Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration

May, Adam; Su, Fei; Dinh, Brian; Ehlen, Rachael; Tran, Christina; Adivikolanu, Harini; Shaw, Peter X.

doi:10.1016/j.exer.2021.108605

Cited by 12 publications

(6 citation statements)

References 119 publications

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“…The role of the complement system in pathogenesis of AMD has been underlined by a genetic study conducted by the "Catalog of Human Genome-Wide Association Studies". They identified 103 genetic risk loci for AMD (Deng et al, 2021b) of which thesingle nucleotide polymorphisms (SNPs) within the complement factor H (CFH) gene is the major heritable determinant of AMD followed by SNPs within the ARMS2/HTRA1 genes (Haines et al, 2005;Maller et al, 2006;May et al, 2021;Mohamad et al, 2019;Thee et al, 2022;Tzoumas et al, 2021). Interestingly, associations between GM, AMD and CFH have been found in our study (see point 2.3.4).…”

Section: Definition Risk Factors and Pathogenesis Of Age-related Macu...supporting

confidence: 52%

The role of the gut microbiome in eye diseases

Zysset-Burri

Morandi

Herzog

et al. 2023

Progress in Retinal and Eye Research

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Section: Definition Risk Factors and Pathogenesis Of Age-related Macu...supporting

confidence: 52%

The role of the gut microbiome in eye diseases

Zysset-Burri

Morandi

Herzog

et al. 2023

Progress in Retinal and Eye Research

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“…The HTRA1 protein is involved in various physiological processes including cell migration, embryogenesis, protein aggregate degradation, and TGF-β signaling, but also calcification and remodeling of ECM, and cleavage of proteins involved in the regulation of the complement pathway. 42,43 The ARMS2/HTRA1 LD block includes HTRA1 promoter variant rs11200638, which likely regulates HTRA1 expression. Several studies reported upregulation of HTRA1 by the high risk AMD genotype, but this has been challenged by other reports.…”

Section: J O U R N a L P R E -P R O O Fmentioning

confidence: 99%

The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1

et al. 2022

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“…2 , Supplementary Material, Appendix 1 ). This topography may reflect the effect of ARMS2/HTRA1 on extracellular matrix remodeling ( 41 ), which may alter foveal morphology.…”

Section: Discussionmentioning

confidence: 99%

Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank

Tzoumas

Kavanagh

Cordell

et al. 2022

Human Molecular Genetics

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To evaluate potential diagnostic and therapeutic biomarkers for age-related macular degeneration (AMD), we identified 8433 UK Biobank participants with rare complement factor I gene (CFI) variants, 579 with optical coherence tomography-derived macular thickness data. We stratified these variants by predicted gene expression and measured their association with retinal pigment epithelium-Bruch’s membrane (RPE-BM) complex and retinal thicknesses at nine macular subfields, as well as AMD risk, using multivariable regression models adjusted for the common CFH p.Y402H and ARMS2 p.A69S risk genotypes. CFI variants associated with low Factor I levels predicted a thinner mean RPE-BM (95% CI −1.66 to −0.37 μm, P = 0.002) and retina (95% CI −5.88 to −0.13 μm, P = 0.04), and a higher AMD risk (OR = 2.26, 95% CI 1.56–3.27, P < 0.001). CFI variants associated with normal Factor I levels did not impact mean RPE-BM/retinal thickness (P = 0.28; P = 0.99), or AMD risk (P = 0.97). CFH p.Y402H was associated with a thinner RPE-BM (95% CI −0.31 to −0.18 μm, P < 0.001 heterozygous; 95% CI −0.62 to −0.42 μm, P < 0.001 homozygous) and retina (95% CI −0.73 to −0.12 μm, P = 0.007 heterozygous; 95% CI −1.08 to −0.21 μm, P = 0.004 homozygous). ARMS2 p.A69S did not influence RPE-BM (P = 0.80 heterozygous; P = 0.12 homozygous) or retinal thickness (P = 0.75 heterozygous; P = 0.07 homozygous). p.Y402H and p.A69S exhibited a significant allele-dose response with AMD risk. Thus, CFI rare variants associated with low Factor I levels are robust predictors of reduced macular thickness and AMD. The observed association between macular thickness and CFH p.Y402H, but not ARMS2 p.A69S, highlights the importance of complement dysregulation in early pathogenesis.

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Ongoing controversies and recent insights of the ARMS2-HTRA1 locus in age-related macular degeneration

Cited by 12 publications

References 119 publications

The role of the gut microbiome in eye diseases

The role of the gut microbiome in eye diseases

The Phenotypic Course of Age-Related Macular Degeneration for ARMS2/HTRA1

Rare complement factor I variants associated with reduced macular thickness and age-related macular degeneration in the UK Biobank

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