Details

Autor(en) / Beteiligte

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

Titel

Genetic determinants of complement activation in the general population

Ist Teil von

• Cell reports (Cambridge), 2024-01, Vol.43 (1), p.113611-113611, Article 113611

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• 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. [Display omitted] •Genome-wide association study of the functional activity of the three complement pathways•Identified genetic loci are pathway specific, not shared between pathways•ABO, KAAG1, SEMA4A, and PTGR2 proteins are causally involved with complement pathways•The lectin pathway is causally associated with mouth ulcer risk Noce et al. conduct a general-population genome-wide association study of the functional activity of complement pathways. Identified loci explain a large genetic heritability fraction, enabling detection of causal relations with proteins and establishing a causal role of the lectin pathway on mouth ulcer risk.