Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis
Joanna L Giles1, Ernest Choy2, Carmen van den Berg3
1Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; MorganBP@cf.ac.uk.
Journal of Immunology (Baltimore, Md. : 1950)
|March 1, 2015
Summary
A specific C5 gene variation (V802I) increases complement activation product C5a in rheumatoid arthritis (RA) patients. This suggests a novel mechanism linking complement C5 gene variants to RA inflammation.
Area of Science:
- Immunology
- Genetics
Background:
- Complement system activation is crucial in rheumatoid arthritis (RA) pathogenesis.
- Genetic variations in complement components are linked to RA susceptibility.
- Previous research indicates single amino acid changes in complement proteins can significantly alter function and disease risk.
Purpose of the Study:
- To investigate the functional consequences of a single nucleotide polymorphism (SNP) rs17611, encoding a V802I polymorphism in complement component 5 (C5).
- To elucidate the mechanism by which this C5 polymorphism contributes to RA pathology.
Main Methods:
- Quantification of plasma C5, C5a, and terminal complement complex levels in healthy and RA donors.
- Correlation of C5 levels with rs17611 polymorphic status.
- Assessment of C5 functionality using purified C5 variants and in vitro assays with elastase.
Main Results:
- Increased plasma C5a levels and decreased C5 levels were observed with higher copy numbers of the RA risk allele for rs17611.
- No significant differences in lytic activity were found between C5 variants, indicating convertase-independent turnover.
- The C5 V802 variant showed increased sensitivity to elastase cleavage, generating biologically active C5a.
Conclusions:
- The rs17611 SNP in C5 may increase RA joint inflammation by enhancing elastase-mediated generation of active C5a.
- This mechanism promotes neutrophil recruitment to the joint, perpetuating the inflammatory cycle in RA.
- C5 polymorphisms represent a potential therapeutic target for managing RA.
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