Common genetic polymorphisms and haplotypes of fibrinogen alpha, beta, and gamma chains affect fibrinogen levels and the response to proinflammatory stimulation in myocardial infarction survivors: the AIRGENE study.
OBJECTIVE
This study was designed to investigate whether single nucleotide polymorphisms (SNPs) and haplotypes of the fibrinogen gene-cluster (fibrinogen chains alpha [FGA], beta [FGB], and gamma [FGG]) could explain the inter- and intraindividual variability of fibrinogen levels in patients with atherosclerosis. We also searched for genetic determinants affecting the responses of fibrinogen genes to proinflammatory stimulation.


BACKGROUND
The mechanisms regulating fibrinogen levels are not fully understood, and they are likely to be regulated by complex gene-environment interactions.


METHODS
In the AIRGENE study, 895 survivors of myocardial infarction from 5 European cities were followed prospectively for 6 to 8 months, and plasma fibrinogen, interleukin (IL)-6, and C-reactive protein levels were determined monthly. We analyzed 21 SNPs and the corresponding haplotypes in the 3 fibrinogen genes.


RESULTS
Eight SNPs in FGA and FGB were significantly associated with fibrinogen levels. Similarly, 2 different haplotypes in FGA and 3 in FGB were also associated with mean fibrinogen levels. The IL-6 levels had a significant impact on the associations between SNPs/haplotypes in FGA/FGB and fibrinogen levels. We also identified SNPs and haplotypes in FGA and FGB with strong impact on the intraindividual variability of fibrinogen during the follow-up period.


CONCLUSIONS
We identified common SNPs and haplotypes on FGA/FGB genes, explaining the interindividual and intraindividual variability of fibrinogen levels, in patients with a history of myocardial infarction. We have also identified for the first time, SNPs/haplotypes on FGA/FGB whose effects on fibrinogen expression are modified by the underlying IL-6 levels. These findings may have an impact on risk stratification and the design of genetically guided therapeutic approaches in patients with advanced atherosclerosis.
Jacquemin
Bénédicte
B
Centre for Environmental Research, Municipal Institute of Medical Research, Barcelona, Spain.
Antoniades
Charalambos
C
Nyberg
Fredrik
F
Plana
Estel
E
Müller
Martina
M
Greven
Sonja
S
Salomaa
Veikko
V
Sunyer
Jordi
J
Bellander
Tom
T
Chalamandaris
Alexandros-Georgios
AG
Pistelli
Ricardo
R
Koenig
Wolfgang
W
Peters
Annette
A
D000368:Aged; D002097:C-Reactive Protein / Q000378:metabolism*; D005340:Fibrinogen / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044465:White People / Q000235:genetics
D015850:Interleukin-6; D005340:Fibrinogen; D002097:C-Reactive Protein