Evidence map›Paper›PMID 33783477›Full record

ArticleHuman molecular genetics2021

The rare C9 P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade.

O McMahon, T M Hallam, S Patel, C L Harris, A Menny, W M Zelek, R Widjajahakim, A Java, T E Cox, N Tzoumas and 13 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Human molecular genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
3.2field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

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.

2 · The registry

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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed, 18 citations in OpenAlex.

  1. Review
  2. Observational
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  4. Review
  5. Article
  6. Rare DysfunctionalOphthalmology science · 2023
    Article
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  8. Article
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  10. Review
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors at 7 institutions in 2 countries.

O McMahonComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
T M HallamComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
S PatelDepartment of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA.
C L HarrisComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
A MennyDepartment of Life Sciences, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, UK.
W M ZelekDivision of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
R WidjajahakimDepartment of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA.
A JavaDivisions of Nephrology and Rheumatology, Department of Medicine, Washington University, St Louis, MO 63110, USA.
T E CoxComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
N TzoumasBiosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
D H W SteelBiosciences Institute, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
V G ShuttleworthComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
K Smith-JacksonComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
V BrocklebankComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
H GriffithsClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
A J CreeClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
J P AtkinsonDivisions of Nephrology and Rheumatology, Department of Medicine, Washington University, St Louis, MO 63110, USA.
A J LoteryClinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton SO16 6YD, UK.
D BubeckDepartment of Life Sciences, Sir Ernst Chain Building, Imperial College London, London SW7 2AZ, UK.
B P MorganDivision of Infection and Immunity, School of Medicine, Systems Immunity Research Institute, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.
K J MarchbankComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
J M SeddonDepartment of Ophthalmology and Visual Sciences, University of Massachusetts Medical School, Worcester, MA 01655, USA.
D KavanaghComplement Therapeutics Research Group, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Royal Victoria Infirmary · GBNewcastle University · GBUniversity of Massachusetts Chan Medical School · USUniversity of Southampton · GBCardiff University · GBImperial College London · GBWashington University in St. Louis · US

Funding

ETIOLOGIC STUDIES OF AGE-RELATED MACULAR DEGENERATIONR01EY011309 · NEI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SEDDON, JOHANNA M · 2003 to 2017
$9.3M
Rare Genetic Variation in Macular DegenerationR01EY028602 · NEI · UNIV OF MASSACHUSETTS MED SCH WORCESTER · PI SEDDON, JOHANNA M · 2018 to 2022
$3.2M
Cancer Research UK 16099Cancer Research UK C26409/A16099HCRW_ HF-19-1595Medical Research Council MR/R000913/1Medical Research Council MR/R001359/1Medical Research Council MR/R014248/1NEI NIH HHS R01 EY011309NEI NIH HHS R01 EY028602
6 · The paper itself

Abstract

Age-related macular degeneration (AMD) is a complex neurodegenerative eye disease with behavioral and genetic etiology and is the leading cause of irreversible vision loss among elderly Caucasians. Functionally significant genetic variants in the alternative pathway of complement have been strongly linked to disease. More recently, a rare variant in the terminal pathway of complement has been associated with increased risk, Complement component 9 (C9) P167S. To assess the functional consequence of this variant, C9 levels were measured in two independent cohorts of AMD patients. In both cohorts, it was demonstrated that the P167S variant was associated with low C9 plasma levels. Further analysis showed that patients with advanced AMD had elevated sC5b-9 compared to those with non-advanced AMD, although this was not associated with the P167S polymorphism. Electron microscopy of membrane attack complexes (MACs) generated using recombinantly produced wild type or P167S C9 demonstrated identical MAC ring structures. In functional assays, the P167S variant displayed a higher propensity to polymerize and a small increase in its ability to induce hemolysis of sheep erythrocytes when added to C9-depleted serum. The demonstration that this C9 P167S AMD risk polymorphism displays increased polymerization and functional activity provides a rationale for the gene therapy trials of sCD59 to inhibit the terminal pathway of complement in AMD that are underway.

Indexed as

MutationAgedAnimalsCase-Control StudiesCHO CellsCohort StudiesComplement C9Complement Membrane Attack ComplexComplement System ProteinsCricetinaeCricetulusFemaleGenetic Predisposition to DiseaseGuinea PigsHemolysisHumansComplement C9Complement Membrane Attack ComplexComplement System ProteinsSC5b-9 protein complex

Identifiers

PMID33783477
PMCPMC8212764
OpenAlexW3119142673

What OpenQuestion holds

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LicenceCC BY
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Registered trials

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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.