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

Introduction 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 novel single-nucleotide polymorphisms (SNPs). Methods In the present study, we sought 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. Results 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, and this SNP was associated with hypo-inflammation and genotype-associated organ dysfunction trajectories. Further related to Th17 responses, the SNP rs11919443 in the non-hub TM4SF19 gene defined genotype-associated systemic IL-17A trajectories and also associated hypo-inflammation with adverse outcomes. In contrast, no Th17-related hub genes were identified in a control group of SNPs. Secondary analysis showed several statistically significant differences in circulating inflammatory mediators not including IL-17A in this control group, and also associated hypo-inflammation with adverse outcomes. Discussion This study thus extends our prior work aimed at defining genetic predisposition to dysregulated inflammation and pathophysiology in the context of critical illness, points to a crucial role for type 17 immune responses, and highlights hypo-inflammation as a pathological immune phenotype in critical illness.