Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population.
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.
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.
Perttu P
PP
Salo
Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
Satu
S
Vaara
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.
Johannes
J
Kettunen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Matti
M
Pirinen
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Antti-Pekka
AP
Sarin
Institute of Clinical Medicine, Department of Internal Medicine, University Central Hospital and University of Oulu, Oulu, Finland.
Heikki
H
Huikuri
School of Medicine, University of Tampere, Tampere, Finland; Fimlab Laboratories Ltd, Tampere University Hospital Region, Tampere, Finland.
Pekka J
PJ
Karhunen
Heart Center, Tampere University Hospital and University of Tampere, School of Medicine, Tampere, Finland.
Markku
M
Eskola
Heart Center, Tampere University Hospital and University of Tampere, School of Medicine, Tampere, Finland.
Kjell
K
Nikus
Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland.
Marja-Liisa
ML
Lokki
Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.
Samuli
S
Ripatti
Health Monitoring Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Aki S
AS
Havulinna
Health Monitoring Unit, Department of Health, National Institute for Health and Welfare, Helsinki, Finland.
Veikko
V
Salomaa
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.
Aarno
A
Palotie
Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
Markku S
MS
Nieminen
Division of Cardiology, Heart and Lung Center HUS, Helsinki University Central Hospital, Helsinki, Finland.
Juha
J
Sinisalo
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.
Markus
M
Perola
D000368:Aged; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D005260:Female; D005387:Finland; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009203:Myocardial Infarction / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results; D012307:Risk Factors
C544299:DRAM2 protein, human; D008565:Membrane Proteins