Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations
Vikrant Kumar1, Richard B Pouw2, Matias I Autio3
1Human Genetics, Genome Institute of Singapore, Singapore, Singapore; Duke-National University of Singapore Medical School, Singapore, Singapore.
American Journal of Human Genetics
|August 25, 2022
Summary
Lowering blood levels of complement factor H (FH) protects against meningococcal disease (MD). A specific genetic variant reduces FH levels, hindering Neisseria meningitidis immune evasion and thus preventing MD.
Area of Science:
- Genetics
- Immunology
- Microbiology
Background:
- Neisseria meningitidis evades complement-mediated killing by binding complement factor H (FH).
- Previous studies linked complement factor H (CFH) gene variations to meningococcal disease (MD) susceptibility, but causal variants and mechanisms were unclear.
Purpose of the Study:
- To identify causal variants in the CFH-CFHR locus associated with MD susceptibility.
- To elucidate the mechanism by which these variants influence FH levels and disease protection.
Main Methods:
- Sequencing of the CFH-CFHR locus and genotype imputation in GWAS datasets.
- Statistical analysis to associate genetic variants with MD and FH levels.
- Dual-luciferase assays and CRISPR gene editing to investigate gene regulation.
Main Results:
- A CFHR3 single nucleotide polymorphism (SNP), rs75703017, was identified as protective against MD (p = 1.1 × 10⁻¹⁶).
- This SNP was associated with decreased blood FH concentrations (p = 1.4 × 10⁻¹¹).
- Deletion of rs75703017 enhanced FH expression in hepatocytes by relieving promoter inhibition.
Conclusions:
- Reduced blood FH concentrations confer protection against meningococcal disease.
- The protective variant rs75703017 increases FH expression, thereby limiting Neisseria meningitidis's ability to evade complement-mediated killing.
