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Genetic variation in the fibrinogen-α and fibrinogen-γ genes in relation to arterial stiffness: the Rotterdam Study

Sie, Mark PSa,b; Isaacs, Aarona; de Maat, Moniek PMc; Mattace-Raso, Francesco USa,b; Uitterlinden, André Ga,b; Kardys, Isabellaa; Hofman, Alberta; Hoeks, Arnold PGd; Reneman, Robert Se; van Duijn, Cornelia Ma; Witteman, Jaqueline CMa

doi: 10.1097/HJH.0b013e32832a95b0
Original papers: Genetic aspects

Objective Arterial stiffness increases with age and predicts cardiovascular disease. Fibrinogen is an acute-phase protein and some studies showed an association with arterial stiffness. We studied genetic variation in the fibrinogen-α (FGA) and fibrinogen-γ (FGG) genes, by means of single nucleotide polymorphisms (FGA: −58 G/A, 1374 G/A, 1526 T/C, 312 Thr/Ala, and FGG: 4288 G/A, 6326 G/A, 7792 T/C) and resultant haplotypes in relation to arterial stiffness.

Methods The present study (n = 3891) was embedded in the Rotterdam Study. Associations of the fibrinogen level, genotypes and haplotypes with aortic stiffness (pulse wave velocity), carotid stiffness (distensibility coefficient) and pulse pressure were investigated in men and women by analyses of variance, linear regression and by haplotype analyses. Analyses were adjusted for age, mean arterial pressure, heart rate, known cardiovascular risk factors and atherosclerosis.

Results Genotype analyses yielded associations of FGA-58 G/A (P = 0.040, for trend) and FGA-1526 T/C (P = 0.004, for trend) with the fibrinogen levels, but no consistent associations with arterial stiffness, in women. FGA-haplotype 4 was associated with the fibrinogen level (P = 0.02) in women. FGA-haplotype 3 and FGG-haplotype 2 were associated with aortic stiffness (P = 0.05) in women. No associations were found in men.

Conclusion Findings indicate that the fibrinogen level and genetic variation in the FGA and FGG genes may influence arterial stiffness in women.

aDepartment of Epidemiology & Biostatistics, the Netherlands

bDepartment of Internal Medicine, the Netherlands

cDepartment of Haematology, Erasmus Medical Center, Rotterdam, the Netherlands

dDepartment of Biophysics, the Netherlands

eDepartment of Physiology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, the Netherlands

Received 2 May, 2008

Revised 27 January, 2009

Accepted 18 February, 2009

Correspondence to J.C.M. Witteman, PhD, Department of Epidemiology & Biostatistics, Erasmus Medical Center, Rotterdam, PO Box 2040, 3000 CA Rotterdam, The Netherlands Tel: +31 10 4087488; fax: +31 10 4089382; e-mail:

© 2009 Lippincott Williams & Wilkins, Inc.