Abstract 13251: Experimental Endotoxemia Uncovers a Genomic Basis for Thermoregulation: Chr7p11.2 Locus in Inflammatory Febrile Response and Temperature Homeostasis
The febrile response is a clinically relevant hallmark of acute activation of innate immunity. Genomic regulation of the degree and nature of febrile response may impact clinical outcomes in acute infections, sepsis and trauma. Yet the genetic determinants of temperature regulation are poorly understood. We investigated the genomic determinants of the febrile response to experimental endotoxemia (LPS 1ng/kg IV) in healthy participants in the Genetics of Evoked Responses to Niacin and Endotoxemia (GENE) Study. Through genome-wide association analysis, we discovered a locus on chr7p11.2 significantly associated with the peak febrile response to LPS (top SNP rs7805622, P=2.4x10-12). Minor allele carriers of rs7805622 had a higher peak response, but also a lower nadir, and greater degree of bidirectional fluctuation in their temperature response post-LPS. This SNP was also associated with temperature change in a critically ill trauma cohort and was associated with death in cohorts of trauma or severe sepsis. The top GWAS SNPs are not located within any protein coding genes, but have significant cis-eQTL associations with expression of several genes ~400Kb upstream, several of which (SUMF2, CCT6A, GBAS) are also regulated by LPS in monocytes, whole blood and adipose. The top SNPs also localize within novel linc-RNAs but whether these are expressed in relevant cells or have regulatory functions remains to be determined. In conclusion, through GWAS applied to experimental endotoxemia, we identified a novel thermoregulatory locus on chr7p11.2 that acts in cis on several candidate genes and also may modulate clinical outcomes in trauma and sepsis.
- © 2013 by American Heart Association, Inc.