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

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• 作者：Miklos D. Kertai ; MD ; PhD^a ; ^f ; ^{miklos.kertai@duke.edu" class="auth_mail" title="E-mail the corresponding author} ; Yi-Ju Li ; PhD^b ; ^c ; ^f ; Yunqi Ji ; PhD^b ; Wenjing Qi ; PhD^b ; Frederick W. Lombard ; MB ; ChB ; FANZCA^a ; Svati H. Shah ; MD ; MHS^c ; ^d ; William E. Kraus ; MD^c ; ^d ; Mark Stafford-Smith ; MD^a ; Mark F. Newman ; MD^a ; Carmelo A. Milano ; MD^e ; Nathan Waldron ; MD^a ; Mihai V. Podgoreanu ; MD^a ; ^f ; Joseph P. Mathew ; MD ; MHSc^a ; ^f ; for the Duke Perioperative Genetics ; Safety Outcomes (PEGASUS) Investigative Team
• 刊名：American Heart Journal
• 出版年：2015
• 出版时间：September 2015
• 年：2015
• 卷：170
• 期：3
• 页码：580-590.e28
• 全文大小：1311 K

文摘

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 魏-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.