Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery

Amanda A. Fox; Mias Pretorius; Kuang Yu Liu; Charles D. Collard; Tjorvi E. Perry; Stanton K. Shernan; Philip L. de Jager; David A. Hafler; Daniel S. Herman; Steven R. DePalma; Dan M. Roden; Jochen D. Muehlschlegel; Brian S. Donahue; Dawood Darbar; J. G. Seidman; Simon C. Body; Christine E. Seidman

doi:10.1371/journal.pone.0024593

Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery

Amanda A. Fox, Mias Pretorius, Kuang Yu Liu, Charles D. Collard, Tjorvi E. Perry, Stanton K. Shernan, Philip L. de Jager, David A. Hafler, Daniel S. Herman, Steven R. DePalma, Dan M. Roden, Jochen D. Muehlschlegel, Brian S. Donahue, Dawood Darbar, J. G. Seidman, Simon C. Body, Christine E. Seidman

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Abstract

Background: Postoperative ventricular dysfunction (VnD) occurs in 9-20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery. Methods: A genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed. Results: Over 100 SNPs were associated with VnD (P<10 ^-4), with one SNP (rs17691914) encoded at 3p22.3 reaching genome-wide significance (P _{additive model} = 2.14×10 ^-8). Meta-analysis of validation and replication study data for 17 SNPs identified three SNPs associated with increased risk for developing postoperative VnD after adjusting for clinical risk factors. These SNPs are located at 3p22.3 (rs17691914, OR _{additive model} = 2.01, P = 0.0002), 3p14.2 (rs17061085, OR _{additive model} = 1.70, P = 0.0001) and 11q23.2 (rs12279572, OR _{recessive model} = 2.19, P = 0.001). Conclusions: No SNPs were consistently associated with strong risk (OR _{additive model}>2.1) of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

Original language	English (US)
Article number	e24593
Journal	PloS one
Volume	6
Issue number	9
DOIs	https://doi.org/10.1371/journal.pone.0024593
State	Published - Sep 30 2011

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Fox, A. A., Pretorius, M., Liu, K. Y., Collard, C. D., Perry, T. E., Shernan, S. K., de Jager, P. L., Hafler, D. A., Herman, D. S., DePalma, S. R., Roden, D. M., Muehlschlegel, J. D., Donahue, B. S., Darbar, D., Seidman, J. G., Body, S. C., & Seidman, C. E. (2011). Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery. PloS one, 6(9), Article e24593. https://doi.org/10.1371/journal.pone.0024593

Fox, AA, Pretorius, M, Liu, KY, Collard, CD, Perry, TE, Shernan, SK, de Jager, PL, Hafler, DA, Herman, DS, DePalma, SR, Roden, DM, Muehlschlegel, JD, Donahue, BS, Darbar, D, Seidman, JG, Body, SC & Seidman, CE 2011, 'Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery', PloS one, vol. 6, no. 9, e24593. https://doi.org/10.1371/journal.pone.0024593

@article{94ba6ec9145f4bdaaa8f060efcc4ce54,

title = "Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery",

abstract = "Background: Postoperative ventricular dysfunction (VnD) occurs in 9-20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery. Methods: A genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed. Results: Over 100 SNPs were associated with VnD (P<10 -4), with one SNP (rs17691914) encoded at 3p22.3 reaching genome-wide significance (P additive model = 2.14×10 -8). Meta-analysis of validation and replication study data for 17 SNPs identified three SNPs associated with increased risk for developing postoperative VnD after adjusting for clinical risk factors. These SNPs are located at 3p22.3 (rs17691914, OR additive model = 2.01, P = 0.0002), 3p14.2 (rs17061085, OR additive model = 1.70, P = 0.0001) and 11q23.2 (rs12279572, OR recessive model = 2.19, P = 0.001). Conclusions: No SNPs were consistently associated with strong risk (OR additive model>2.1) of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.",

author = "Fox, {Amanda A.} and Mias Pretorius and Liu, {Kuang Yu} and Collard, {Charles D.} and Perry, {Tjorvi E.} and Shernan, {Stanton K.} and {de Jager}, {Philip L.} and Hafler, {David A.} and Herman, {Daniel S.} and DePalma, {Steven R.} and Roden, {Dan M.} and Muehlschlegel, {Jochen D.} and Donahue, {Brian S.} and Dawood Darbar and Seidman, {J. G.} and Body, {Simon C.} and Seidman, {Christine E.}",

year = "2011",

month = sep,

day = "30",

doi = "10.1371/journal.pone.0024593",

language = "English (US)",

volume = "6",

journal = "PloS one",

issn = "1932-6203",

publisher = "Public Library of Science",

number = "9",

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TY - JOUR

T1 - Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery

AU - Fox, Amanda A.

AU - Pretorius, Mias

AU - Liu, Kuang Yu

AU - Collard, Charles D.

AU - Perry, Tjorvi E.

AU - Shernan, Stanton K.

AU - de Jager, Philip L.

AU - Hafler, David A.

AU - Herman, Daniel S.

AU - DePalma, Steven R.

AU - Roden, Dan M.

AU - Muehlschlegel, Jochen D.

AU - Donahue, Brian S.

AU - Darbar, Dawood

AU - Seidman, J. G.

AU - Body, Simon C.

AU - Seidman, Christine E.

PY - 2011/9/30

Y1 - 2011/9/30

N2 - Background: Postoperative ventricular dysfunction (VnD) occurs in 9-20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery. Methods: A genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed. Results: Over 100 SNPs were associated with VnD (P<10 -4), with one SNP (rs17691914) encoded at 3p22.3 reaching genome-wide significance (P additive model = 2.14×10 -8). Meta-analysis of validation and replication study data for 17 SNPs identified three SNPs associated with increased risk for developing postoperative VnD after adjusting for clinical risk factors. These SNPs are located at 3p22.3 (rs17691914, OR additive model = 2.01, P = 0.0002), 3p14.2 (rs17061085, OR additive model = 1.70, P = 0.0001) and 11q23.2 (rs12279572, OR recessive model = 2.19, P = 0.001). Conclusions: No SNPs were consistently associated with strong risk (OR additive model>2.1) of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

AB - Background: Postoperative ventricular dysfunction (VnD) occurs in 9-20% of coronary artery bypass graft (CABG) surgical patients and is associated with increased postoperative morbidity and mortality. Understanding genetic causes of postoperative VnD should enhance patient risk stratification and improve treatment and prevention strategies. We aimed to determine if genetic variants associate with occurrence of in-hospital VnD after CABG surgery. Methods: A genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with postoperative VnD in male subjects of European ancestry undergoing isolated primary CABG surgery with cardiopulmonary bypass. VnD was defined as the need for ≥2 inotropes or mechanical ventricular support after CABG surgery. Validated SNPs were assessed further in two replication CABG cohorts and meta-analysis was performed. Results: Over 100 SNPs were associated with VnD (P<10 -4), with one SNP (rs17691914) encoded at 3p22.3 reaching genome-wide significance (P additive model = 2.14×10 -8). Meta-analysis of validation and replication study data for 17 SNPs identified three SNPs associated with increased risk for developing postoperative VnD after adjusting for clinical risk factors. These SNPs are located at 3p22.3 (rs17691914, OR additive model = 2.01, P = 0.0002), 3p14.2 (rs17061085, OR additive model = 1.70, P = 0.0001) and 11q23.2 (rs12279572, OR recessive model = 2.19, P = 0.001). Conclusions: No SNPs were consistently associated with strong risk (OR additive model>2.1) of developing in-hospital VnD after CABG surgery. However, three genetic loci identified by meta-analysis were more modestly associated with development of postoperative VnD. Studies of larger cohorts to assess these loci as well as to define other genetic mechanisms and related biology that link genetic variants to postoperative ventricular dysfunction are warranted.

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Genome-wide assessment for genetic variants associated with ventricular dysfunction after primary coronary artery bypass graft surgery

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