학술논문
Genetic determinants of complement activation in the general population
Document Type
article
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
Source
Cell Reports, Vol 43, Iss 1, Pp 113611- (2024)
Subject
Language
English
ISSN
2211-1247
Abstract
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.