Network Analysis of Rare Single-Nucleotide Polymorphisms Suggests a Central Role for Type 17 Immune Responses in Trauma-induced, Genotypically Associated Hypo-Inflammation and Critical Illness

Abstract

Critical illness stemming from severe traumatic injury is a leading cause of morbidity and mortality worldwide, involves the dysfunction of multiple organ systems, and is driven at least in part by dysregulated inflammation that involves type 17 immunity. We and others have demonstrated a genetic predisposition to adverse critical illness outcomes associated with single-nucleotide polymorphisms (SNPs) in novel loci distinct from those which impact type 17 immune responses yet acting in concert with those responses. We have recently developed SNPScanner, an algorithm that enables rapid scanning through a large SNP dataset and associated inflammation biomarkers and clinical data, and in the present study leveraged this algorithm in concert with existing bioinformatics tools to define networks of interaction among rare SNPs (defined operationally as being present in 5-10% of patients due to the study cohort size) assessed in critically ill trauma patients. RAR-related orphan receptor A (RORA), a transcription factor central to the differentiation of Th17 cells, was inferred as a hub gene via its SNP rs4774381; stratification of trauma patients based on homozygous genotype at this SNP pointed to distinct organ dysfunction trajectories associated with network-defined hypo-inflammation. Further, the SNP rs11919443 in the non-hub TM4SF19 gene distinguished genotype-associated systemic IL-17A trajectories, and associated hypo-inflammation with adverse outcomes. In contrast, no Th17-related hub genes were identified in a control group of SNPs associated algorithmically with adverse clinical outcomes but with genotypically indistinct systemic inflammatory responses; the main inferred hub gene in this control group was solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1)/glucose transporter 1 (GLUT1). Secondary analysis showed several statistically significant differences in circulating inflammatory mediators not including IL-17A, and also associated network-based hypo-inflammation with adverse outcomes in this control group. This study thus extends our prior work aimed at defining genetic predisposition to dysregulated inflammation and pathophysiology in the context of critical illness, and points to a crucial role for type 17 immune responses.