Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis

The Journal of Immunology : Official Journal of the American Association of Immunologists
Joanna L GilesClaire L Harris

Abstract

Complement is implicated in the pathogenesis of rheumatoid arthritis (RA); elevated levels of complement activation products have been measured in plasma, synovial fluid, and synovial tissues of patients. Complement polymorphisms are associated with RA in genome-wide association studies. Coding-region polymorphisms may directly impact protein activity; indeed, we have shown that complement polymorphisms affecting a single amino acid change cause subtle changes in individual component function that in combination have dramatic effects on complement activity and disease risk. In this study, we explore the functional consequences of a single nucleotide polymorphism (SNP) (rs17611) encoding a V802I polymorphism in C5 and propose a mechanism for its link to RA pathology. Plasma levels of C5, C5a, and terminal complement complex were measured in healthy and RA donors and correlated to rs17611 polymorphic status. Impact of the SNP on C5 functionality was assessed. Plasma C5a levels were significantly increased and C5 levels significantly lower with higher copy number of the RA risk allele for rs17611, suggesting increased turnover of C5 V802. Functional assays using purified C5 variants revealed no significant differences in lytic act...Continue Reading

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Citations

Nov 5, 2016·Nature Reviews. Rheumatology·Kwangwoo KimSang-Cheol Bae
Jan 18, 2017·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·L A MichielsenH G Otten
Jun 21, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Joanna L GilesClaire L Harris
Sep 28, 2017·Seminars in Immunopathology·Simon J Clark, Paul N Bishop
Jun 21, 2015·The Journal of Immunology : Official Journal of the American Association of Immunologists·Tobias MessemakerFina Kurreeman
May 28, 2017·Scientific Reports·Katherine V GatesLeigh G Griffiths
Dec 8, 2019·Translational Stroke Research·Bart J van DijkMervyn D I Vergouwen
Jan 6, 2021·Nature Immunology·Ahmet OzenMichael J Lenardo
Aug 14, 2021·KI Reports·Chiara CantarelliPaolo Cravedi

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Methods Mentioned

BETA
ELISA
gel filtration
Genotyping

Software Mentioned

ImageJ
Graphpad prism
GraphPad
Alexion

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