450) is an enzyme that plays a crucial role in the metabolism of long-chain polyunsaturated fatty acids (LCPUFAs) into epoxydocosapentaenoic acids and epoxyeicosatetraenoic acids that ultimately regulate vascular function, and it has been suggested that CitP450 monooxygenase plays a vital role in inhibiting nAMD via LCPUFA metabolites [45]. Polymorphisms in several cholesterol pathway genes including apolipoprotein E (APOE), ATP Binding Cassette Subfamily A Member 1 (ABCA1), lipase C (LIPC), Advanced Glycosylation End-Product Specific Receptor (AGER), and cholesterol ester transferase (CETP) genes have been found to be associated with the disease [46][47][48]. LIPC and ABCA1 associate with intermediate and large drusen [49].…”

Section: Dysfunction Of Proteostasis and Lipid Homeostasismentioning

confidence: 99%

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

et al. 2022

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Age-related macular degeneration (AMD) is a complex, multifactorial, progressive retinal disease that affects millions of people worldwide and has become the leading cause of visual impairment in developed countries. The disease etiopathogenesis is not understood fully, although many triggers and processes that lead to dysfunction and degeneration of the retinal pigment epithelium (RPE) already have been identified. Thus, the lack of cellular control of oxidative stress, altered proteostasis, dysfunction of lipid homeostasis, and mitochondrial dysfunction form an internal feedback loop that causes the RPE to fail and allows accumulation of abnormal misfolded proteins and abnormal lipids that will form drusen. An inadequate antioxidant response, deficits in autophagy mechanisms, and dysregulation of the extracellular matrix (ECM) help to increase the deposition of abnormal drusen material over time. The drusen then act as inflammatory centers that trigger chronic inflammation of the subretinal space in which microglia and recruited macrophages also are involved, and the complement system is a key component. Choriocapillaris degeneration and nutritional influences are also classic elements recognized in the AMD pathophysiology. The genetic component of the disease is embodied in the recognition of the described risk or protective polymorphisms of some complement (mainly complement factor H, CFH) and ECM related genes (mainly age-related maculopathy susceptibility 2/high-temperature requirement protein A1, ARMS2/HTRA1). Carriers of the risk haplotype at ARMS2/HTRA1 have a higher risk of developing late AMD at a younger age. Finally, gut microbiota and epigenetics may play a role in modulating the progression to advanced AMD with the presence of local inflammatory conditions. Because of multiple implicated processes, different complex combinations of treatments will probably be the best option to obtain the best visual results; they in turn will differ depending on the type and spectrum of disease affecting individual patients or the disease stage in each patient at a specific moment. This will undoubtedly lead to personalized medicine for control and hopefully a future cure, which necessitates the continued unraveling of all the processes involved in the pathogenesis of AMD that must be understood to devise the combinations of treatments for different concurrent or subsequent problems.

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Section: Dysfunction Of Proteostasis and Lipid Homeostasismentioning

confidence: 99%

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

et al. 2022

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“…Variants in genetic loci within other regions are additional considerations when assessing risk. Particularly, gene polymorphisms related to the complement cascade (C2, C3, complement factor B [CFB], and complement factor I [CFI]) and lipid metabolism (apolipoprotein E [APOE], cholesterol ester transfer protein (CETP), and lipase C [LIPC]) modulate disease incidence and progression [ 15 , 20 , 31 , 32 , 33 ]. Summarily stated, these variants emphasize the role of local inflammatory processes in the pathogenesis of dry AMD and its progression to GA.…”

Section: Risk Factorsmentioning

confidence: 99%

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration

Patel

Land

et al. 2022

Biomedicines

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Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss in the elderly population. AMD is characterized in its late form by neovascularization (wet type) or geographic atrophy of the retinal pigment epithelium cell layer (dry type). Regarding the latter type, there is growing evidence supporting an association between the pathophysiology of dry AMD and key proteins in the complement cascade. The complement cascade works as a central part of the innate immune system by defending against foreign pathogens and modified self-tissues. Through three distinct pathways, a series of plasma and membrane-associated serum proteins are activated upon identification of a foreign entity. Several of these proteins have been implicated in the development and progression of dry AMD. Potential therapeutic targets include C1q, C3, C5, complement factors (B, D, H, I), membrane attack complex, and properdin. In this review, we provide an understanding of the role of the complement system in dry AMD and discuss the emerging therapies in early phase clinical trials. The tentative hope is that these drugs may offer the potential to intervene at earlier stages in dry AMD pathogenesis, thereby preventing progression to late disease.

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“…The retina has a high metabolic activity and concentration of polyunsaturated fatty acids in photoreceptors that promotes pro-oxidative and pro-inflammatory pathways [8]. The complement pathway plays a role in the clearance of cellular debris and apoptotic cells.…”

Section: Advances In Risk Factor Classification and Positive Determin...mentioning

confidence: 99%

“…The rare variants were all found to be on or near complement genes and the protective variants were involved in complement activation and lipid metabolism [3,7]. The receptor for advanced glycation end products, involved in cascade of processes in the aging mechanism (AGER) was also found to have a higher risk of atrophic ARMD [8]. Looking at environmental, demographic, genetic, molecular and phenotypic risk factors is important to developing new treatment modalities.…”

Section: Advances In Defining Genetic Mutations Associated With Geogr...mentioning

confidence: 99%

“…Multiple pathways of pathogenesis have been suggested, however, the exact mechanism is not yet fully understood. Complement activation, lipid metabolism, retinal oxidative stress, drusen buildup, visual cycle and extracellular matrix modulation are currently of interest [7,8]. Herein, we will provide an overview and discussion of the status of GA including advances in mechanism of pathogenesis, diagnosis, classification and treatment modalities.…”

Section: Introductionmentioning

confidence: 99%

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Geographic atrophy: where we are now and where we are going

Richard

Duker

Reichel

2021

Current Opinion in Ophthalmology

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Purpose of reviewAge-related macular degeneration (AMD) affects a significant percentage of the elderly population and end-stage disease classified by either geographic atrophy (GA) or neovascular AMD (nvAMD) is one of the leading causes of vision loss worldwide. Despite the fact that there are currently treatments for nvAMD, there are no treatments in practice to prevent disease onset or progression of GA. This topic is at the forefront of ophthalmic research demonstrated by the recent advances in disease characterization, genetic and environmental risk factor classification, biomarker discovery and mechanism of pathogenesis categorization. There are also numerous clinical treatment trials underway, targeting proposed pathways and biomarkers associated with GA that are promising. Recent findingsWith several clinical trials of potential treatments underway and numerous recent publications on disease diagnosis and classification, the understanding of GA pathogenesis has increased substantially. Although the exact mechanism of pathology is still elusive, recent literature has highlighted the utilization of current and new ophthalmic imaging modalities and discovery of objective and functional markers that can lead to earlier diagnosis and treatment. SummaryHerein, we will provide an overview and discussion of the current status of GA including advances in mechanism of pathogenesis, diagnosis, classification and current treatment modalities.

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Association of genetic variants at CETP, AGER, and CYP4F2 locus with the risk of atrophic age‐related macular degeneration

Cited by 5 publications

References 62 publications

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

Pathophysiology of Age-Related Macular Degeneration: Implications for Treatment

Targeting the Complement Cascade for Treatment of Dry Age-Related Macular Degeneration

Geographic atrophy: where we are now and where we are going

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