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.
Abstract:
Neisseria meningitidis protects itself from complement-mediated killing by binding complement factor H (FH). Previous studies associated susceptibility to meningococcal disease (MD) with variation in CFH, but the causal variants and underlying mechanism remained unknown. Here we attempted to define the association more accurately by sequencing the CFH-CFHR locus and imputing missing genotypes in previously obtained GWAS datasets of MD-affected individuals of European ancestry and matched controls. We identified a CFHR3 SNP that provides protection from MD (rs75703017, p value = 1.1 × 10-16) by decreasing the concentration of FH in the blood (p value = 1.4 × 10-11). We subsequently used dual-luciferase studies and CRISPR gene editing to establish that deletion of rs75703017 increased FH expression in hepatocyte by preventing promotor inhibition. Our data suggest that reduced concentrations of FH in the blood confer protection from MD; with reduced access to FH, N. meningitidis is less able to shield itself from complement-mediated killing.
Insights
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.
