Medical Records-Based Genetic Studies of the Complement System
Atlas Khan1, Ning Shang2, Lynn Petukhova3,4
1Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York.
Summary
Genetic variants significantly impact complement C3 and C4 levels, revealing links to various diseases. These findings advance our understanding of complement activation in human health and illness.
Area of Science:
- Genetics
- Immunology
- Human Health
Background:
- Genetic variants in complement genes are linked to numerous human diseases.
- Large-scale genetic association studies of complement activation are lacking in diverse populations.
Purpose of the Study:
- To identify genetic determinants of plasma C3 and C4 levels.
- To explore the clinical correlations of genetic variants influencing complement activation.
Main Methods:
- Genome-wide and phenome-wide association studies (GWAS/PheWAS) were conducted using electronic health records from the eMERGE network.
- Analysis included single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for C3 and C4 levels.
Main Results:
- Two genome-wide significant loci for C3 levels (CFH and C3) were identified.
- A strong genome-wide significant locus for C4 levels (C4) was detected, explaining substantial variance.
- Specific C4 copy number variants (C4-BS, C4-AL-BS) demonstrated significant effects on C4 levels.
- Phenome-wide association studies revealed genetic links between complement activation and autoimmune, cardiometabolic, and kidney diseases.
Conclusions:
- Genetic variants regulating C3 and C4 levels were discovered using eMERGE data.
- These variants have substantial effects and broad clinical relevance across complement-related human diseases.
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