| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Cell Reports, Vol 43, Iss 1, Pp 113611- (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2211-1247 |
| DOI: |
10.1016/j.celrep.2023.113611 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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