ArticleInvestigative ophthalmology & visual science2015
Rare Variants in the Functional Domains of Complement Factor H Are Associated With Age-Related Macular Degeneration.
Article in Investigative ophthalmology & visual science, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
45 citing papers in PubMed, 1 synthesis or guideline pooled it, 72 citations in OpenAlex.
- Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration†.Human molecular genetics · 2016Pooled it
- Trial
- Mapping rare, deleterious mutations in Factor H: Association with early onset, drusen burden, and lower antigenic levels in familial AMD.Scientific reports · 2016Trial
- Disease Progression in Age-Related Macular Degeneration Patients Carrying Rare Variants in the Complement Factor H or Complement Factor I Genes.Investigative ophthalmology & visual science · 2025Article
- Rare predicted loss-of-function and damaging missense variants in CFHR5 associate with protection from age-related macular degeneration.American journal of human genetics · 2025Article
- Age-Related Macular Degeneration and Extramacular Drusen: Genetic Associations in the Coimbra Eye Study.Investigative ophthalmology & visual science · 2024Article
- Whole genome sequencing of 4,787 individuals identifies gene-based rare variants in age-related macular degeneration.Human molecular genetics · 2024Article
- Recent Advances in Our Understanding of Age-Related Macular Degeneration: Mitochondrial Dysfunction, Redox Signaling, and the Complement System.Aging and disease · 2024Review
- Identification of complement factor H variants that predispose to pre-eclampsia: A genetic and functional study.BJOG : an international journal of obstetrics and gynaecology · 2023Article
- Rare DysfunctionalOphthalmology science · 2023Article
- Identifying Novel Genes and Variants in Immune and Coagulation Pathways Associated with Macular Degeneration.Ophthalmology science · 2023Article
- Functional analysis of rare genetic variants in complement factor I in advanced age-related macular degeneration.Human molecular genetics · 2022Article
- Phenotypic Expression of CFH Rare Variants in Age-Related Macular Degeneration Patients in the Coimbra Eye Study.Investigative ophthalmology & visual science · 2022Article
- Consequences of a Rare Complement Factor H Variant for Age-Related Macular Degeneration in the Amish.Investigative ophthalmology & visual science · 2022Article
- Review
- A Phase I, Single Ascending Dose Study of GEM103 (Recombinant Human Complement Factor H) in Patients with Geographic Atrophy.Ophthalmology science · 2022Article
- A novel method for real-time analysis of the complement C3b:FH:FI complex reveals dominant negativeFrontiers in immunology · 2022Article
- Semi-Quantitative Multiplex Profiling of the Complement System Identifies Associations of Complement Proteins with Genetic Variants and Metabolites in Age-Related Macular Degeneration.Journal of personalized medicine · 2021Article
- Beyond factor H: The impact of genetic-risk variants for age-related macular degeneration on circulating factor-H-like 1 and factor-H-related protein concentrations.American journal of human genetics · 2021Article
- Functional Analysis of Rare Genetic Variants in Complement Factor I (Translational vision science & technology · 2020Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
purposeAge-related macular degeneration (AMD) has a substantial genetic risk component, as evidenced by the risk from common genetic variants uncovered in the first genome-wide association studies. More recently, it has become apparent that rare genetic variants also play an independent role in AMD risk. We sought to determine if rare variants in complement factor H (CFH) played a role in AMD risk.
methodsWe had previously collected DNA from a large population of patients with advanced age-related macular degeneration (A-AMD) and controls for targeted deep sequencing of candidate AMD risk genes. In this analysis, we tested for an increased burden of rare variants in CFH in 1665 cases and 752 controls from this cohort.
resultsWe identified 65 missense, nonsense, or splice-site mutations with a minor allele frequency ≤ 1%. Rare variants with minor allele frequency ≤ 1% (odds ratio [OR] = 1.5, P = 4.4 × 10⁻²), 0.5% (OR = 1.6, P = 2.6 × 10⁻²), and all singletons (OR = 2.3, P = 3.3 × 10⁻²) were enriched in A-AMD cases. Moreover, we observed loss-of-function rare variants (nonsense, splice-site, and loss of a conserved cysteine) in 10 cases and serum levels of FH were decreased in all 5 with an available sample (haploinsufficiency). Further, rare variants in the major functional domains of CFH were increased in cases (OR = 3.2; P = 1.4 × 10⁻³) and the magnitude of the effect correlated with the disruptive nature of the variant, location in an active site, and inversely with minor allele frequency.
conclusionsIn this large A-AMD cohort, rare variants in the CFH gene were enriched and tended to be located in functional sites or led to low serum levels. These data, combined with those indicating a similar, but even more striking, increase in rare variants found in CFI, strongly implicate complement activation in A-AMD etiopathogenesis as CFH and CFI interact to inhibit the alternative pathway.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.