Abstract Rationale Pneumonia is a leading cause of death worldwide. The alternative pathway of complement is a key component of the host defense against pneumonia. Identification of genetic variants in the alternative pathway that are associated with pneumonia may enable earlier recognition of high-risk populations and lead to improved precision medicine approaches. Methods We leveraged summary data from a Veterans Affairs (VA) Million Veteran Program (MVP) genome-wide by phenome-wide (GwPheWAS) investigation of over 600,000 individuals. We extracted results for single nucleotide polymorphisms (SNPs) in or near genes encoding alternative pathway proteins and receptors (17 genes in total) in patients with 9 pneumonia Phecodes (a classification scheme based on electronic medical record coding) grouped by pathogen type. Putative regulatory variants were identified as those with likely phenotypic effects based upon expression quantitative trait loci (eQTL) and in silico models (Combined Annotation Dependent Depletion CADD and RegulomeDB scores). Results were based upon MVP trans-ancestral meta-analysis summary data for each Phecode (650-44,325 cases). Baseline significance threshold was corrected for multiple observations via gene-by-gene Li and Ji transformation. Significant SNPs were clustered by linkage disequilibrium (LD) using LDMatrix and lead SNPs were identified by the Sum of Single Effects (SuSiE) R package. Results We identified 40 unique genic lead variants in the MVP trans-ancestral meta-analysis that were significantly associated with pneumonia Phecodes. Most (n = 32) were intronic, but 5 were exonic (of which 3 were nonsynonymous). We also identified 10 unique intergenic SNPs with in silico data suggesting regulatory impacts. Finally, there were 19 additional intergenic SNPs with eQTL data to support altered expression of alternative pathway genes. In specific pathogen subgroups, we identified 6 unique SNPs that were associated with bacterial pneumonia, 32 that were associated with viral pneumonia, and 2 that were associated with fungal pneumonia. Bacterial and fungal pneumonia were associated with variants impacting alternative pathway activators (CFB/CFD, n = 4/8 50%) and receptors for immunostimulatory complement end-products (C5AR1 and CR1/CR2, n = 3/8 38%) while viral pneumonia was associated with mutations in alternative pathway inhibitors/regulators (CFH and CFHR1-4, n = 25/32 78%). Conclusions We identified potentially clinically relevant genetic variation in the alternative complement pathway that may contribute to individual susceptibility to pneumonia. Our preliminary results suggest that variants impacting alternative pathway activation affect susceptibility to bacterial and fungal pneumonia while variants impacting alternative pathway inhibition and regulation affect susceptibility to viral pneumonia. Further study is required to understand the mechanisms behind these associations. This abstract is funded by: T32(HL007563)
Inman et al. (Fri,) studied this question.
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