Systems genomics in age-related macular degeneration

Hollander, Anneke I. den; Mullins, Robert F.; Orozco, Luz D.; Voigt, Andrew P.; Chen, Hsu-Hsin; Strunz, Tobias; Graßmann, Felix; Haines, Jonathan L.; Kuiper, Jonas J.W.; Tumminia, Santa J.; Allikmets, Rando; Hageman, Gregory S.; Stambolian, Dwight; Klaver, Caroline C W; Boeke, Jef D.; Chen, Hao; Honigberg, Lee; Katti, Suresh; Frazer, Kelly A.; Weber, Bernhard H. F.; Gorin, Michael B.

doi:10.1016/j.exer.2022.109248

Cited by 13 publications

(7 citation statements)

References 107 publications

(164 reference statements)

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“…12 This study identified a variant in the CFH locus that associates with idiopathic MFC. This risk variant is in full LD with rs10922109, a variant that is associated with age-related macular degeneration (AMD) 23,24,27 and rs1410996 that has previously been associated with MFC using targeted SNV analysis carried out on 48 cases. 13 Among the established genetic loci associated with AMD, 28 we detected only a suggestive association for another variant in the CFH gene (rs570618 LD = 0.99 with rs1061170[Y402H]; P = 1.1 × 10 −5 ) (eTable 7 in Supplement 2).…”

Section: Discussionmentioning

confidence: 97%

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

et al. 2023

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ImportanceIdiopathic multifocal choroiditis (MFC) is poorly understood, thereby hindering optimal treatment and monitoring of patients.ObjectiveTo identify the genes and pathways associated with idiopathic MFC.Design, Setting, and ParticipantsThis was a case-control genome-wide association study (GWAS) and protein study of blood plasma samples conducted from March 2006 to February 2022. This was a multicenter study involving 6 Dutch universities. Participants were grouped into 2 cohorts: cohort 1 consisted of Dutch patients with idiopathic MFC and controls, and cohort 2 consisted of patients with MFC and controls. Plasma samples from patients with idiopathic MFC who had not received treatment were subjected to targeted proteomics. Idiopathic MFC was diagnosed according to the Standardization of Uveitis Nomenclature (SUN) Working Group guidelines for punctate inner choroidopathy and multifocal choroiditis with panuveitis. Data were analyzed from July 2021 to October 2022.Main outcomes and measuresGenetic variants associated with idiopathic MFC and risk variants associated with plasma protein concentrations in patients.ResultsThis study included a total of 4437 participants in cohort 1 (170 [3.8%] Dutch patients with idiopathic MFC and 4267 [96.2%] controls; mean [SD] age, 55 [18] years; 2443 female [55%]) and 1344 participants in cohort 2 (52 [3.9%] patients with MFC and 1292 [96.1%] controls; 737 male [55%]). The primary GWAS association mapped to the CFH gene with genome-wide significance (lead variant the A allele of rs7535263; odds ratio [OR], 0.52; 95% CI, 0.41-0.64; P = 9.3 × 10−9). There was no genome-wide significant association with classical human leukocyte antigen (HLA) alleles (lead classical allele, HLA-A*31:01; P = .002). The association with rs7535263 showed consistent direction of effect in an independent cohort of 52 cases and 1292 control samples (combined meta-analysis OR, 0.58; 95% CI, 0.38-0.77; P = 3.0 × 10−8). In proteomic analysis of 87 patients, the risk allele G of rs7535263 in the CFH gene was strongly associated with increased plasma concentrations of factor H–related (FHR) proteins (eg, FHR-2, likelihood ratio test, adjusted P = 1.1 × 10−3) and proteins involved in platelet activation and the complement cascade.Conclusions and relevanceResults suggest that CFH gene variants increase systemic concentrations of key factors of the complement and coagulation cascades, thereby conferring susceptibility to idiopathic MFC. These findings suggest that the complement and coagulation pathways may be key targets for the treatment of idiopathic MFC.

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Section: Discussionmentioning

confidence: 97%

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

et al. 2023

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“…Furthermore, there was a progressive loss of MCT3 with an increasing severity of dry AMD [ 96 ]. An increase in the expression of HTRA1 protein was reported in iPSC-RPE cell line from subjects carrying a high-risk genotype at 10q26 locus [ 65 , 128 ], and a clinical trial evaluating the inhibition of HTRA1 is ongoing [ 129 ]. Mutations in RDH5 have been reported in a subset of patients with macular atrophy [ 63 , 130 ].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Dhingra

Tobias

Philp

et al. 2023

IJMS

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LC3b (Map1lc3b) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b to promote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes, such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells, utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis, and neuroprotection. In a mouse model of retinal lipid steatosis-mice lacking LC3b (LC3b−/−), we observed increased lipid deposition, metabolic dysregulation, and enhanced inflammation. Herein, we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b−/− mice revealed 1533 DEGs, with ~73% upregulated and 27% downregulated. Enriched gene ontology (GO) terms included inflammatory response (upregulated DEGs), fatty acid metabolism, and vascular transport (downregulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with a potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.

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“…Furthermore, there was a progressive loss of MCT3 with increasing severity of dry AMD [125]. Increase in expression of HTRA1 protein was reported in iPSC-RPE cell line from subjects carrying high risk genotype at 10q26 locus [66,126,127] and a clinical trial evaluating inhibition of HTRA1 is ongoing [128]. Mutations in RDH5 have been reported in a subset of patients with macular atrophy [64,129].…”

Section: Discussionmentioning

confidence: 99%

Transcriptomic changes predict metabolic alterations in LC3 associated phagocytosis in aged mice

Dhingra

Tobias

Boesze‐Battaglia

2023

Preprint

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LC3b (Map1lc3b) plays an essential role in canonical autophagy and is one of several components of the autophagy machinery that mediates non-canonical autophagic functions. Phagosomes are often associated with lipidated LC3b, to promote phagosome maturation in a process called LC3-associated phagocytosis (LAP). Specialized phagocytes such as mammary epithelial cells, retinal pigment epithelial (RPE) cells, and sertoli cells utilize LAP for optimal degradation of phagocytosed material, including debris. In the visual system, LAP is critical to maintain retinal function, lipid homeostasis and neuroprotection. In a mouse model of retinal lipid steatosis - mice lacking LC3b (LC3b-/-), we observed increased lipid deposition, metabolic dysregulation and enhanced inflammation. Herein we present a non-biased approach to determine if loss of LAP mediated processes modulate the expression of various genes related to metabolic homeostasis, lipid handling, and inflammation. A comparison of the RPE transcriptome of WT and LC3b-/-mice revealed 1533 DEGs, with ~73% up-regulated and 27% down-regulated. Enriched gene ontology (GO) terms included inflammatory response (up-regulated DEGs), fatty acid metabolism and vascular transport (down-regulated DEGs). Gene set enrichment analysis (GSEA) identified 34 pathways; 28 were upregulated (dominated by inflammation/related pathways) and 6 were downregulated (dominated by metabolic pathways). Analysis of additional gene families identified significant differences for genes in the solute carrier family, RPE signature genes, and genes with potential role in age-related macular degeneration. These data indicate that loss of LC3b induces robust changes in the RPE transcriptome contributing to lipid dysregulation and metabolic imbalance, RPE atrophy, inflammation, and disease pathophysiology.

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Systems genomics in age-related macular degeneration

Cited by 13 publications

References 107 publications

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Association of Risk Variants in the CFH Gene With Elevated Levels of Coagulation and Complement Factors in Idiopathic Multifocal Choroiditis

Transcriptomic Changes Predict Metabolic Alterations in LC3 Associated Phagocytosis in Aged Mice

Transcriptomic changes predict metabolic alterations in LC3 associated phagocytosis in aged mice

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