Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels

Bruna Gigante; Max Vikström; Linda Strömqvist Meuzelaar; Ekaterina Chernogubova; Angela Silveira; Ferdinand van’t Hooft; Anders Hamsten; Ulf de Faire

doi:10.1160/TH08-09-0612

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2009; 101(05): 943-953
DOI: 10.1160/TH08-09-0612

Cardiovascular Biology and Cell Signalling

Schattauer GmbH

Variants in the coagulation factor 2 receptor (F2R) gene influence the risk of myocardial infarction in men through an interaction with interleukin 6 serum levels

Bruna Gigante

¹Institute of Environmental Medicine, Division of Cardiovascular Epidemiology, Karolinska Institute, Stockholm, Sweden

,

Max Vikström

¹Institute of Environmental Medicine, Division of Cardiovascular Epidemiology, Karolinska Institute, Stockholm, Sweden

,

Linda Strömqvist Meuzelaar

²Department of Genetics, University of Leicester, Leicester, UK

,

Ekaterina Chernogubova

³Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, Stockholm, Sweden

,

Angela Silveira

³Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, Stockholm, Sweden

,

Ferdinand van’t Hooft

³Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, Stockholm, Sweden

,

Anders Hamsten

³Department of Medicine, Atherosclerosis Research Unit, Karolinska Institute, Stockholm, Sweden

⁴Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

,

Ulf de Faire

¹Institute of Environmental Medicine, Division of Cardiovascular Epidemiology, Karolinska Institute, Stockholm, Sweden

⁴Department of Cardiology, Karolinska University Hospital, Stockholm, Sweden

› Author Affiliations

Abstract

Summary

Thrombin-activated factor 2 receptor (F2R) links thrombosis to inflammation modulating interleukin (IL)6 synthesis. We have investigated the role of F2R genetic variants and their interaction with IL6 serum levels in the occurrence of myocardial infarction (MI) in the Stockholm Heart Epidemiology Program (SHEEP). Seven SNPs –1738 G/A, –506-/GGCCGCGGGAAGC (D/I), 2860 G/A, 2930 T/C, 9113 C/A, 9333 C/T and 120813 T/C within F2R locus were genotyped in the SHEEP (n=2,774). The C allele at position 2930 was associated with a slight reduction in MI risk in men. IL6 serum levels were higher in male cases carrying genotypes AA at the –1738 (p= 0.01) and GG at the 2860 loci (p= 0.03) and both alleles were found to differentially modulate IL6 serum levels in the context of selective haplotypes. High IL6 serum levels (>75^th percentile), were independently associated with an increased risk of MI in men with an odds ratio (OR) (95% confidence interval [CI]) of 2.44 (1.72–3.46), (p=0.0016), but not in women ( OR 0.83 [95%CI 0.50–1.36], p=0.64). In the presence of high IL6 serum levels, the –1738A allele increased and the 2860A allele reduced the risk of MI (all p≤0.02). Consistently, the AG diplotype increased MI risk (OR 1.71 [95%CI 1.17–2.51], p=0.005). The –1738 and 2860 loci association with IL6 serum levels was replicated in men in the Stockholm Coronary Artery Risk Factor (SCARF) study (both p≤0.04). In the pooled data from the two populations, the A and G allele modulated the risk of MI in men with high IL6 serum levels (p≤0.03). Our results demonstrate that in men F2R genetic variants influence the risk of MI mainly through an interaction with IL6 serum levels.

Keywords

Thrombin - cytokines - atherothrombosis - epidemiological studies - myocardial infarction

Full Text

References

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