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CLINICAL RESEARCH: GENETICS AND GENOMICS

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

Bénédicte Jacquemin, MD, PhD^_*, Charalambos Antoniades, MD, PhD^,,_*, Fredrik Nyberg, MD, PhD^,||, Estel Plana, MSc^_*, Martina Müller, MSc, PhD^#,_**, Sonja Greven, MSc, PhD^#,,, Veikko Salomaa, MD, PhD, Jordi Sunyer, MD, PhD^_*,||||, Tom Bellander, MD, PhD, Alexandros-Georgios Chalamandaris, MSc^¶¶, Ricardo Pistelli, MD^##, Wolfgang Koenig, MD, PhD^¶ and Annette Peters, MSc, PhD^#

^_* Centre for Environmental Research, Municipal Institute of Medical Research, Barcelona, Spain
1st Cardiology Department, Athens University Medical School, Athens, Greece
Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom
Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
^|| AstraZeneca R&D Mölndal, Mölndal, Sweden
^¶ Department of Internal Medicine II Cardiology, University of Ulm Medical Centre, Ulm, Germany
^# Institute of Epidemiology, Research Units "Air Pollution Health Effects" and "Chronic Disease Epidemiology" German Research Center for Environmental Health (GmbH), Neuherberg, Germany
^_** LMU-IBE, Chair of Epidemiology, University of Munich, Neuherberg, Germany
LMU Institute of Statistics, University of Munich, Munich, Germany
Department of Biostatistics, John Hopkins University, Baltimore, Maryland
National Public Health Institute (KTL), Helsinki, Finland
^|||| Universitat Pompeu Fabra, Barcelona, Spain
^¶¶ Department of Hygiene and Epidemiology, Athens University Medical School, Athens, Greece
^## Catholic University, Rome, Italy

Manuscript received February 29, 2008; revised manuscript received May 28, 2008, accepted June 2, 2008.

^_* Reprint request and correspondence: Dr. Charalambos Antoniades, Athens University Medical School, 1st Cardiology Department, Ilias 8, Gerakas Attikis, 153 44, Athens, Greece (Email: antoniades{at}vodafone.net.gr).

Objectives: 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.

Key Words: fibrinogen • genetics • inflammation • myocardial infarction

Abbreviations and Acronyms   CRP = C-reactive protein   FGA = fibrinogen chain alpha   FGB = fibrinogen chain beta   FGG = fibrinogen chain gamma   IL = interleukin   LD = linkage disequilibrium   MI = myocardial infarction   SNP = single nucleotide polymorphism