Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery

Miklos D. Kertai; Yi Ju Li; Yunqi Ji; Wenjing Qi; Frederick W. Lombard; Svati H. Shah; William E. Kraus; Mark Stafford-Smith; Mark F. Newman; Carmelo A. Milano; Nathan Waldron; Mihai V. Podgoreanu; Joseph P. Mathew

doi:10.1016/j.ahj.2015.06.009

Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery

Miklos D. Kertai, Yi Ju Li, Yunqi Ji, Wenjing Qi, Frederick W. Lombard, Svati H. Shah, William E. Kraus, Mark Stafford-Smith, Mark F. Newman, Carmelo A. Milano, Nathan Waldron, Mihai V. Podgoreanu, Joseph P. Mathew

Anesthesiology

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

Background Postoperative atrial fibrillation (AF) is a potentially life-threatening complication after coronary artery bypass graft (CABG) surgery. Genetic predisposition may predict risk for developing postoperative AF. Methods Study subjects underwent CABG surgery with cardiopulmonary bypass at Duke University Medical Center. In a discovery cohort of 877 individuals from the Perioperative Genetics and Safety Outcomes Study, we performed a genome-wide association study using a logistic regression model with a covariate adjustment for AF risk index. Single-nucleotide polymorphisms (SNPs) that met a P < 5 × 10^-5 were further tested using a replication dataset of 304 individuals from the CATHeterization GENetics biorepository, followed by meta-analysis. Potential pathways related to postoperative AF were identified through gene enrichment analysis using the top genome-wide association study SNPs (P < 10^-4). Results Nineteen SNPs met the a priori defined discovery threshold for replication, but only 3 met nominal significance (P <.05) in the CATHeterization GENetics group, with only one - rs10504554, in the intronic region in lymphocyte antigen 96 (LY96) - showing the same direction of the effect for postoperative AF (odds ratio [OR] 0.48, 95% CI 0.34-0.68, P = 2.9 × 10^-5 vs OR 0.55, 95% CI 0.31-0.99, P =.046) and strong overall association by meta-analysis (meta-P = 4.0 × 10^-6). Gene enrichment analysis highlighted the role of LY96 in pathways of biologic relevance to activation and modulation of innate immune responses. Our analysis also showed potential association between LY96 and nuclear factor κ-B interaction and postoperative AF through their relevance to inflammatory signaling pathways. Conclusions In patients undergoing CABG surgery, we found genetic polymorphisms in LY96 associated with decreased risk of postoperative AF.

Original language	English
Pages (from-to)	580-590.e28
Journal	American Heart Journal
Volume	170
Issue number	3
DOIs	https://doi.org/10.1016/j.ahj.2015.06.009
State	Published - Sep 1 2015

Bibliographical note

Funding Information:
Sources of funding: This work was supported, in part, by National Institutes of Health grants HL075273 and HL092071 (to Dr Podgoreanu); AG09663 , HL054316 , and HL069081 (to Dr Newman); HL096978 , HL108280 , and HL109971 (to Dr Mathew); HL095987 (to Dr Shah); and HL101621 (to Dr Kraus) and by American Heart Association grants 9970128N (to Dr Newman), 9951185U (to Dr Mathew), and 0120492U (to Dr Podgoreanu). CATHGEN provided logistics support.

Publisher Copyright:
© 2015 Elsevier Inc. All rights reserved.

ASJC Scopus subject areas

Cardiology and Cardiovascular Medicine

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10.1016/j.ahj.2015.06.009

Cite this

Kertai, M. D., Li, Y. J., Ji, Y., Qi, W., Lombard, F. W., Shah, S. H., Kraus, W. E., Stafford-Smith, M., Newman, M. F., Milano, C. A., Waldron, N., Podgoreanu, M. V., & Mathew, J. P. (2015). Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery. American Heart Journal, 170(3), 580-590.e28. https://doi.org/10.1016/j.ahj.2015.06.009

@article{7b632185513e4d7cbb2c792a6efff22a,

title = "Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery",

abstract = "Background Postoperative atrial fibrillation (AF) is a potentially life-threatening complication after coronary artery bypass graft (CABG) surgery. Genetic predisposition may predict risk for developing postoperative AF. Methods Study subjects underwent CABG surgery with cardiopulmonary bypass at Duke University Medical Center. In a discovery cohort of 877 individuals from the Perioperative Genetics and Safety Outcomes Study, we performed a genome-wide association study using a logistic regression model with a covariate adjustment for AF risk index. Single-nucleotide polymorphisms (SNPs) that met a P < 5 × 10-5 were further tested using a replication dataset of 304 individuals from the CATHeterization GENetics biorepository, followed by meta-analysis. Potential pathways related to postoperative AF were identified through gene enrichment analysis using the top genome-wide association study SNPs (P < 10-4). Results Nineteen SNPs met the a priori defined discovery threshold for replication, but only 3 met nominal significance (P <.05) in the CATHeterization GENetics group, with only one - rs10504554, in the intronic region in lymphocyte antigen 96 (LY96) - showing the same direction of the effect for postoperative AF (odds ratio [OR] 0.48, 95% CI 0.34-0.68, P = 2.9 × 10-5 vs OR 0.55, 95% CI 0.31-0.99, P =.046) and strong overall association by meta-analysis (meta-P = 4.0 × 10-6). Gene enrichment analysis highlighted the role of LY96 in pathways of biologic relevance to activation and modulation of innate immune responses. Our analysis also showed potential association between LY96 and nuclear factor κ-B interaction and postoperative AF through their relevance to inflammatory signaling pathways. Conclusions In patients undergoing CABG surgery, we found genetic polymorphisms in LY96 associated with decreased risk of postoperative AF.",

author = "Kertai, {Miklos D.} and Li, {Yi Ju} and Yunqi Ji and Wenjing Qi and Lombard, {Frederick W.} and Shah, {Svati H.} and Kraus, {William E.} and Mark Stafford-Smith and Newman, {Mark F.} and Milano, {Carmelo A.} and Nathan Waldron and Podgoreanu, {Mihai V.} and Mathew, {Joseph P.}",

note = "Funding Information: Sources of funding: This work was supported, in part, by National Institutes of Health grants HL075273 and HL092071 (to Dr Podgoreanu); AG09663 , HL054316 , and HL069081 (to Dr Newman); HL096978 , HL108280 , and HL109971 (to Dr Mathew); HL095987 (to Dr Shah); and HL101621 (to Dr Kraus) and by American Heart Association grants 9970128N (to Dr Newman), 9951185U (to Dr Mathew), and 0120492U (to Dr Podgoreanu). CATHGEN provided logistics support. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc. All rights reserved.",

year = "2015",

month = sep,

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doi = "10.1016/j.ahj.2015.06.009",

language = "English",

volume = "170",

pages = "580--590.e28",

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T1 - Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery

AU - Kertai, Miklos D.

AU - Li, Yi Ju

AU - Ji, Yunqi

AU - Qi, Wenjing

AU - Lombard, Frederick W.

AU - Shah, Svati H.

AU - Kraus, William E.

AU - Stafford-Smith, Mark

AU - Newman, Mark F.

AU - Milano, Carmelo A.

AU - Waldron, Nathan

AU - Podgoreanu, Mihai V.

AU - Mathew, Joseph P.

N1 - Funding Information: Sources of funding: This work was supported, in part, by National Institutes of Health grants HL075273 and HL092071 (to Dr Podgoreanu); AG09663 , HL054316 , and HL069081 (to Dr Newman); HL096978 , HL108280 , and HL109971 (to Dr Mathew); HL095987 (to Dr Shah); and HL101621 (to Dr Kraus) and by American Heart Association grants 9970128N (to Dr Newman), 9951185U (to Dr Mathew), and 0120492U (to Dr Podgoreanu). CATHGEN provided logistics support. Publisher Copyright: © 2015 Elsevier Inc. All rights reserved.

PY - 2015/9/1

Y1 - 2015/9/1

N2 - Background Postoperative atrial fibrillation (AF) is a potentially life-threatening complication after coronary artery bypass graft (CABG) surgery. Genetic predisposition may predict risk for developing postoperative AF. Methods Study subjects underwent CABG surgery with cardiopulmonary bypass at Duke University Medical Center. In a discovery cohort of 877 individuals from the Perioperative Genetics and Safety Outcomes Study, we performed a genome-wide association study using a logistic regression model with a covariate adjustment for AF risk index. Single-nucleotide polymorphisms (SNPs) that met a P < 5 × 10-5 were further tested using a replication dataset of 304 individuals from the CATHeterization GENetics biorepository, followed by meta-analysis. Potential pathways related to postoperative AF were identified through gene enrichment analysis using the top genome-wide association study SNPs (P < 10-4). Results Nineteen SNPs met the a priori defined discovery threshold for replication, but only 3 met nominal significance (P <.05) in the CATHeterization GENetics group, with only one - rs10504554, in the intronic region in lymphocyte antigen 96 (LY96) - showing the same direction of the effect for postoperative AF (odds ratio [OR] 0.48, 95% CI 0.34-0.68, P = 2.9 × 10-5 vs OR 0.55, 95% CI 0.31-0.99, P =.046) and strong overall association by meta-analysis (meta-P = 4.0 × 10-6). Gene enrichment analysis highlighted the role of LY96 in pathways of biologic relevance to activation and modulation of innate immune responses. Our analysis also showed potential association between LY96 and nuclear factor κ-B interaction and postoperative AF through their relevance to inflammatory signaling pathways. Conclusions In patients undergoing CABG surgery, we found genetic polymorphisms in LY96 associated with decreased risk of postoperative AF.

AB - Background Postoperative atrial fibrillation (AF) is a potentially life-threatening complication after coronary artery bypass graft (CABG) surgery. Genetic predisposition may predict risk for developing postoperative AF. Methods Study subjects underwent CABG surgery with cardiopulmonary bypass at Duke University Medical Center. In a discovery cohort of 877 individuals from the Perioperative Genetics and Safety Outcomes Study, we performed a genome-wide association study using a logistic regression model with a covariate adjustment for AF risk index. Single-nucleotide polymorphisms (SNPs) that met a P < 5 × 10-5 were further tested using a replication dataset of 304 individuals from the CATHeterization GENetics biorepository, followed by meta-analysis. Potential pathways related to postoperative AF were identified through gene enrichment analysis using the top genome-wide association study SNPs (P < 10-4). Results Nineteen SNPs met the a priori defined discovery threshold for replication, but only 3 met nominal significance (P <.05) in the CATHeterization GENetics group, with only one - rs10504554, in the intronic region in lymphocyte antigen 96 (LY96) - showing the same direction of the effect for postoperative AF (odds ratio [OR] 0.48, 95% CI 0.34-0.68, P = 2.9 × 10-5 vs OR 0.55, 95% CI 0.31-0.99, P =.046) and strong overall association by meta-analysis (meta-P = 4.0 × 10-6). Gene enrichment analysis highlighted the role of LY96 in pathways of biologic relevance to activation and modulation of innate immune responses. Our analysis also showed potential association between LY96 and nuclear factor κ-B interaction and postoperative AF through their relevance to inflammatory signaling pathways. Conclusions In patients undergoing CABG surgery, we found genetic polymorphisms in LY96 associated with decreased risk of postoperative AF.

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Genome-wide association study of new-onset atrial fibrillation after coronary artery bypass grafting surgery

Abstract

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