Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Vikrant Kumar; Richard B. Pouw; EUCLIDS consortium; Matias I. Autio; Manfred G. Sagmeister; Zai Yang Phua; Lisa Borghini; Victoria J. Wright; Clive Hoggart; Bangfen Pan; Antson Kiat Yee Tan; Alexander Binder; Mieke C. Brouwer; Ellie Pinnock; Ronald De Groot; Jan Hazelzet; Marieke Emonts; Michiel Van Der Flier; Karl Reiter; Markus M. Nöthen; Per Hoffmann; Luregn J. Schlapbach; Evangelos Bellos; Suzanne Anderson; Fatou Secka; Federico Martinón-Torres; Antonio Salas; Colin Fink; Enitan D. Carrol; Andrew J. Pollard; Lachlan J. Coin; Werner Zenz; Diana Wouters; Lay Teng Ang; Martin L. Hibberd; Michael Levin; Taco W. Kuijpers; Sonia Davila

doi:10.1016/j.ajhg.2022.08.001

Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

Vikrant Kumar, Richard B. Pouw, EUCLIDS consortium, Matias I. Autio, Manfred G. Sagmeister, Zai Yang Phua, Lisa Borghini, Victoria J. Wright, Clive Hoggart, Bangfen Pan, Antson Kiat Yee Tan, Alexander Binder, Mieke C. Brouwer, Ellie Pinnock, Ronald De Groot, Jan Hazelzet, Marieke Emonts, Michiel Van Der Flier, Karl Reiter, Markus M. NöthenPer Hoffmann, Luregn J. Schlapbach, Evangelos Bellos, Suzanne Anderson, Fatou Secka, Federico Martinón-Torres, Antonio Salas, Colin Fink, Enitan D. Carrol, Andrew J. Pollard, Lachlan J. Coin, Werner Zenz, Diana Wouters, Lay Teng Ang, Martin L. Hibberd, Michael Levin, Taco W. Kuijpers^*, Sonia Davila

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Pages (from-to)	1680-1691
Number of pages	12
Journal	American Journal of Human Genetics
Volume	109
Issue number	9
DOIs	https://doi.org/10.1016/j.ajhg.2022.08.001
Publication status	Published - 1 Sept 2022

Bibliographical note

Acknowledgments:
We would like to thank all individuals who participated in this study. All samples have been collected under country-specific institutional review boards (UK EC3263; Netherlands: 37986.091.11/RvB12.51320; Austria: 24-116 ex 11/12; Spain: 2011/298; Swiss: Cantonal Ethics Committee, Inselspital, University of Bern, no. KEK- 029/11). This work has been partially supported by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement no. 279185, and by funding from the Agency for Science, Technology, and Research of Singapore (A∗STAR). Additional funding supporting the establishment of the MD cohorts used in this study are kindly acknowledged and listed in the supplemental information. R.B.P. M.C.B. D.W. and T.W.K. are co-inventors of patents or patent applications describing FH potentiating antibodies and uses thereof. A.J.P. is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation. F.M.-T. has received honoraria from GSK group of companies, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F.M.-T. has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. All other authors declare no relevant competing interest related to the contents of this manuscript.

Publisher Copyright: © 2022 The Authors

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Kumar, V., Pouw, R. B., EUCLIDS consortium, Autio, M. I., Sagmeister, M. G., Phua, Z. Y., Borghini, L., Wright, V. J., Hoggart, C., Pan, B., Tan, A. K. Y., Binder, A., Brouwer, M. C., Pinnock, E., De Groot, R., Hazelzet, J., Emonts, M., Van Der Flier, M., Reiter, K., ... Davila, S. (2022). Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations. American Journal of Human Genetics, 109(9), 1680-1691. https://doi.org/10.1016/j.ajhg.2022.08.001

@article{4c836a22409c4c11a0a81b06f6545bf8,

title = "Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations",

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.",

author = "Vikrant Kumar and Pouw, \{Richard B.\} and \{EUCLIDS consortium\} and Autio, \{Matias I.\} and Sagmeister, \{Manfred G.\} and Phua, \{Zai Yang\} and Lisa Borghini and Wright, \{Victoria J.\} and Clive Hoggart and Bangfen Pan and Tan, \{Antson Kiat Yee\} and Alexander Binder and Brouwer, \{Mieke C.\} and Ellie Pinnock and \{De Groot\}, Ronald and Jan Hazelzet and Marieke Emonts and \{Van Der Flier\}, Michiel and Karl Reiter and N{\"o}then, \{Markus M.\} and Per Hoffmann and Schlapbach, \{Luregn J.\} and Evangelos Bellos and Suzanne Anderson and Fatou Secka and Federico Martin{\'o}n-Torres and Antonio Salas and Colin Fink and Carrol, \{Enitan D.\} and Pollard, \{Andrew J.\} and Coin, \{Lachlan J.\} and Werner Zenz and Diana Wouters and Ang, \{Lay Teng\} and Hibberd, \{Martin L.\} and Michael Levin and Kuijpers, \{Taco W.\} and Sonia Davila",

note = "Acknowledgments: We would like to thank all individuals who participated in this study. All samples have been collected under country-specific institutional review boards (UK EC3263; Netherlands: 37986.091.11/RvB12.51320; Austria: 24-116 ex 11/12; Spain: 2011/298; Swiss: Cantonal Ethics Committee, Inselspital, University of Bern, no. KEK- 029/11). This work has been partially supported by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement no. 279185, and by funding from the Agency for Science, Technology, and Research of Singapore (A∗STAR). Additional funding supporting the establishment of the MD cohorts used in this study are kindly acknowledged and listed in the supplemental information. R.B.P. M.C.B. D.W. and T.W.K. are co-inventors of patents or patent applications describing FH potentiating antibodies and uses thereof. A.J.P. is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation. F.M.-T. has received honoraria from GSK group of companies, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F.M.-T. has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. All other authors declare no relevant competing interest related to the contents of this manuscript. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = sep,

day = "1",

doi = "10.1016/j.ajhg.2022.08.001",

language = "English",

volume = "109",

pages = "1680--1691",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

number = "9",

}

Kumar, V, Pouw, RB, EUCLIDS consortium, Autio, MI, Sagmeister, MG, Phua, ZY, Borghini, L, Wright, VJ, Hoggart, C, Pan, B, Tan, AKY, Binder, A, Brouwer, MC, Pinnock, E, De Groot, R, Hazelzet, J, Emonts, M, Van Der Flier, M, Reiter, K, Nöthen, MM, Hoffmann, P, Schlapbach, LJ, Bellos, E, Anderson, S, Secka, F, Martinón-Torres, F, Salas, A, Fink, C, Carrol, ED, Pollard, AJ, Coin, LJ, Zenz, W, Wouters, D, Ang, LT, Hibberd, ML, Levin, M, Kuijpers, TW & Davila, S 2022, 'Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations', American Journal of Human Genetics, vol. 109, no. 9, pp. 1680-1691. https://doi.org/10.1016/j.ajhg.2022.08.001

TY - JOUR

T1 - Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

AU - Kumar, Vikrant

AU - Pouw, Richard B.

AU - EUCLIDS consortium

AU - Autio, Matias I.

AU - Sagmeister, Manfred G.

AU - Phua, Zai Yang

AU - Borghini, Lisa

AU - Wright, Victoria J.

AU - Hoggart, Clive

AU - Pan, Bangfen

AU - Tan, Antson Kiat Yee

AU - Binder, Alexander

AU - Brouwer, Mieke C.

AU - Pinnock, Ellie

AU - De Groot, Ronald

AU - Hazelzet, Jan

AU - Emonts, Marieke

AU - Van Der Flier, Michiel

AU - Reiter, Karl

AU - Nöthen, Markus M.

AU - Hoffmann, Per

AU - Schlapbach, Luregn J.

AU - Bellos, Evangelos

AU - Anderson, Suzanne

AU - Secka, Fatou

AU - Martinón-Torres, Federico

AU - Salas, Antonio

AU - Fink, Colin

AU - Carrol, Enitan D.

AU - Pollard, Andrew J.

AU - Coin, Lachlan J.

AU - Zenz, Werner

AU - Wouters, Diana

AU - Ang, Lay Teng

AU - Hibberd, Martin L.

AU - Levin, Michael

AU - Kuijpers, Taco W.

AU - Davila, Sonia

N1 - Acknowledgments: We would like to thank all individuals who participated in this study. All samples have been collected under country-specific institutional review boards (UK EC3263; Netherlands: 37986.091.11/RvB12.51320; Austria: 24-116 ex 11/12; Spain: 2011/298; Swiss: Cantonal Ethics Committee, Inselspital, University of Bern, no. KEK- 029/11). This work has been partially supported by the European Seventh Framework Programme for Research and Technological Development (FP7) under EUCLIDS Grant Agreement no. 279185, and by funding from the Agency for Science, Technology, and Research of Singapore (A∗STAR). Additional funding supporting the establishment of the MD cohorts used in this study are kindly acknowledged and listed in the supplemental information. R.B.P. M.C.B. D.W. and T.W.K. are co-inventors of patents or patent applications describing FH potentiating antibodies and uses thereof. A.J.P. is chair of the UK Department of Health and Social Care's Joint Committee on Vaccination and Immunisation. F.M.-T. has received honoraria from GSK group of companies, Pfizer Inc, Sanofi Pasteur, MSD, Seqirus, Biofabri, and Janssen for taking part in advisory boards and expert meetings and for acting as a speaker in congresses outside the scope of the submitted work. F.M.-T. has also acted as principal investigator in randomized controlled trials of the above-mentioned companies as well as Ablynx, Gilead, Regeneron, Roche, Abbott, Novavax, and MedImmune, with honoraria paid to his institution. All other authors declare no relevant competing interest related to the contents of this manuscript. Publisher Copyright: © 2022 The Authors

PY - 2022/9/1

Y1 - 2022/9/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85137092784

U2 - 10.1016/j.ajhg.2022.08.001

DO - 10.1016/j.ajhg.2022.08.001

M3 - Article

C2 - 36007525

AN - SCOPUS:85137092784

SN - 0002-9297

VL - 109

SP - 1680

EP - 1691

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

IS - 9

ER -

Variation in CFHR3 determines susceptibility to meningococcal disease by controlling factor H concentrations

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