Genetic determinants of complement activation in the general population.
Cell reports 2023 ; 43: 113611.
Noce D, Foco L, Orth-Höller D, König E, Barbieri G, Pietzner M, Ghasemi-Semeskandeh D, Coassin S, Fuchsberger C, Gögele M, Del Greco M F, De Grandi A, Summerer M, Wheeler E, Langenberg C, Lass-Flörl C, Pramstaller PP, Kronenberg F, Würzner R, Pattaro C
DOI : 10.1016/j.celrep.2023.113611
PubMed ID : 38159276
PMCID :
URL : https://linkinghub.elsevier.com/retrieve/pii/S2211124723016236
Abstract
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.