Contribution of haplotypes across the fibrinogen gene cluster to variation in risk of myocardial infarction
Maria Nastase Mannila
1
Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Per Eriksson
1
Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Pia Lundman
2
Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Ann Samnegård
2
Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Susanna Boquist
2
Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Carl-Göran Ericsson
2
Cardiology Unit, Division of Medicine, Karolinska Institutet, Danderyd Hospital, Stockholm, Sweden
,
Per Tornvall
3
Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Anders Hamsten
1
Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
3
Department of Cardiology, Karolinska University Hospital, Solna, Stockholm, Sweden
,
Angela Silveira
1
Atherosclerosis Research Unit, Karolinska Institutet, King Gustaf V Research Institute, Karolinska University Hospital, Solna, Stockholm, Sweden
› Author AffiliationsGrant support: This study was supported by grants from the Swedish Medical Research Council (8691), the Swedish Heart-Lung Foundation, the Torsten and Ragnar Söderberg Foundation, the Petrus and Augusta Hedlund Foundation, the King Gustaf V and Queen Victoria Foundation, the Foundation for Old Servants, the Professor Nanna Svartz Foundation, the Stockholm County Council and Karolinska Institutet.
Fibrinogen has consistently been recognized as an independent predictor of myocardial infarction (MI). Multiple mechanisms link fibrinogen to MI; therefore disentangling the factors underlying variation in plasma fibrinogen concentration is essential. Candidate regions in the fibrinogen gamma (FGG), alpha (FGA) and beta (FGB) genes were screened for single nucleotide polymorphisms (SNPs). Several novel SNPs were detected in the FGG and FGA genes in addition to the previously known SNPs in the fibrinogen genes. Tight linkage disequilibrium extending over various physical distances was observed between most SNPs. Consequently, eight SNPs were chosen and determined in 377 postinfarction patients and 387 healthy individuals. None of the SNPs were associated with plasma fibrinogen concentration or MI. Haplotype analyses revealed a consistent pattern of hap-lotypes associated with variation in risk of MI. Of the four haplo-types inferred using the FGA –58G> A and FGG 1299+79T> C SNPs, the most frequent haplotype, FGG-FGA*1 (prevalence 46.6%), was associated with increased risk of MI (OR 1.51; 95%CI 1.18, 1.93), whereas the least frequent haplotype, FGGFGA*4 (11.8%), was associated with lower risk of MI (OR 0.79 95%CI 0.64, 0.98). In conclusion, fibrinogen haplotypes, but not SNPs in isolation, are associated with variation in risk of MI.
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