Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population

Perttu P Salo; Satu Vaara; Johannes Kettunen; Matti Pirinen; Antti-Pekka Sarin; Heikki Huikuri; Pekka J Karhunen; Markku Eskola; Kjell Nikus; Marja-Liisa Lokki; Samuli Ripatti; Aki S Havulinna; Veikko Salomaa; Aarno Palotie; Markku S Nieminen; Juha Sinisalo; Markus Perola

doi:10.1371/journal.pone.0140576

Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population

PLoS One. 2015 Oct 28;10(10):e0140576. doi: 10.1371/journal.pone.0140576. eCollection 2015.

Authors

Perttu P Salo¹, Satu Vaara², Johannes Kettunen³, Matti Pirinen⁴, Antti-Pekka Sarin⁴, Heikki Huikuri⁵, Pekka J Karhunen⁶, Markku Eskola⁷, Kjell Nikus⁷, Marja-Liisa Lokki⁸, Samuli Ripatti⁴, Aki S Havulinna⁹, Veikko Salomaa⁹, Aarno Palotie¹⁰, Markku S Nieminen², Juha Sinisalo², Markus Perola¹¹

Affiliations

¹ Genomics and Biomarkers Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Children's Hospital, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
² Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
³ Genomics and Biomarkers Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁴ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
⁵ Institute of Clinical Medicine, Department of Internal Medicine, University Central Hospital and University of Oulu, Oulu, Finland.
⁶ School of Medicine, University of Tampere, Tampere, Finland; Fimlab Laboratories Ltd, Tampere University Hospital Region, Tampere, Finland.
⁷ Heart Center, Tampere University Hospital and University of Tampere, School of Medicine, Tampere, Finland.
⁸ Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
⁹ Health Monitoring Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
¹⁰ Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; Broad Institute, Cambridge, MA, United States of America.
¹¹ Genomics and Biomarkers Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland; Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; The Estonian Genome Center of the University of Tartu, Tartu, Estonia.

Abstract

Myocardial infarction (MI) is divided into either ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI), differing in a number of clinical characteristics. We sought to identify genetic variants conferring risk to NSTEMI or STEMI by conducting a genome-wide association study (GWAS) of MI stratified into NSTEMI and STEMI in a consecutive sample of 1,579 acute MI cases with 1,576 controls. Subsequently, we followed the results in an independent population-based sample of 562 cases and 566 controls, a partially independent prospective cohort (N = 16,627 with 163 incident NSTEMI cases), and examined the effect of disease-associated variants on gene expression in 513 healthy participants. Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with NSTEMI (rs656843; odds ratio 1.57, P = 3.11 × 10(-10)) in the case-control analysis with a consistent but not statistically significant effect in the prospective cohort (rs656843; hazard ratio 1.13, P = 0.43). These variants were not associated with STEMI (rs656843; odds ratio, 1.11, P = 0.20; hazard ratio 0.97, P = 0.87), appearing to have a pronounced effect on NSTEMI risk. A majority of the variants at 1p13.3 associated with NSTEMI were also associated with the expression level of DRAM2 in blood leukocytes of healthy controls (top-ranked variant rs325927, P = 1.50 × 10(-12)). The results suggest that genetic factors may in part influence whether coronary artery disease results in NSTEMI rather than STEMI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Chromosomes, Human, Pair 1 / genetics*
Female
Finland
Gene Expression Regulation
Genetic Association Studies*
Genetic Loci
Genetic Predisposition to Disease*
Genetic Variation*
Genome-Wide Association Study
Humans
Linkage Disequilibrium / genetics
Male
Membrane Proteins / genetics*
Membrane Proteins / metabolism
Middle Aged
Myocardial Infarction / genetics*
Phenotype
Polymorphism, Single Nucleotide / genetics
Reproducibility of Results
Risk Factors

Substances

DRAM2 protein, human
Membrane Proteins

Grants and funding

This work was supported by grants from Aarne Koskelo Foundation, Helsinki University Central Hospital, Tampere University Hospital special government funds (EVO), the Finnish Foundation for Cardiovascular research, the Academy of Finland, and the Finnish Funding Agency for Technology and Innovation. PPS was supported by the Integrative Life Science Doctoral Program of the University of Helsinki. PJK has been supported by the Medical Research Fund of Tampere University Hospital, Pirkanmaa Regional Fund of the Finnish Cultural Foundation and the Finnish Foundation for Cardiovascular Research. HH is supported by the Sigrid Juselius Foundation. VS is supported by the Academy of Finland [grant #139635] and the Finnish Foundation for Cardiovascular Diseases. MSN is partly financially supported for this work by the Finnish Academy [grant #129388]. MP (Markus Perola) is partly financially supported for this work by the EU FP7 under grant agreements nr. 313010 (BBMRI-LPC), nr. 305280 (MIMOmics), and nr. 261433 (BioSHaRE-EU), the Finnish Academy grant no. 269517, the Yrjö Jahnsson Foundation, and the Juho Vainio Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.