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Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations
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EUCLIDS Consortium (Including:
). (2022) Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations. The American Journal of Human Genetics, 109 (9). pp. 1680-1691. doi:10.1016/j.ajhg.2022.08.001 ISSN 0002-9297.
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WRAP-Variation-in-CFHR3-determines-susceptibility-to-meningococcal-disease-by-controlling-factor-H-concentrations-Fink-2022.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution Non-commercial No Derivatives 4.0. Download (1965Kb) | Preview |
Official URL: http://dx.doi.org/10.1016/j.ajhg.2022.08.001
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.
Item Type: | Journal Article | |||||||||
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Subjects: | Q Science > QR Microbiology R Medicine > RC Internal medicine |
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Divisions: | Faculty of Science, Engineering and Medicine > Science > Life Sciences (2010- ) | |||||||||
Library of Congress Subject Headings (LCSH): | Neisseria meningitidis, Meningococcal infections -- Treatment, Meningitis, Septicemia | |||||||||
Journal or Publication Title: | The American Journal of Human Genetics | |||||||||
Publisher: | Cell Press | |||||||||
ISSN: | 0002-9297 | |||||||||
Official Date: | 1 September 2022 | |||||||||
Dates: |
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Volume: | 109 | |||||||||
Number: | 9 | |||||||||
Page Range: | pp. 1680-1691 | |||||||||
DOI: | 10.1016/j.ajhg.2022.08.001 | |||||||||
Status: | Peer Reviewed | |||||||||
Publication Status: | Published | |||||||||
Access rights to Published version: | Open Access (Creative Commons) | |||||||||
Date of first compliant deposit: | 7 September 2022 | |||||||||
Date of first compliant Open Access: | 8 September 2022 | |||||||||
RIOXX Funder/Project Grant: |
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