Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

Thomas M. Morgan; John A. House; Sharon Cresci; Philip Jones; Hooman Allayee; Stanley L. Hazen; Yesha Patel; Riyaz S. Patel; Danny J. Eapen; Salina P. Waddy; Arshed A. Quyyumi; Marcus E. Kleber; Winfried März; Bernhard R. Winkelmann; Bernhard O. Boehm; Harlan M. Krumholz; John A. Spertus

doi:10.1186/1471-2350-12-127

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

Thomas M. Morgan, John A. House, Sharon Cresci, Philip Jones, Hooman Allayee, Stanley L. Hazen, Yesha Patel, Riyaz S. Patel, Danny J. Eapen, Salina P. Waddy, Arshed A. Quyyumi, Marcus E. Kleber, Winfried März, Bernhard R. Winkelmann, Bernhard O. Boehm, Harlan M. Krumholz, John A. Spertus

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Abstract

Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.

Original language	English
Article number	127
Journal	BMC Medical Genetics
Volume	12
DOIs	https://doi.org/10.1186/1471-2350-12-127
State	Published - Sep 29 2011

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Morgan, T. M., House, J. A., Cresci, S., Jones, P., Allayee, H., Hazen, S. L., Patel, Y., Patel, R. S., Eapen, D. J., Waddy, S. P., Quyyumi, A. A., Kleber, M. E., März, W., Winkelmann, B. R., Boehm, B. O., Krumholz, H. M., & Spertus, J. A. (2011). Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome. BMC Medical Genetics, 12, Article 127. https://doi.org/10.1186/1471-2350-12-127

@article{186f265da33a4b58837e04d491feb3b7,

title = "Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome",

abstract = "Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.",

author = "Morgan, {Thomas M.} and House, {John A.} and Sharon Cresci and Philip Jones and Hooman Allayee and Hazen, {Stanley L.} and Yesha Patel and Patel, {Riyaz S.} and Eapen, {Danny J.} and Waddy, {Salina P.} and Quyyumi, {Arshed A.} and Kleber, {Marcus E.} and Winfried M{\"a}rz and Winkelmann, {Bernhard R.} and Boehm, {Bernhard O.} and Krumholz, {Harlan M.} and Spertus, {John A.}",

note = "Funding Information: This project was funded by grants from the Saint Luke{\textquoteright}s Hospital Foundation, Kansas City, MO, and by grants R-01 HS11282-01 from the Agency for Healthcare Research and Quality, Rockville, MD and P50 HL077113 from the National Heart, Lung and Blood Institute. Dr. Morgan{\textquoteright}s research was supported by a Mentored Patient-Oriented Research Grant (NHLBI K23 HI77272). These funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Morgan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.",

year = "2011",

month = sep,

day = "29",

doi = "10.1186/1471-2350-12-127",

language = "English",

volume = "12",

journal = "BMC Medical Genetics",

issn = "1471-2350",

}

Morgan, TM, House, JA, Cresci, S, Jones, P, Allayee, H, Hazen, SL, Patel, Y, Patel, RS, Eapen, DJ, Waddy, SP, Quyyumi, AA, Kleber, ME, März, W, Winkelmann, BR, Boehm, BO, Krumholz, HM & Spertus, JA 2011, 'Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome', BMC Medical Genetics, vol. 12, 127. https://doi.org/10.1186/1471-2350-12-127

TY - JOUR

T1 - Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

AU - Morgan, Thomas M.

AU - House, John A.

AU - Cresci, Sharon

AU - Jones, Philip

AU - Allayee, Hooman

AU - Hazen, Stanley L.

AU - Patel, Yesha

AU - Patel, Riyaz S.

AU - Eapen, Danny J.

AU - Waddy, Salina P.

AU - Quyyumi, Arshed A.

AU - Kleber, Marcus E.

AU - März, Winfried

AU - Winkelmann, Bernhard R.

AU - Boehm, Bernhard O.

AU - Krumholz, Harlan M.

AU - Spertus, John A.

N1 - Funding Information: This project was funded by grants from the Saint Luke’s Hospital Foundation, Kansas City, MO, and by grants R-01 HS11282-01 from the Agency for Healthcare Research and Quality, Rockville, MD and P50 HL077113 from the National Heart, Lung and Blood Institute. Dr. Morgan’s research was supported by a Mentored Patient-Oriented Research Grant (NHLBI K23 HI77272). These funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript. Dr. Morgan had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

PY - 2011/9/29

Y1 - 2011/9/29

N2 - Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.

AB - Background: Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.Methods: We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.Results: After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).Conclusions: We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.

UR - http://www.scopus.com/inward/record.url?scp=80053175382&partnerID=8YFLogxK

U2 - 10.1186/1471-2350-12-127

DO - 10.1186/1471-2350-12-127

M3 - Article

C2 - 21957892

AN - SCOPUS:80053175382

SN - 1471-2350

VL - 12

JO - BMC Medical Genetics

JF - BMC Medical Genetics

M1 - 127

ER -

Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

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