title: Interleukin-1β gene variants are associated with QTc interval prolongation following cardiac surgery: a prospective observational study.
abstract: BACKGROUND
  We characterized cardiac surgery-induced dynamic changes of the corrected QT (QTc) interval and tested the hypothesis that genetic factors are associated with perioperative QTc prolongation independent of clinical and procedural factors.
  
  
  METHODS
  All study subjects were ascertained from a prospective study of patients who underwent elective cardiac surgery during August 1999 to April 2002. We defined a prolonged QTc interval as > 440 msec, measured from 24-hr pre- and postoperative 12-lead electrocardiograms. The association of 37 single nucleotide polymorphisms (SNPs) in 21 candidate genes -involved in modulating arrhythmia susceptibility pathways with postoperative QTc changes- was investigated in a two-stage design with a stage I cohort (n = 497) nested within a stage II cohort (n = 957). Empirical P values (Pemp) were obtained by permutation tests with 10,000 repeats.
  
  
  RESULTS
  After adjusting for clinical and procedural risk factors, we selected four SNPs (P value range, 0.03-0.1) in stage I, which we then tested in the stage II cohort. Two functional SNPs in the pro-inflammatory cytokine interleukin-1β (IL1β), rs1143633 (odds ratio [OR], 0.71; 95% confidence interval [CI], 0.53 to 0.95; Pemp = 0.02) and rs16944 (OR, 1.31; 95% CI, 1.01 to 1.70; Pemp = 0.04), remained independent predictors of postoperative QTc prolongation. The ability of a clinico-genetic model incorporating the two IL1B polymorphisms to classify patients at risk for developing prolonged postoperative QTc was superior to a clinical model alone, with a net reclassification improvement of 0.308 (P = 0.0003) and an integrated discrimination improvement of 0.02 (P = 0.000024).
  
  
  CONCLUSIONS
  The results suggest a contribution of IL1β in modulating susceptibility to postoperative QTc prolongation after cardiac surgery.
authors: Duke Perioperative Genomics Program, Department of Anesthesiology, Duke University Medical Center, DUMC 3094, Durham, NC, 27710, USA.
authors: Miklos D
authors: MD
authors: Kertai
authors: Department of Biostatistics and Bioinformatics, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors: Yunqi
authors: Y
authors: Ji
authors: Duke Perioperative Genomics Program, Department of Anesthesiology, Duke University Medical Center, DUMC 3094, Durham, NC, 27710, USA.|Department of Biostatistics and Bioinformatics, Duke Molecular Physiology Institute, Duke University Medical Center, Durham, NC, USA.
authors: Yi-Ju
authors: YJ
authors: Li
authors: Duke Perioperative Genomics Program, Department of Anesthesiology, Duke University Medical Center, DUMC 3094, Durham, NC, 27710, USA.
authors: Joseph P
authors: JP
authors: Mathew
authors: Clinical Electrophysiology Section, Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Duke Clinical Research Institute, Durham, NC, 27710, USA.
authors: James P
authors: JP
authors: Daubert
authors: Duke Perioperative Genomics Program, Department of Anesthesiology, Duke University Medical Center, DUMC 3094, Durham, NC, 27710, USA. Mihai.podgoreanu@duke.edu.|Duke Clinical Research Institute, Durham, NC, 27710, USA. Mihai.podgoreanu@duke.edu.
authors: Mihai V
authors: http://orcid.org/0000-0001-5539-4674
authors: MV
authors: Podgoreanu
mesh_terms: D006348:Cardiac Surgical Procedures / Q000009:adverse effects*; D004562:Electrocardiography; D006239:Haplotypes; D006801:Humans; D053583:Interleukin-1beta / Q000096:biosynthesis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000209:etiology*; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: C508585:IL1B protein, human; D053583:Interleukin-1beta