Genetic determinants of complement activation in the general population
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 alt...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723016236 |
| _version_ | 1797372023336337408 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Damia Noce |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-08T18:29:26Z |
| format | Article |
| id | doaj.art-1509f3ea44c84e049cafc3e294f444b1 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-08T18:29:26Z |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-1509f3ea44c84e049cafc3e294f444b12023-12-30T04:44:11ZengElsevierCell Reports2211-12472024-01-01431113611Genetic determinants of complement activation in the general populationDamia Noce0Luisa Foco1Dorothea Orth-Höller2Eva König3Giulia Barbieri4Maik Pietzner5Dariush Ghasemi-Semeskandeh6Stefan Coassin7Christian Fuchsberger8Martin Gögele9Fabiola Del Greco M.10Alessandro De Grandi11Monika Summerer12Eleanor Wheeler13Claudia Langenberg14Cornelia Lass-Flörl15Peter Paul Pramstaller16Florian Kronenberg17Reinhard Würzner18Cristian Pattaro19Institute 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, AustriaInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute 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, AustriaInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute 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, ItalyComputational Medicine, Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, Germany; MRC Epidemiology Unit, University of Cambridge, Cambridge, UKInstitute 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 NetherlandsInstitute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, AustriaInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, AustriaMRC Epidemiology Unit, University of Cambridge, Cambridge, UKComputational Medicine, Berlin Institute of Health (BIH) at Charité – Universitätsmedizin Berlin, Berlin, GermanyInstitute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, AustriaInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, ItalyInstitute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; Corresponding authorInstitute of Hygiene & Medical Microbiology, Department of Hygiene, Microbiology and Public Health, Medical University of Innsbruck, Schöpfstr. 41, 6020 Innsbruck, Austria; Corresponding authorInstitute for Biomedicine (affiliated to the University of Lübeck), Eurac Research, Via Volta 21, 39100 Bolzano, Italy; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124723016236CP: GenomicsCP: Immunology |
| spellingShingle | 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 Genetic determinants of complement activation in the general population Cell Reports CP: Genomics CP: Immunology |
| title | Genetic determinants of complement activation in the general population |
| title_full | Genetic determinants of complement activation in the general population |
| title_fullStr | Genetic determinants of complement activation in the general population |
| title_full_unstemmed | Genetic determinants of complement activation in the general population |
| title_short | Genetic determinants of complement activation in the general population |
| title_sort | genetic determinants of complement activation in the general population |
| topic | CP: Genomics CP: Immunology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723016236 |
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