Polymorphism of 9p21.3 Locus Is Associated with 5-Year Survival in High-Risk Patients with Myocardial Infarction

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Abstract

Objective

The rs10757278, rs1333049 and rs4977574 are single nucleotide polymorphisms (SNPs) of chromosome 9p21 locus associated with a prevalence of acute coronary syndromes (ACS). Reports concerning their association with long-term outcome after an ACS are equivocal. The aim of our study was to investigate the association of the 9p21.3 locus with 5-year overall mortality in patients with ST-elevation myocardial infarction (STEMI).

Materials and methods

We performed a retrospective analysis of data collected prospectively in 2 independent registries of consecutive patients with STEMI (derivation and validation group). Genotyping was performed with the TaqMan method. The analyzed end-point was total mortality.

Results

The derivation group comprised 589 patients: 25.3% female (n = 149), mean age 62.4±12.0 years, total 5-year mortality 16.6% (n = 98). When all the study group was analyzed, no significant differences in mortality were found between the genotypes. However, in high-risk patients (GRACE risk score ≥155 points, n = 238), homozygotes associated with higher risk for ACS had significantly better 5-year survival compared to other genotypes. The hazard ratio associated with the high-risk genotype (a homozygote of high risk for ACS or a heterozygote) was: HR = 2.2 (1.15–4.2) for the rs10757278 polymorphism, HR = 2.7 (95% CI 1.3–5.4) for the rs4977574 one and HR = 2.3 (1.2–4.5) for the rs1333049 one (Cox proportional hazards model). Survival analysis in the validation group (n = 365) showed a clear trend towards better prognosis in GG homozygotes of the rs10757278 SNP, which confirms our initial results (p = 0.09, log-rank test).

Conclusions

The 9p21.3 locus is associated with 5-year mortality in high-risk patients with STEMI. The genotypes associated with higher risk for ACS show a protective effect in terms of further survival (instead of a deteriorating prognosis, as reported previously). This finding, due to the very high size of the effect, could potentially be applied to clinical practice, if appropriate methods are elaborated.

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Most cited references 23

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Genomewide association analysis of coronary artery disease.

Nilesh J. Samani, Jeanette Erdmann, Alistair S. Hall … (2007)

Modern genotyping platforms permit a systematic search for inherited components of complex diseases. We performed a joint analysis of two genomewide association studies of coronary artery disease. We first identified chromosomal loci that were strongly associated with coronary artery disease in the Wellcome Trust Case Control Consortium (WTCCC) study (which involved 1926 case subjects with coronary artery disease and 2938 controls) and looked for replication in the German MI [Myocardial Infarction] Family Study (which involved 875 case subjects with myocardial infarction and 1644 controls). Data on other single-nucleotide polymorphisms (SNPs) that were significantly associated with coronary artery disease in either study (P 80%) of a true association: chromosomes 1p13.3 (rs599839), 1q41 (rs17465637), 10q11.21 (rs501120), and 15q22.33 (rs17228212). We identified several genetic loci that, individually and in aggregate, substantially affect the risk of development of coronary artery disease. Copyright 2007 Massachusetts Medical Society.

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Predictors of hospital mortality in the global registry of acute coronary events.

Christopher Granger, Robert J. Goldberg, Omar Dabbous … (2003)

Management of acute coronary syndromes (ACS) should be guided by an estimate of patient risk. To develop a simple model to assess the risk for in-hospital mortality for the entire spectrum of ACS treated in general clinical practice. A multivariable logistic regression model was developed using 11 389 patients (including 509 in-hospital deaths) with ACS with and without ST-segment elevation enrolled in the Global Registry of Acute Coronary Events (GRACE) from April 1, 1999, through March 31, 2001. Validation data sets included a subsequent cohort of 3972 patients enrolled in GRACE and 12 142 in the Global Use of Strategies to Open Occluded Coronary Arteries IIb (GUSTO-IIb) trial. The following 8 independent risk factors accounted for 89.9% of the prognostic information: age (odds ratio [OR], 1.7 per 10 years), Killip class (OR, 2.0 per class), systolic blood pressure (OR, 1.4 per 20-mm Hg decrease), ST-segment deviation (OR, 2.4), cardiac arrest during presentation (OR, 4.3), serum creatinine level (OR, 1.2 per 1-mg/dL [88.4- micro mol/L] increase), positive initial cardiac enzyme findings (OR, 1.6), and heart rate (OR, 1.3 per 30-beat/min increase). The discrimination ability of the simplified model was excellent with c statistics of 0.83 in the derived database, 0.84 in the confirmation GRACE data set, and 0.79 in the GUSTO-IIb database. Across the entire spectrum of ACS and in general clinical practice, this model provides excellent ability to assess the risk for death and can be used as a simple nomogram to estimate risk in individual patients.

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A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry.

Kim Eagle, Michael Lim, Omar Dabbous … (2004)

Accurate estimation of risk for untoward outcomes after patients have been hospitalized for an acute coronary syndrome (ACS) may help clinicians guide the type and intensity of therapy. To develop a simple decision tool for bedside risk estimation of 6-month mortality in patients surviving admission for an ACS. A multinational registry, involving 94 hospitals in 14 countries, that used data from the Global Registry of Acute Coronary Events (GRACE) to develop and validate a multivariable stepwise regression model for death during 6 months postdischarge. From 17,142 patients presenting with an ACS from April 1, 1999, to March 31, 2002, and discharged alive, 15,007 (87.5%) had complete 6-month follow-up and represented the development cohort for a model that was subsequently tested on a validation cohort of 7638 patients admitted from April 1, 2002, to December 31, 2003. All-cause mortality during 6 months postdischarge after admission for an ACS. The 6-month mortality rates were similar in the development (n = 717; 4.8%) and validation cohorts (n = 331; 4.7%). The risk-prediction tool for all forms of ACS identified 9 variables predictive of 6-month mortality: older age, history of myocardial infarction, history of heart failure, increased pulse rate at presentation, lower systolic blood pressure at presentation, elevated initial serum creatinine level, elevated initial serum cardiac biomarker levels, ST-segment depression on presenting electrocardiogram, and not having a percutaneous coronary intervention performed in hospital. The c statistics for the development and validation cohorts were 0.81 and 0.75, respectively. The GRACE 6-month postdischarge prediction model is a simple, robust tool for predicting mortality in patients with ACS. Clinicians may find it simple to use and applicable to clinical practice.

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Author and article information

Contributors

Dan E. Arking: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, USA )

ISSN (Electronic): 1932-6203

Publication date Collection: 2014

Publication date (Electronic): 8 August 2014

Volume: 9

Issue: 8

Electronic Location Identifier: e104635

Affiliations

[1 ]Department of Cardiology, Medical University of Bialystok, Bialystok, Poland

[2 ]Department of Cardiology, Medical University of Warsaw, Warsaw, Poland

[3 ]Department of Forensic Medicine, Medical University of Bialystok, Bialystok, Poland

[4 ]Laboratory of Molecular Biology, Institute of Cardiology, Warsaw, Poland

[5 ]Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland

[6 ]Department of Invasive Cardiology, Medical University of Bialystok, Bialystok, Poland

Johns Hopkins University, United States of America

Author notes

* E-mail: fizklin@ 123456wp.pl

Competing Interests: The authors have declared that no competing interests exist.

Conceived and designed the experiments: AS KAK MK WP. Performed the experiments: EW MS MF. Analyzed the data: AS KAK MK WP. Contributed reagents/materials/analysis tools: WJM AN-J RP GO. Contributed to the writing of the manuscript: AS. Responsible for overall content as guarantor: KAK WJM AN-J RP SD GO.

Article

Publisher ID: PONE-D-14-14817

DOI: 10.1371/journal.pone.0104635

PMC ID: 4126747

PubMed ID: 25105296

SO-VID: bb35e38a-557b-49b6-b498-36b2dadf5d4d

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 2 April 2014

Date accepted : 9 July 2014

Page count

Pages: 11

Funding

This work was supported by National Science Center, Poland (N N 402 529139). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Data Availability The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. Public deposition of the data set would breach ethical compliance. However, raw data are available upon request. The requests may be sent to Department of Cardiology, Medical University of Bialystok, ul. M. Sklodowskiej-Curie 24a, 15-276 Bialystok, fax: 0048 85 746 7604, e-mail: fizklin@ 123456wp.pl .

Polymorphism of 9p21.3 Locus Is Associated with 5-Year Survival in High-Risk Patients with Myocardial Infarction

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Abstract

Objective

Materials and methods

Results

Conclusions

Related collections

PLOS Climate

Most cited references 23

Genomewide association analysis of coronary artery disease.

Predictors of hospital mortality in the global registry of acute coronary events.

A validated prediction model for all forms of acute coronary syndrome: estimating the risk of 6-month postdischarge death in an international registry.

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