Association of plasma fibrinogen, C-reactive protein and G-455>A polymorphism with early atherosclerosis in the VITA Project cohort

Summary

While increased fibrinogen is associated with vascular events, only few data are available on its association with preclinical atherosclerosis. We aimed at evaluating the association between fibrinogen levels, fibrinogen polymorphism G-455>A and C-reactive protein and preclinical atherosclerosis in a population-based, cross-sectional study. A cohort of 2,580 subjects was enrolled. Fibrinogen was measured at time of original enrolment and at time of the second visit, when ultrasound examination of both left and right common carotid arteries was performed, together with evaluation of C-reactive protein (CRP) and of the fibrinogen G-455>A polymorphism. CRP and fibrinogen levels at baseline were the two variables mostly influencing fibrinogen levels at the follow-up visit (p<0.0001). Carriers of the H2H2 genotype of the G-455>A polymorphism had increased fibrinogen levels, particularly in association with increased CRP levels. Increased fibrinogen levels were independently associated with presence of carotid plaques, particularly in those subjects having a persistent increase of fibrinogen (odds ratio 1.98, 95% confidence interval 1.47–2.67). An association between the H2H2 genotype and presence of carotid plaques was observed only in a subgroup of subjects with CRP > 0.5 mg/dl. A persistent increase of plasma fibrinogen is associated with an increased risk of early atherosclerosis.

Keywords

Carotid atherosclerosis - fibrinogen - ultrasonography - epidemiology - C-reactive protein

• References

• 1 Roy SN, Mukhopadhyay G, Redman CM. Regulation of fibrinogen assembly. Transfection of Hep G2 cells with B beta cDNA specifically enhances synthesis of the three component chains of fibrinogen. J Biol Chem 1990; 265: 6389-6393.
• 2 Danesh J, Collins R, Appleby P. et al. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heart disease: meta-analyses of prospective studies. J Am Med Assoc 1998; 279: 1477-1482.
• 3 Danesh J, Lewington S, Thompson SG. et al. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. J Am Med Assoc 2005; 294: 1799-1809.
• 4 Smith GD, Harbord R, Milton J. et al. Does elevated plasma fibrinogen increase the risk of coronary heart disease? Evidence from a meta-analysis of genetic association studies. Arterioscler Thromb Vasc Biol 2005; 25: 2228-2233.
• 5 Verschuur M, de Jong M, Felida L. et al. A hepatocyte nuclear factor-3 site in the fibrinogen beta promoter is important for interleukin 6-induced expression, and its activity is influenced by the adjacent –148C/T polymorphism. J Biol Chem 2005; 280: 16763-16771.
• 6 Lowe GD. Circulating inflammatory markers and risks of cardiovascular and non-cardiovascular disease. J Thromb Haemost 2005; 3: 1618-1627.
• 7 Rodeghiero F, Tosetto A. The VITA Project: Population-based distribution of protein C, antithrombin III, heparin cofactor II and plasminogen. Relationship with physiological variables and establishment of reference ranges. Thromb Haemost 1996; 76: 226-233.
• 8 Rodeghiero F, Tosetto A. The epidemiology of inherited thrombophilia: the VITA Project. Thromb Haemost 1997; 78: 636-640.
• 9 Tosetto A, Prati P, Baracchini C. et al. Age-adjusted reference limits for carotid intima-media thickness as better indicator of vascular risk: population-based estimates from the VITA project. J Thromb Haemost 2005; 3: 1224-1230.
• 10 Ingram G. The determination of plasma fibrinogen by the clot-weight method. Biochem J 1952; 51: 583-585.
• 11 Humphries SE, Ye S, Talmud P. et al. European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment. Arterioscler Thromb Vasc Biol 1995; 15: 96-104.
• 12 Kleinbaum DG, Kupper LL, Muller KE. Applied regression analysis and other multivariable methods. PWS-Kent Publishing Company; Boston: 1988
• 13 Hosmer DW, Lemeshow S. Applied logistic regression. John Wiley & Sons; New York: 1989
• 14 Lawlor DA, Harbord RM, Sterne JA. et al. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med 2008; 27: 1133-1163.
• 15 StataCorp.. Stata Statistical Software: Release 11.0. Stata Corporation, College Station, TX, USA 2010.
• 16 Meade TW. Fibrinogen measurement to assess the risk of arterial thrombosis in individual patients: yes. J Thromb Haemost 2005; 3: 632-634.
• 17 Wilhelmsen L, Svardsudd K, Korsan-Bengtsen K. et al. Fibrinogen as a risk factor for stroke and myocardial infarction. N Engl J Med 1984; 311: 501-505.
• 18 Meade TW, Brozovic MM, Chakrabarti RR. et al. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986; ii: 533-537.
• 19 Yarnell JW, Baker IA, Sweetnam PM. et al. Fibrinogen, viscosity, and white clood cell count are major risk factors for ischemic heart disease. The Caerphilly and Speedwell collaborative Heart Disease Studies. Circulation 1991; 83: 836-844.
• 20 Chambless LE, Heiss G, Folsom AR. et al. Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987–1993. Am J Epidemiol 1997; 146: 483-494.
• 21 Ebrahim S, Papacosta O, Whincup P. et al. Carotid plaque, intima media thickness, cardiovascular risk factors, and prevalent cardiovascular disease in men and women: the British Regional Heart Study. Stroke 1999; 30: 841-850.
• 22 Prati P, Tosetto A, Vanuzzo D. et al. Carotid intima media thickness and plaques can predict the occurrence of ischemic cerebrovascular events. Stroke 2008; 39: 2470-2476.
• 23 Zureik M, Touboul PJ, Bonithon-Kopp C. et al. Cross-sectional and 4-year longitudinal associations between brachial pulse pressure and common carotid intima-media thickness in a general population. The EVA study. Stroke 1999; 30: 550-555.
• 24 van der Meer I, Bots ML, Hofman A. et al. Predictive value of noninvasive measures of atherosclerosis for incident myocardial infarction: the Rotterdam Study. Circulation 2004; 109: 1089-1094.
• 25 O’Leary DH, Polak JF, Kronmal RA. et al. Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. Stroke 1996; 27: 224-231.
• 26 O’Leary DH, Polak JF, Kronmal RA. et al. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. New Engl J Med 1999; 340: 14-22.
• 27 Tsivgoulis G, Vemmos K, Papamichael C. et al. Common carotid artery intima-media thickness and the risk of stroke recurrence. Stroke 2006; 37: 1913-1916.
• 28 Lee AJ, Mowbray PI, Lowe GD. et al. Blood viscosity and elevated carotid intima-media thickness in men and women: the Edinburgh Artery Study. Circulation 1998; 97: 1467-1473.
• 29 Branson HE, Katz J, Marble R. et al. Inherited protein C deficiency and coumarin-responsive chronic relapsing purpura fulminans in a newborn infant. Lancet 1983; 2: 1165-1168.
• 30 Grebe M, Luu B, Sedding D. et al. Fibrinogen Promotes Early Atherosclerotic Changes of the Carotid Artery in Young, Healthy Adults. J Atheroscler Thromb 2010; 17: 1003-1008.
• 31 Fibrinogen Studies Collaboration.. Plasma fibrinogen and the risk of major cardiovascular diseases and non-vascular mortality: meta-analysis of individual data for 151,649 adults in 31 prospective studies. J Am Med Assoc 2005; 294: 1799-1809.
• 32 Hamsten A, Mannila MN, Silveira A. Quest for genes regulating plasma fibrinogen concentration: still a long way to go. Arterioscler Thromb Vasc Biol 2005; 25: 1100-1101.
• 33 Soria JM, Almasy L, Souto JC. et al. A genome search for genetic determinants that influence plasma fibrinogen levels. Arterioscler Thromb Vasc Biol 2005; 25: 1287-1292.
• 34 Green D, Foiles N, Chan C. et al. Elevated fibrinogen levels and subsequent sub-clinical atherosclerosis: the CARDIA Study. Atherosclerosis 2009; 202: 623-631.
• 35 Woodward M, Rumley A, Welsh P. et al. A comparison of the associations between seven hemostatic or inflammatory variables and coronary heart disease. J Thromb Haemost 2007; 5: 1795-1800.
• 36 Prahl U, Wikstrand J, Bergstrom G. et al. Slightly Elevated High-Sensitivity C-Reactive Protein (hsCRP) Concentrations Are Associated With Carotid Atherosclerosis in Women With Varying Degrees of Glucose Tolerance. Angiology 2010; 61: 793-801.