V Eric Kerchberger1,2, Yi Huang3, Tatsuki Koyama3, M Benjamin Shoemaker4, Dawood Darbar5, Julie A Bastarache1,6, Lorraine B Ware1,7, Ciara M Shaver1. 1. Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. 2. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN. 3. Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN. 4. Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN. 5. Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL. 6. Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN. 7. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN.
Abstract
OBJECTIVES: New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU. DESIGN: Retrospective sub-study of a prospective observational cohort study. SETTING: Medical and general surgical ICUs in a tertiary academic medical center. PATIENTS: One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30-0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27-2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009). CONCLUSIONS: We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU.
OBJECTIVES: New-onset atrial fibrillation during critical illness is an independent risk factor for mortality. The ability to identify patients at high risk for new-onset atrial fibrillation is limited. We hypothesized that genetic susceptibility contributes to risk of new-onset atrial fibrillation in the ICU. DESIGN: Retrospective sub-study of a prospective observational cohort study. SETTING: Medical and general surgical ICUs in a tertiary academic medical center. PATIENTS: One-thousand three-hundred sixty-nine critically ill patients admitted to the ICU for at least 2 days with no known history of atrial fibrillation who had DNA available for genotyping. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We genotyped 21 single-nucleotide polymorphisms associated with atrial fibrillation in ambulatory studies using a Sequenom platform (San Diego, CA). We collected demographics, medical history, and development of new-onset atrial fibrillation during the first four days of ICU admission. New-onset atrial fibrillation occurred in 98 patients (7.2%) and was associated with age, male sex, coronary artery disease, and vasopressor use. Single-nucleotide polymorphisms associated with new-onset atrial fibrillation were rs3853445 (near PITX2, p = 0.0002), rs6838973 (near PITX2, p = 0.01), and rs12415501 (in NEURL, p = 0.03) on univariate testing. When controlling for clinical factors, rs3853445 (odds ratio, 0.47; 95% CI, 0.30-0.73; p = 0.001) and rs12415501 (odds ratio, 1.72; 95% CI, 1.27-2.59; p = 0.01) remained significantly associated with new-onset atrial fibrillation. The addition of genetic variables to clinical factors improved new-onset atrial fibrillation discrimination in a multivariable logistic regression model (C-statistic 0.82 vs 0.78; p = 0.0009). CONCLUSIONS: We identified several single-nucleotide polymorphisms associated with new-onset atrial fibrillation in a large cohort of critically ill ICU patients, suggesting there is genetic susceptibility underlying this common clinical condition. This finding may provide new targets for future mechanistic studies and additional insight into the application of genomic information to identify patients at elevated risk for a common and important condition in the ICU.
Authors: S T Sherry; M H Ward; M Kholodov; J Baker; L Phan; E M Smigielski; K Sirotkin Journal: Nucleic Acids Res Date: 2001-01-01 Impact factor: 16.971
Authors: Jun Wang; Elzbieta Klysik; Subeena Sood; Randy L Johnson; Xander H T Wehrens; James F Martin Journal: Proc Natl Acad Sci U S A Date: 2010-05-10 Impact factor: 11.205
Authors: Moritz F Sinner; Nathan R Tucker; Kathryn L Lunetta; Kouichi Ozaki; J Gustav Smith; Stella Trompet; Joshua C Bis; Honghuang Lin; Mina K Chung; Jonas B Nielsen; Steven A Lubitz; Bouwe P Krijthe; Jared W Magnani; Jiangchuan Ye; Michael H Gollob; Tatsuhiko Tsunoda; Martina Müller-Nurasyid; Peter Lichtner; Annette Peters; Elena Dolmatova; Michiaki Kubo; Jonathan D Smith; Bruce M Psaty; Nicholas L Smith; J Wouter Jukema; Daniel I Chasman; Christine M Albert; Yusuke Ebana; Tetsushi Furukawa; Peter W Macfarlane; Tamara B Harris; Dawood Darbar; Marcus Dörr; Anders G Holst; Jesper H Svendsen; Albert Hofman; Andre G Uitterlinden; Vilmundur Gudnason; Mitsuaki Isobe; Rainer Malik; Martin Dichgans; Jonathan Rosand; David R Van Wagoner; Emelia J Benjamin; David J Milan; Olle Melander; Susan R Heckbert; Ian Ford; Yongmei Liu; John Barnard; Morten S Olesen; Bruno H C Stricker; Toshihiro Tanaka; Stefan Kääb; Patrick T Ellinor Journal: Circulation Date: 2014-08-14 Impact factor: 29.690
Authors: Steven A Lubitz; Kathryn L Lunetta; Honghuang Lin; Dan E Arking; Stella Trompet; Guo Li; Bouwe P Krijthe; Daniel I Chasman; John Barnard; Marcus E Kleber; Marcus Dörr; Kouichi Ozaki; Albert V Smith; Martina Müller-Nurasyid; Stefan Walter; Joanne M Murabito; Moritz F Sinner; Vilmundur Gudnason; Stephan B Felix; Winfried März; Mina Chung; Christine M Albert; Bruno H Stricker; Toshihiro Tanaka; Susan R Heckbert; J Wouter Jukema; Alvaro Alonso; Emelia J Benjamin; Patrick T Ellinor; Sunil K Agarwal; Joshua C Bis; Jennifer A Brody; Lin Y Chen; Brendan M Everett; Ian Ford; Oscar H Franco; Tamara B Harris; Albert Hofman; Stefan Kääb; Saagar Mahida; Sekar Kathiresan; Michiaki Kubo; Lenore J Launer; Peter W MacFarlane; Jared W Magnani; Barbara McKnight; David D McManus; Annette Peters; Bruce M Psaty; Lynda M Rose; Jerome I Rotter; Guenther Silbernagel; Jonathan D Smith; Nona Sotoodehnia; David J Stott; Kent D Taylor; Andreas Tomaschitz; Tatsuhiko Tsunoda; Andre G Uitterlinden; David R Van Wagoner; Uwe Völker; Henry Völzke Journal: J Am Coll Cardiol Date: 2014-01-30 Impact factor: 24.094
Authors: Patrick T Ellinor; Kathryn L Lunetta; Christine M Albert; Nicole L Glazer; Marylyn D Ritchie; Albert V Smith; Dan E Arking; Martina Müller-Nurasyid; Bouwe P Krijthe; Steven A Lubitz; Joshua C Bis; Mina K Chung; Marcus Dörr; Kouichi Ozaki; Jason D Roberts; J Gustav Smith; Arne Pfeufer; Moritz F Sinner; Kurt Lohman; Jingzhong Ding; Nicholas L Smith; Jonathan D Smith; Michiel Rienstra; Kenneth M Rice; David R Van Wagoner; Jared W Magnani; Reza Wakili; Sebastian Clauss; Jerome I Rotter; Gerhard Steinbeck; Lenore J Launer; Robert W Davies; Matthew Borkovich; Tamara B Harris; Honghuang Lin; Uwe Völker; Henry Völzke; David J Milan; Albert Hofman; Eric Boerwinkle; Lin Y Chen; Elsayed Z Soliman; Benjamin F Voight; Guo Li; Aravinda Chakravarti; Michiaki Kubo; Usha B Tedrow; Lynda M Rose; Paul M Ridker; David Conen; Tatsuhiko Tsunoda; Tetsushi Furukawa; Nona Sotoodehnia; Siyan Xu; Naoyuki Kamatani; Daniel Levy; Yusuke Nakamura; Babar Parvez; Saagar Mahida; Karen L Furie; Jonathan Rosand; Raafia Muhammad; Bruce M Psaty; Thomas Meitinger; Siegfried Perz; H-Erich Wichmann; Jacqueline C M Witteman; W H Linda Kao; Sekar Kathiresan; Dan M Roden; Andre G Uitterlinden; Fernando Rivadeneira; Barbara McKnight; Marketa Sjögren; Anne B Newman; Yongmei Liu; Michael H Gollob; Olle Melander; Toshihiro Tanaka; Bruno H Ch Stricker; Stephan B Felix; Alvaro Alonso; Dawood Darbar; John Barnard; Daniel I Chasman; Susan R Heckbert; Emelia J Benjamin; Vilmundur Gudnason; Stefan Kääb Journal: Nat Genet Date: 2012-04-29 Impact factor: 38.330
Authors: Stefan Kääb; Dawood Darbar; Charlotte van Noord; Josée Dupuis; Arne Pfeufer; Christopher Newton-Cheh; Renate Schnabel; Seiko Makino; Moritz F Sinner; Prince J Kannankeril; Britt M Beckmann; Subbarao Choudry; Brian S Donahue; Jan Heeringa; Siegfried Perz; Kathryn L Lunetta; Martin G Larson; Daniel Levy; Calum A MacRae; Jeremy N Ruskin; Annette Wacker; Albert Schömig; H-Erich Wichmann; Gerhard Steinbeck; Thomas Meitinger; André G Uitterlinden; Jacqueline C M Witteman; Dan M Roden; Emelia J Benjamin; Patrick T Ellinor Journal: Eur Heart J Date: 2009-01-13 Impact factor: 29.983