A new perspective on lipid research in age-related macular degeneration

Leeuwen, Elisabeth M. van; Emri, Eszter; Merle, Bénédicte M. J.; Colijn, Johanna M.; Kersten, Eveline; Cougnard‐Grégoire, Audrey; Dammeier, Sascha; Meester-Smoor, Magda A.; Pool, Frances M.; Jong, Eiko K. de; Delcourt, Cécile; Rodrigez-Bocanegra, Eduardo; Biarnés, Marc; Luthert, Philip J; Ueffing, Marius; Klaver, Caroline C W; Nogoceke, Everson; Hollander, Anneke I. den; Lengyel, Imre

doi:10.1016/j.preteyeres.2018.04.006

Cited by 185 publications

(208 citation statements)

References 383 publications

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“…A GWAS meta-analysis has identified 52 independent common and rare variants associated with AMD risk at a level of genome-wide significance 9 . Several of these regions are linked to lipids or lipid-related biology, such as the CETP, LIPC and APOE gene regions 21 . Lipid particles are deposited within drusen in the different layers of Bruch's membrane in AMD patients 21 .…”

Section: Resultsmentioning

confidence: 99%

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Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

et al. 2020

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Modern high-throughput experiments provide a rich resource to investigate causal determinants of disease risk. Mendelian randomization (MR) is the use of genetic variants as instrumental variables to infer the causal effect of a specific risk factor on an outcome. Multivariable MR is an extension of the standard MR framework to consider multiple potential risk factors in a single model. However, current implementations of multivariable MR use standard linear regression and hence perform poorly with many risk factors. Here, we propose a two-sample multivariable MR approach based on Bayesian model averaging (MR-BMA) that scales to high-throughput experiments. In a realistic simulation study, we show that MR-BMA can detect true causal risk factors even when the candidate risk factors are highly correlated. We illustrate MR-BMA by analysing publicly-available summarized data on metabolites to prioritise likely causal biomarkers for age-related macular degeneration.

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Section: Resultsmentioning

confidence: 99%

“…Several of these regions are linked to lipids or lipid-related biology, such as the CETP, LIPC and APOE gene regions 21 . Lipid particles are deposited within drusen in the different layers of Bruch's membrane in AMD patients 21 . A recent observational study has highlighted strong associations between lipid metabolites and AMD risk 22 .…”

Section: Resultsmentioning

confidence: 99%

Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

et al. 2020

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“…These alterations in Bruch’s membrane structure alter physiological conductivity and therefore impede a correct transport of oxygen or nutrients from the choroidal network to the RPE cells [35-38], resulting in a condition of hypoxia [39] and starvation. In addition, lifestyle habits, like smoking or maintaining a high-fat diet, both risk factors for AMD [7, 40], add oxidative stress to the retina [41, 42], and in particular to the mitochondria of RPE cells and photoreceptors [11]. With age, and more pronounced in AMD patients, mitochondrial damage is augmented [10, 43], thus leading to energy misbalance in the RPE cells.…”

Section: Discussionmentioning

confidence: 99%

“…The retinal microenvironment is highly oxidized due to a very high energy demand and photo-oxidation. Ageing processes in combination with external stressors, such as smoking or a high fat diet [7, 8], force RPE cells to deal with excessive levels of oxidative stress. In fact, energy metabolism of primary RPE cells isolated from AMD patients was found to be strongly impaired compared to RPE cells from healthy controls [9].…”

Section: Introductionmentioning

confidence: 99%

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

Armento¹,

Honisch²,

Panagiotakopoulou

et al. 2020

Preprint

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Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly population. About 50% of AMD patients present polymorphisms in the Complement Factor H (CFH) gene, coding for Factor H protein (FH). AMD-associated CFH risk variants, Y402H in particular, impair FH function leading to complement overactivation. In AMD, retinal homeostasis is compromised due to dysfunction of retinal pigment epithelium (RPE) cells. Whether FH contributes to AMD pathogenesis only via complement system dysregulation remains unclear. To investigate the potential role of FH on energy metabolism and oxidative stress in RPE cells, we silenced CFH in human hTERT-RPE1 cells. FH-deprived RPE cells exposed to oxidative insult, showed altered metabolic homeostasis, including reduction of glycolysis and mitochondrial respiration, paralleled by an increase in lipid peroxidation. Our data suggest that FH protects RPE cells from oxidative stress and metabolic reprogramming, highlighting a novel function for FH in AMD pathogenesis.Graphical abstract

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“…These PUFAs include both long chain omega-3 (n-3) and omega-6 (n-6) fatty acids such as docosahexaenoic acid (DHA) and arachidonic acid (AA). DHA is the major polyunsaturated fatty acid found in the retina and has been shown to play diverse roles in photoreceptor function, protection in oxidative stress, as well as retinal development 39 .…”

Section: A Molecular Link Between Long-chain Pufas In Age-related Eyementioning

confidence: 99%

The Lipid Elongation Enzyme ELOVL2 is a molecular regulator of aging in the retina

Chen¹,

Chao²,

Rocha³

et al. 2019

Preprint

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Methylation of the regulatory region of the Elongation Of Very Long Chain Fatty Acids-Like 2 (ELOVL2) gene, an enzyme involved in elongation of long-chain polyunsaturated fatty acids, is one of the most robust biomarkers of human age, but the critical question of whether ELOVL2 plays a functional role in molecular aging has not been resolved.Here, we report that Elovl2 regulates age-associated functional and anatomical aging in vivo, focusing on mouse retina, with direct relevance to age-related eye diseases. We show that an age-related decrease in Elovl2 expression is associated with increased DNA methylation of its promoter. Reversal of Elovl2 promoter hypermethylation in vivo through intravitreal injection of 5-Aza-2'-deoxycytidine (5-aza-dc) leads to increased Elovl2 expression and rescue of age-related decline in visual function. Mice carrying a point mutation C234W that disrupts Elovl2-specific enzymatic activity show electrophysiological characteristics of premature visual decline, as well as early appearance of autofluorescent deposits, well-established markers of aging in the mouse retina. Finally, we find deposits underneath the retinal pigment epithelium in Elovl2 mutant mice, containing components of complement system and lipid metabolism. These findings indicate that ELOVL2 activity regulates aging in mouse retina, provide a molecular link between polyunsaturated fatty acids elongation and visual functions, and suggest novel therapeutic strategies for treatment of age-related eye diseases.

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A new perspective on lipid research in age-related macular degeneration

Cited by 185 publications

References 383 publications

Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

Selecting likely causal risk factors from high-throughput experiments using multivariable Mendelian randomization

Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells

The Lipid Elongation Enzyme ELOVL2 is a molecular regulator of aging in the retina

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