Joint association of complement component 3 and CC-cytokine ligand2 (<i>CCL2</i>) or complement component 3 and <i>CFH</i> polymorphisms in age-related macular degeneration

Bonyadi, Mortaza; Bonyadi, Mohammad Reza; Yaseri, Mehdi; Mohammadian, Tahereh; Fotouhi, Nikou; Javadzadeh, Alireza; Soheilian, Masoud

doi:10.1080/13816810.2016.1242019

Cited by 6 publications

(3 citation statements)

References 25 publications

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“…Sharma reported that GG genotype and G allele of MCP-1 rs1024611 variant are significantly correlated with increased risk of AMD in Indians [31]. However, Bonyadi found that CCL2 -2518 (rs1024611) was not significantly association with AMD in Iranians [32]. This may derive from genotype distribution differences of rs1024611 in various ethnic populations.…”

Section: Discussionmentioning

confidence: 98%

Association Between Monocyte Chemotactic Protein 1 Variants and Age-Related Macular Degeneration Onset Among Chinese People

Zhang

Zhao

2020

Med Sci Monit

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Departmental sources Background:We assessed the potential association between monocyte chemotactic protein 1 (MCP-1) variants (rs1024611 and rs3760396) and age-related macular degeneration (AMD) susceptibility among Chinese Han people. Material/Methods:Our research included 129 AMD patients and 131 healthy controls. Genotyping for MCP-1 variants was performed in the 2 groups, and genotype and allele distributions were checked between groups by c 2 analysis. Odds ratio (OR) and 95% confidence interval (CI) reflected the potential association between MCP-1 variants and AMD risk. The linkage disequilibrium of polymorphisms was detected using Haploview. Results:Significant differences in rs1024611 genotype distributions were detected between the 2 groups, and homozygous carriers with GG genotype had higher AMD incidence (P<0.05, OR=2.650, 95% CI=1.127 -6.231). The rs1024611 G allele frequency was significantly higher in AMD patients, suggesting that the G allele promotes AMD onset (P<0.05, OR=1.447, 95% CI=1.013 -2.068). Strong linkage disequilibrium was found between rs1024611 and rs3760396, and haplotype A rs1024611 -C rs3760396 was significantly associated with decreased risk of AMD (P=0.001, OR=0.502, 95% CI=0.335 -0.752). Conclusions:MCP-1 rs1024611 variant appears to contribute to risk of AMD in the Chinese Han population, and the interaction of MCP-1 polymorphisms may also influence individual susceptibility to AMD.

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Section: Discussionmentioning

confidence: 98%

Association Between Monocyte Chemotactic Protein 1 Variants and Age-Related Macular Degeneration Onset Among Chinese People

Zhang

Zhao

2020

Med Sci Monit

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“…MCP1/ CCL2 is linked to both inflammation and angiogenesis and is released from Müller glia and the RPE under stress conditions to attract microglia/macrophages expressing chemokine receptor 2 (CCR2) to sites of retinal damage [41]. MCP1/CCL2 polymorphisms have been linked to AMD [42,43]. Furthermore, MCP1/CCL2 has been shown to attract microglia to amyloid-β plaques in the brain and mediate their clearance in Alzheimer's disease [44].…”

Section: Discussionmentioning

confidence: 99%

In vitro stem cell modelling demonstrates a proof‐of‐concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy

Hongisto

Dewing

Christensen

et al. 2020

The Journal of Pathology

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Sorsby fundus dystrophy (SFD) is a rare autosomal dominant disease of the macula that leads to bilateral loss of central vision and is caused by mutations in the TIMP3 gene. However, the mechanisms by which TIMP3 mutations cause SFD are poorly understood. Here, we generated human induced pluripotent stem cell‐derived retinal pigmented epithelial (hiPSC‐RPE) cells from three SFD patients carrying TIMP3 p.(Ser204Cys) and three non‐affected controls to study disease‐related structural and functional differences in the RPE. SFD‐hiPSC‐RPE exhibited characteristic RPE structure and physiology but showed significantly reduced transepithelial electrical resistance associated with enriched expression of cytoskeletal remodelling proteins. SFD‐hiPSC‐RPE exhibited basolateral accumulation of TIMP3 monomers, despite no change in TIMP3 gene expression. TIMP3 dimers were observed in both SFD and control hiPSC‐RPE, suggesting that mutant TIMP3 dimerisation does not drive SFD pathology. Furthermore, mutant TIMP3 retained matrix metalloproteinase activity. Proteomic profiling showed increased expression of ECM proteins, endothelial cell interactions and angiogenesis‐related pathways in SFD‐hiPSC‐RPE. By contrast, there were no changes in VEGF secretion. However, SFD‐hiPSC‐RPE secreted higher levels of monocyte chemoattractant protein 1, PDGF and angiogenin. Our findings provide a proof‐of‐concept that SFD patient‐derived hiPSC‐RPE mimic mature RPE cells and support the hypothesis that excess accumulation of mutant TIMP3, rather than an absence or deficiency of functional TIMP3, drives ECM and angiogenesis‐related changes in SFD. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…Cell-based inflammatory responses within the RPE/choroid complex are a core feature of exudative AMD (30). Recently, a synergistic risk for AMD was found between genotype of ccl2 (ccl2−2518) and C3 (31), linking in human the recruitment of microglia/macrophage cells and the complement pathway activation. Indeed, microglia/macrophage cells play a key role in local regulation of complement in the retina (32), producing VEGF (33) and enhanced laser-induced CNV (28).…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of FH Protection Against Neovascular AMD

et al. 2020

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A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NT al region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CT al region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.

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Joint association of complement component 3 and CC-cytokine ligand2 (CCL2) or complement component 3 and CFH polymorphisms in age-related macular degeneration

Cited by 6 publications

References 25 publications

Association Between Monocyte Chemotactic Protein 1 Variants and Age-Related Macular Degeneration Onset Among Chinese People

Association Between Monocyte Chemotactic Protein 1 Variants and Age-Related Macular Degeneration Onset Among Chinese People

In vitro stem cell modelling demonstrates a proof‐of‐concept for excess functional mutant TIMP3 as the cause of Sorsby fundus dystrophy

Mechanisms of FH Protection Against Neovascular AMD

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