title: Pathway genetic load allows simultaneous evaluation of multiple genetic associations.
abstract: OBJECTIVE
  Despite the general success of genome-wide association studies, much heritability remains unidentified in many disease states. Some of this 'missing' heritability may lie in epistatic interactions among multiple loci, which are typically ignored. We utilized a method for simultaneous evaluation of epistatic interactions between allelic variations within genes confined to a single pathway, which we have termed as pathway genetic load (PGL).
  
  
  METHODS
  In separate analyses, we evaluated the risk for sepsis and for death associated with alleles at six loci in the TLR4 signaling and response pathway previously known or suspected to be linked to the development of sepsis after traumatic injury. We evaluated 155 patients with > or =15% TBSA burns and without significant non-burn trauma [ISS < or =16], traumatic or anoxic brain injury or spinal cord injury, who survived > 48 h post-admission. Clinical data were collected prospectively and candidate genotypes were determined by TaqMan assay.
  
  
  RESULTS
  After adjustment for burn size, inhalation injury, age, gender and race, PGL was associated with increased probability for complicated sepsis (aOR=1.59; 95%CI=1.11-2.29; p=0.011) and death (aOR=1.75; 95%CI=1.11-2.76; p=0.017).
  
  
  CONCLUSIONS
  Relative size and variability of aORs indicate greater power to detect genetic associations with PGL compared to the analysis of loci individually by multivariate logistic regression.
authors.affiliation: Department of Surgery, The University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.
authors.forename: Ryan M
authors.initials: RM
authors.lastname: Huebinger
authors.forename: Harold R
authors.initials: HR
authors.lastname: Garner
authors.forename: Robert C
authors.initials: RC
authors.lastname: Barber
mesh_terms: D000328:Adult; D000483:Alleles; D002056:Burns / Q000150:complications* / Q000401:mortality; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D012306:Risk; D018805:Sepsis / Q000235:genetics*; D051197:Toll-Like Receptor 4 / Q000235:genetics; D055815:Young Adult
chemical_list: D051197:Toll-Like Receptor 4