Macular retinal thickness differs markedly in age-related macular degeneration driven by risk polymorphisms on chromosomes 1 and 10

Zouache, Moussa A.; Bennion, Alex; Hageman, Jill L.; Pappas, Christian; Richards, Burt; Hageman, Gregory S.

doi:10.1038/s41598-020-78059-x

Cited by 23 publications

(32 citation statements)

References 79 publications

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“…AMD pathology typically initiates at the interface between the retinal pigment epithelium (RPE) and Bruch's membrane (BM), which consists of an elastin layer confined between inner and outer collagenous layers. Collectively, the specialized RPE-BM structure forms a key component of the outer blood-retinal barrier and separates the neural retina from the choriocapillaris, the dense microvascular bed of the choroid (2). Hallmark phenotypes associated with AMD include the appearance of pathologic basal laminar deposits and/or soft drusen-like material beneath the RPE.…”

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confidence: 99%

Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Williams

Seager

Gardiner

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Genome-wide association studies have identified the chromosome 10q26 (Chr10) locus, which contains the age-related maculopathy susceptibility 2 (ARMS2) and high temperature requirement A serine peptidase 1 (HTRA1) genes, as the strongest genetic risk factor for age-related macular degeneration (AMD) [L.G. Fritsche et al., Annu. Rev. Genomics Hum. Genet. 15, 151–171, (2014)]. To date, it has been difficult to assign causality to any specific single nucleotide polymorphism (SNP), haplotype, or gene within this region because of high linkage disequilibrium among the disease-associated variants [J. Jakobsdottir et al. Am. J. Hum. Genet. 77, 389–407 (2005); A. Rivera et al. Hum. Mol. Genet. 14, 3227–3236 (2005)]. Here, we show that HTRA1 messenger RNA (mRNA) is reduced in retinal pigment epithelium (RPE) but not in neural retina or choroid tissues derived from human donors with homozygous risk at the 10q26 locus. This tissue-specific decrease is mediated by the presence of a noncoding, cis-regulatory element overlapping the ARMS2 intron, which contains a potential Lhx2 transcription factor binding site that is disrupted by risk variant rs36212733. HtrA1 protein increases with age in the RPE–Bruch’s membrane (BM) interface in Chr10 nonrisk donors but fails to increase in donors with homozygous risk at the 10q26 locus. We propose that HtrA1, an extracellular chaperone and serine protease, functions to maintain the optimal integrity of the RPE–BM interface during the aging process and that reduced expression of HTRA1 mRNA and protein in Chr10 risk donors impairs this protective function, leading to increased risk of AMD pathogenesis. HtrA1 augmentation, not inhibition, in high-risk patients should be considered as a potential therapy for AMD.

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confidence: 99%

Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Williams

Seager

Gardiner

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Genomic DNA was isolated from cultured CECs to genotype for the following AMD‐related variants: rs800292 ( CFH I62V), rs1061170 ( CFH Y402H), rs1410996 (proxy for protective block), rs12144939 (proxy for CFHR3/CFHR1 deletion), rs10490924 ( ARMS2 A69S), rs11200638 ( HTRA1 promoter), and rs2230199 ( C3 R102G) through the Steele Center for Macular Degeneration. CECs used in this study all had a low to moderate risk of AMD, which was determined by AMD odds ratios based upon data from over 6000 case/control individuals 27 . Each experiment used CECs that were obtained from three different donors.…”

Section: Methodsmentioning

confidence: 99%

Active Rap1‐mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells

et al. 2021

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Neovascular age‐related macular degeneration (nAMD) is a leading cause of blindness. The pathophysiology involves activation of choroidal endothelial cells (CECs) to transmigrate the retinal pigment epithelial (RPE) monolayer and form choroidal neovascularization (CNV) in the neural retina. The multidomain GTPase binding protein, IQGAP1, binds active Rac1 and sustains activation of CECs, thereby enabling migration associated with vision‐threatening CNV. IQGAP1 also binds the GTPase, Rap1, which when activated reduces Rac1 activation in CECs and CNV. In this study, we tested the hypothesis that active Rap1 binding to IQGAP1 is necessary and sufficient to reduce Rac1 activation in CECs, and CNV. We found that pharmacologic activation of Rap1 or adenoviral transduction of constitutively active Rap1a reduced VEGF‐mediated Rac1 activation, migration, and tube formation in CECs. Following pharmacologic activation of Rap1, VEGF‐mediated Rac1 activation was reduced in CECs transfected with an IQGAP1 construct that increased active Rap1‐IQGAP1 binding but not in CECs transfected with an IQGAP1 construct lacking the Rap1 binding domain. Specific knockout of IQGAP1 in endothelial cells reduced laser‐induced CNV and Rac1 activation in CNV lesions, but pharmacologic activation of Rap1 did not further reduce CNV compared to littermate controls. Taken together, our findings provide evidence that active Rap1 binding to the IQ domain of IQGAP1 is sufficient to interfere with active Rac1‐mediated CEC activation and CNV formation.

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“…The study identified an association between haplotypes based on a proxy for rs1410996 and the index SNP for locus 1.6 and circulating levels of complement factor-related 4 protein. This study and others [ 51 – 54 ] highlight the need to adequately account for genetic protection at Chr1 to fully elucidate the genetic etiology and pathophysiology of AMD.…”

Section: Introductionmentioning

confidence: 78%

Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci

et al. 2021

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Background Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus) and ARMS2/HTRA1 gene on chromosome 10q26 (Chr10 locus). Results By refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10 risk variants essentially neutralized by protective CFH-CFHR5 haplotypes. Conclusions Our study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.

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Macular retinal thickness differs markedly in age-related macular degeneration driven by risk polymorphisms on chromosomes 1 and 10

Cited by 23 publications

References 79 publications

Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Chromosome 10q26–driven age-related macular degeneration is associated with reduced levels of HTRA1 in human retinal pigment epithelium

Active Rap1‐mediated inhibition of choroidal neovascularization requires interactions with IQGAP1 in choroidal endothelial cells

Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci

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