Genetic Variation in the Alternative Complement Pathway Contributes to Individual Susceptibility to Bacteremia and Sepsis.

The alternative complement pathway is a key component of host defense against bacteremia and other infections. However, dysregulated activation can contribute to excessive inflammation and worse clinical outcomes during bacteremia and infectious syndromes such as sepsis. We aim to identify variants in alternative pathway (AP) genes that influence the risk for bacteremia and sepsis. We used summary statistics from a Veterans Affairs Million Veteran Program (MVP) genome-wide by phenome-wide association study of more than 600,000 individuals. Using seven electronic health record-derived Phecodes for bacteremia or sepsis, we investigated associations with single-nucleotide polymorphisms (SNPs) in genes encoding multiple AP components. We also investigated potential regulatory SNPs near candidate genes based on expression quantitative trait loci (eQTL) data or in silico modeling (Combined Annotation Dependent Depletion and RegulomeDB scores). In the MVP trans-ancestral meta-analysis, we identified 25 unique lead genic SNPs with a minor allele frequency of greater than 1% that were significantly associated with incidence of sepsis or bacteremia Phecodes. Most were intronic (n = 21), with four exonic variants, including one in C5AR1 (rs4804049) that has novel associations with multiple Phecodes. Outside of AP gene loci, we also identified significant associations in 14 unique SNPs with predicted regulatory effects by in silico modeling and 11 unique SNPs with eQTL data suggesting an impact on AP gene expression. Variants in complement factor B (CFB), complement factor I (CFI), and C5a receptors (C5AR1/C5AR2) accounted for most of the significant genic SNPs, while noncoding functional variants primarily affected CFB, CFD, and the C5a receptor 1 (C5AR1). We identified potentially clinically relevant genetic variation in the alternative complement pathway that may contribute to individual susceptibility to bacteremia and sepsis syndromes. Further study is required to understand the mechanisms behind these associations and their clinical impacts.