Genetic determinants of complement activation in the general population
Damia Noce1, Luisa Foco2, Dorothea Orth-Höller3
1Institute 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, Austria.
Cell Reports
|December 30, 2023
Summary
This study identifies key genetic variants influencing complement pathways, revealing their significant role in immune response and disease risk. These findings enhance our understanding of the complement system
Area of Science:
- Immunology
- Genetics
- Systems Biology
Background:
- The complement system is crucial for innate immunity, and its dysregulation is linked to severe systemic diseases.
- Understanding the genetic basis of complement pathway activity is essential for elucidating its role in health and disease.
Purpose of the Study:
- To identify genetic variants associated with the functional activity of the classical (CP), lectin (LP), and alternative (AP) complement pathways.
- To investigate the causal relationships between complement pathways, related molecules, and disease risk.
Main Methods:
- Genome-wide association studies (GWAS) were performed on complement pathway activity in a large cohort (n=4,990).
- Pathway-specific variants in complement and non-complement genes were identified.
- Two-sample Mendelian randomization analyses, supported by colocalization with transcriptome-wide and proteome-wide data, were used to infer causality.
Main Results:
- Seven loci with 13 independent, pathway-specific variants were identified, explaining up to 74% of heritability for complement pathways.
- Variants near complement genes (CFHR4, C7, C2, MBL2) and non-complement genes (PDE3A, TNXB, ABO) were implicated.
- Causality was confirmed for known pathways and established for ABO on LP, and CFHR2/C7 on AP. LP was causally linked to collectin-11, KAAG1, and mouth ulcer risk.
Conclusions:
- This study provides a comprehensive genetic resource for the complement system.
- The findings highlight the genetic architecture of complement pathways and their causal impact on immune function and disease.
- Further research can leverage these results to explore complement's role in human health and disease pathogenesis.
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