Genetic determinants of complement activation in the general population

Damia Noce; Luisa Foco; Dorothea Orth-Höller; Eva König; Giulia Barbieri; Maik Pietzner; Dariush Ghasemi-Semeskandeh; Stefan Coassin; Christian Fuchsberger; Martin Gögele; Fabiola Del Greco M.; Alessandro De Grandi; Monika Summerer; Eleanor Wheeler; Claudia Langenberg; Cornelia Lass-Flörl; Peter Paul Pramstaller; Florian Kronenberg; Reinhard Würzner; Cristian Pattaro

Cell Reports (Jan 2024)

Genetic determinants of complement activation in the general population

Damia Noce,
Luisa Foco,
Dorothea Orth-Höller,
Eva König,
Giulia Barbieri,
Maik Pietzner,
Dariush Ghasemi-Semeskandeh,
Stefan Coassin,
Christian Fuchsberger,
Martin Gögele,
Fabiola Del Greco M.,
Alessandro De Grandi,
Monika Summerer,
Eleanor Wheeler,
Claudia Langenberg,
Cornelia Lass-Flörl,
Peter Paul Pramstaller,
Florian Kronenberg,
Reinhard Würzner,
Cristian Pattaro

Affiliations

Damia Noce: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Luisa Foco: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Dorothea Orth-Höller: Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; MB-LAB – Clinical Microbiology Laboratory, Franz-Fischer-Str. 7b, 6020 Innsbruck, Austria
Eva König: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Giulia Barbieri: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy
Maik Pietzner: Computational Medicine, Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany; MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
Dariush Ghasemi-Semeskandeh: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Stefan Coassin: Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Christian Fuchsberger: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Martin Gögele: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Fabiola Del Greco M.: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Alessandro De Grandi: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Monika Summerer: Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Eleanor Wheeler: MRC Epidemiology Unit, University of Cambridge, Cambridge, UK
Claudia Langenberg: Computational Medicine, Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany
Cornelia Lass-Flörl: Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria
Peter Paul Pramstaller: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy
Florian Kronenberg: Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; Corresponding author
Reinhard Würzner: Institute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; Corresponding author
Cristian Pattaro: Institute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Corresponding author

Journal volume & issue: Vol. 43, no. 1
p. 113611

Abstract

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Summary: Complement is a fundamental innate immune response component. Its alterations are associated with severe systemic diseases. To illuminate the complement’s genetic underpinnings, we conduct genome-wide association studies of the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways in the Cooperative Health Research in South Tyrol study (n = 4,990). We identify seven loci, encompassing 13 independent, pathway-specific variants located in or near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO), explaining up to 74% of complement pathways’ genetic heritability and implicating long-range haplotypes associated with LP at MBL2. Two-sample Mendelian randomization analyses, supported by transcriptome- and proteome-wide colocalization, confirm known causal pathways, establish within-complement feedback loops, and implicate causality of ABO on LP and of CFHR2 and C7 on AP. LP causally influences collectin-11 and KAAG1 levels and the risk of mouth ulcers. These results build a comprehensive resource to investigate the role of complement in human health.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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