title: Integrative genomics identifies 7p11.2 as a novel locus for fever and clinical stress response in humans.
abstract: Fever predicts clinical outcomes in sepsis, trauma and during cardiovascular stress, yet the genetic determinants are poorly understood. We used an integrative genomics approach to identify novel genomic determinants of the febrile response to experimental endotoxemia. We highlight multiple integrated lines of evidence establishing the clinical relevance of this novel fever locus. Through genome-wide association study (GWAS) of evoked endotoxemia (lipopolysaccharide (LPS) 1 ng/kg IV) in healthy subjects of European ancestry we discovered a locus on chr7p11.2 significantly associated with the peak febrile response to LPS (top single nucleotide polymorphism (SNP) rs7805622, P = 2.4 × 10(-12)), as well as with temperature fluctuation over time. We replicated this association in a smaller independent LPS study (rs7805622, P = 0.03). In clinical translation, this locus was also associated with temperature and mortality in critically ill patients with trauma or severe sepsis. The top GWAS SNPs are not located within protein-coding genes, but have significant cis-expression quantitative trait loci (eQTL) associations with expression of a cluster of genes ∼400 kb upstream, several of which (SUMF2, CCT6A, GBAS) are regulated by LPS in vivo in blood cells. LPS- and cold-treatment of adipose stromal cells in vitro suggest genotype-specific modulation of eQTL candidate genes (PSPH). Several eQTL genes were up-regulated in brown and white adipose following cold exposure in mice, highlighting a potential role in thermogenesis. Thus, through genomic interrogation of experimental endotoxemia, we identified and replicated a novel fever locus on chr7p11.2 that modulates clinical responses in trauma and sepsis, and highlight integrated in vivo and in vitro evidence for possible novel cis candidate genes conserved across human and mouse.
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine, Division of Cardiovascular Medicine, Vanderbilt University, Nashville, TN, USA jane.f.ferguson@vanderbilt.edu.
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.affiliation: Division of Pulmonary, Allergy and Critical Care.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.affiliation: Department of Biostatistics and Epidemiology.
authors.forename: Liming
authors.initials: L
authors.lastname: Qu
authors.affiliation: Department of Biostatistics and Epidemiology.
authors.forename: Chenyi
authors.initials: C
authors.lastname: Xue
authors.affiliation: Department of Biostatistics and Epidemiology.
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine.
authors.forename: Stephanie L
authors.initials: SL
authors.lastname: DerOhannessian
authors.affiliation: Division of Pulmonary, Allergy and Critical Care.
authors.forename: Melanie
authors.initials: M
authors.lastname: Rushefski
authors.affiliation: Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Georgios K
authors.initials: GK
authors.lastname: Paschos
authors.affiliation: Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Soonyew
authors.initials: S
authors.lastname: Tang
authors.affiliation: Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Schadt
authors.affiliation: Department of Biostatistics and Epidemiology.
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.affiliation: Division of Pulmonary, Allergy and Critical Care.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.affiliation: Cardiovascular Institute, Perelman School of Medicine.
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002897:Chromosomes, Human, Pair 7; D005260:Female; D005334:Fever / Q000139:chemically induced / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D050436:Regulatory Elements, Transcriptional; D018805:Sepsis / Q000235:genetics; D013312:Stress, Physiological / Q000187:drug effects / Q000235:genetics*; D044465:White People / Q000235:genetics; D014947:Wounds and Injuries / Q000235:genetics; D055815:Young Adult
chemical_list: D008070:Lipopolysaccharides