Bertina, R.M.

Doggen, C.J.M.

Rosendaal, F.R.

Visser, M.C.H. de

Willige, S.U. de

Leiden University Scholary Publications

Haplotypes of the fibrinogen gamma gene do not affect the riskof myocardial infarctionS . U ITTE D E WILL IGE ,* C . J . M . DOGGEN, M. C . H . DE V ISSER ,* R . M. BERT INA*and F . R . ROS ENDAAL**Department of Hematology, Hemostasis and Thrombosis Research Center; Department of Clinical Epidemiology, Leiden University MedicalCenter, Leiden, the NetherlandsTo cite this article: Uitte de Willige S, Doggen CJM, de Visser MCH, Bertina RM, Rosendaal FR. Haplotypes of the fibrinogen gamma gene do notaffect the risk of myocardial infarction. J Thromb Haemost 2006; 4: 474–6.As the precursor of fibrin, fibrinogen plays an important role inhemostasis [1]. Of all the components of the coagulationsystem, elevated plasma fibrinogen levels have most consis-tently been shown to be associated with occlusive vasculardisorders [2–5]. Several polymorphisms in the fibrinogen genes(FGA, FGB, FGG) have been reported to be associated withfibrinogen levels. Most studies focused on FGB polymor-phisms. However, results are not consistent and none of thesepolymorphisms has been found to be associated with anincreased risk of venous [6,7] or arterial thrombosis [7].Recently, we reported that a specific haplotype (H2) of thefibrinogen gamma gene (FGG) was associated with a 2.4-foldincreased risk of deep venous thrombosis [95% confidenceintervals (CI): 1.5–3.9] [6]. In the same study, we found thatanother haplotype (FGG-H3) was associated with a slightreduction in risk [odds ratio (OR) ¼ 0.8, 95% CI: 0.6–1.0].None of these haplotypes was associated with total fibrinogenlevels. However, the FGG-H2 haplotype was associated withreduced levels of fibrinogen c¢, a product of alternative splicingof the FGG gene. In a recent report, Mannila et al. [8] studiedthe effect of haplotypes across the fibrinogen gene cluster onthe risk of myocardial infarction (MI). They determined the*216C > T polymorphism, which is identical to FGG-H2tagging SNP 10034 C/T [rs2066865]. In their study, the FGG-H2 haplotype was not associated with the risk ofMI. However,they found a significant difference in the frequency distributionof the minor allele of the 1299 + 79T > C polymorphismbetween patients and controls (0.294 vs. 0.342, P ¼ 0.04),which suggests that this haplotype might be protective againstthe development of MI. This polymorphism is identical toFGG-H3 tagging SNP 9340 T/C [rs1049636].The aim of the present study was to investigate the effect ofthe four most common haplotypes of the FGG gene on the riskof MI. For this study, a large population-based case–controlstudy, Study of Myocardial Infarctions Leiden (SMILE) wasused. Full details of the SMILE study have been describedTable 1 Variant allele and haplotype group frequencies for VKORC1 and CYP2C9 in selected populations (actual SNP locations in parentheses).Haplotype groups A and B are based on classifications fromReider et al. [1] where haplotype A represents individuals at risk for excessive anticoagulationwith standard warfarin dosing, and haplotype B represents individuals at risk for subtherapeutic anticoagulation from standard warfarin dosing. Overalllow dose group defines individuals with at least one haplotype A and/or at least one CYP2C9 variant allele. Combined haplotype A and CYP2C9 groupdefines individuals with at least one haplotype A in combination with at least one CYP2C9 variant allele. The functional significance of haplotypes not ingroup A or group B (other) is currently unknown. IVS is standard nomenclature for intronic sequencePeruvian Mexican European–American African–American African AsianVKORC1 861 C > A ()4451C > A) 0.04 0.15 0.33 0.12 0.04 0.02VKORC1 5808 T > G (IVS1 + 324T > G) 0.02 0.13 0.21 0.06 0.00 0.00VKORC1 6853 G > C (IVS2 + 124G > C) 0.31 0.49 0.37 0.22 0.25 0.91VKORC1 9041 G > A (626G > A) 0.62 0.46 0.45 0.49 0.46 0.13CYP2C9*2 (3608C > T) 0.00 0.06 0.14 0.02 0.01 0CYP2C9*3 (42614A > C) 0.01 0.02 0.06 0.01 0.01 0.04VKORC1 haplotype group A 0.27 0.38 0.42 0.21 0.23 0.85VKORC1 haplotype group B 0.71 0.57 0.57 0.58 0.49 0.14VKORC1 haplotype group – other 0.02 0.05 0.01 0.21 0.28 0.01Overall low dose group 0.28 0.45 0.55 0.22 0.23 0.86Combined haplotype A and CYP2C9 group 0.00 0.03 0.18 0.01 0.01 0.06Correspondence: Shirley Uitte de Willige, Department of Hematology,Hemostasis and Thrombosis Research Center, D2-25, LeidenUniversity Medical Center, Albinusdreef 2, 2333 ZA, (P.O. Box9600, 2300 RC) Leiden, The Netherlands.Tel.: +31 71 526 6689; fax: +31 71 526 6755; e-mail: s.uitte_de_willige@lumc.nlReceived 7 October 2005, accepted 10 October 2005474 Letters to the Editor 2006 International Society on Thrombosis and Haemostasiselsewhere [9]. The subjects used in our previous study onvenous thrombosis [6] were all of Dutch origin and fourcommon haplotypes of the fibrinogen gamma gene werepresent in this population. Because the subjects of the SMILEstudy were all Dutch men, we assumed that in the SMILEpopulation only these four common haplotypes would bepresent. To tag these four common haplotypes, all subjectswere genotyped for three haplotype-tagging polymorphisms bythe 5¢ nuclease/TaqMan assay [10]. Polymorphism 10034 C/T[rs2066865] tagged FGG-H2, polymorphism 9340 T/C[rs1049636] tagged FGG-H3 and polymorphism 5836 G/A[rs2066860] tagged FGG-H4 [6]. FGG-H1 consisted of thecommon alleles of the three-mentioned polymorphisms. (Posi-tion numbering according to SeattleSNPs [11], GenBankAccession number AF350254).The distribution of the genotypes among control subjectswas as expected for a population in Hardy–Weinberg equilib-rium.No haplotypes could be assigned to four patients and twocontrol subjects, because of intragenic recombination. Thesesamples were excluded from the analyses. As shown in Table 1,overall none of the haplotypes of the FGG gene was associatedwith the risk of MI, including FGG-H2, which we found to bea risk factor for venous thrombosis [6]. The allele frequency ofFGG-H2 was 0.276 in cases and 0.277 in control subjects. Thisis in agreement with the data of Mannila et al. [8], who did notfind an association in 377 MI patients and 387 control subjectsaged<60 years in Sweden.However, we could not confirm thereduction in risk for FGG-H3 found by Mannila et al. Wefound allele frequencies of 0.298 and 0.284 for patients andcontrol subjects, respectively (Table 1).Most patients with MI are middle-aged or elderly. Thosesuffering MI at a younger age usually have an excess of riskfactors, including genetic factors. In men below the age of 50(150 patients and 158 control subjects), the risk of MI wasslightly decreased for FGG-H1 (Table 1) and slightly increasedfor FGG-H2. There was no effect on risk for FGG-H3 andFGG-H4. For men aged 50 or above, there was no effect onrisk in any of the haplotypes. So, we only found a slightincrease in risk for FGG-H2 in men below the age of 50. Thismight be an indication that FGG-H2 not only affects venousthrombosis risk, but also the risk of myocardial infarction,although the effect was weak (OR for FGG-H2H2 carriers 1.5)with a wide CI (0.7–3.5). The sample size of this youngsubgroup was relatively small and it would be useful toinvestigate the role of FGG-H2 in a larger study of patientswith myocardial infarction at a young age.Furthermore, we investigated the combined effect of FGGhaplotypes and cardiovascular risk factors such as smoking(345 patients and 214 control subjects) or metabolic riskfactors (203 patients and 197 control subjects), in whichhaving a metabolic risk factor was defined as the presence ofobesity, diabetes, hypertension or hypercholesterolemia [9].The risks of the four haplotypes in the different subgroupswith or without the cardiovascular risk factors did notchange compared with the risks in the overall population. Infact, the risks did not exceed that of the single effects of thecardiovascular risk factors, so we did not find evidence forsynergistic effects between FGG haplotypes and cardiovas-cular risk factors.In addition, we studied the relation between the FGGhaplotypes and fibrinogen levels. In the control subjects,fibrinogen levels were measured in plasma using the Claussthrombin time method as described previously [12]. We did notobserve an association of FGG haplotypes with fibrinogenTable 1 The risk of myocardial infarction in the presence of the four most common haplotypes of the fibrinogen gamma geneHaplotype (htSNP) Patients (%) n ¼ 556 Controls (%) n ¼ 644 OR 95% CI<50 years ‡50 yearsOR 95% CI OR 95% CIH1 (all common)HxHx 210 (37.8) 228 (35.4) 1* 1* 1*H1Hx 265 (47.7) 318 (49.4) 0.9 0.7–1.2 0.7 0.4–1.2 1.0 0.7–1.3H1H1 81 (14.6) 98 (15.2) 0.9 0.6–1.3 0.7 0.4–1.4 1.0 0.6–1.5Frequency H1 0.384 0.399H2 (10034 C/T)HxHx 290 (52.2) 336 (52.2) 1* 1* 1*H2Hx 225 (40.5) 259 (40.2) 1.0 0.8–1.3 1.3 0.8–2.1 0.9 0.7–1.2H2H2 41 (7.4) 49 (7.6) 1.0 0.6–1.5 1.5 0.7–3.5 0.8 0.5–1.4Frequency H2 0.276 0.277H3 (9340 T/C)HxHx 266 (47.8) 322 (50.0) 1* 1* 1*H3Hx 249 (44.8) 278 (43.2) 1.1 0.9–1.4 1.1 0.7–1.7 1.1 0.8–1.5H3H3 41 (7.1) 44 (6.8) 1.1 0.7–1.8 1.1 0.4–2.9 1.2 0.7–1.9Frequency H3 0.298 0.284H4 (5836 G/A)HxHx 509 (91.5) 593 (92.1) 1* 1* 1*H4Hx 47 (8.5) 51 (7.9) 1.1 0.7–1.6 0.9 0.4–2.1 1.2 0.7–1.8H4H4 – – – – – – – –Frequency H4 0.042 0.040*Reference category.Letters to the Editor 475 2006 International Society on Thrombosis and Haemostasislevels in these control subjects. This is consistent with aprevious study in which we did not find an association of thesehaplotypes with fibrinogen levels in the 473 control subjects ofthe Leiden Thrombophilia Study [6].We conclude that none of the four common haplotypes ofthe FGG gamma gene has a strong effect on the risk of MI.Homozygosity for FGG-H2, which we found previously to bea risk factor for venous thrombosis, might slightly increase therisk ofMI in patients younger than 50 years. These findings arein line with the studies on other prothrombotic factors thataffect the risk of venous thrombosis but have small or no effectson arterial disease [13].AcknowledgementsThis study was financially supported by grant 912-02-036 fromthe Netherlands Organization for Scientific Research (NWO).The SMILE study was supported by grant 92.345 from theNetherlands Heart Foundation.References1 Mosesson MW, Siebenlist KR, Meh DA. The structure and biolo-gical features of fibrinogen and fibrin. Ann NY Acad Sci 2001; 936:11–30.2 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR,North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Hae-mostatic function and ischaemic heart disease: principal results of theNorthwick Park Heart Study. Lancet 1986; 2: 533–7.3 Kannel WB, Wolf PA, Castelli WP, D’Agostino RB. Fibrinogen andrisk of cardiovascular disease. The Framingham Study. JAMA 1987;258: 1183–6.4 Yarnell JW, Baker IA, Sweetnam PM, Bainton D, O’Brien JR,Whitehead PJ, Elwood PC. Fibrinogen, viscosity, and white blood cellcount are major risk factors for ischemic heart disease. The Caerphillyand Speedwell collaborative heart disease studies. Circulation 1991; 83:836–44.5 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP,Bertina RM. Venous thrombosis due to poor anticoagulant responseto activated protein C: Leiden Thrombophilia Study.Lancet 1993; 342:1503–6.6 Uitte de Willige S, de Visser MC, Houwing-Duistermaat JJ,Rosendaal FR, Vos HL, Bertina RM. Genetic variation in thefibrinogen gamma gene increases the risk of deep venous thrombosisby reducing plasma fibrinogen {gamma}¢ levels. Blood 2005; 106:4176–83.7 Lane DA, Grant PJ. Role of hemostatic gene polymorphisms invenous and arterial thrombotic disease. Blood 2000; 95: 1517–32.8 Mannila MN, Eriksson P, Lundman P, Samnegard A, Boquist S,Ericsson CG, Tornvall P, Hamsten A, Silveira A. Contribution ofhaplotypes across the fibrinogen gene cluster to variation in risk ofmyocardial infarction. Thromb Haemost 2005; 93: 570–7.9 Doggen CJM, Cats VM, Bertina RM, Rosendaal FR. Interaction ofcoagulation defects and cardiovascular risk factors: increased risk ofmyocardial infarction associated with factor V Leiden or prothrombin20210A. Circulation 1998; 97: 1037–41.10 Livak KJ. Allelic discrimination using fluorogenic probes and the 5¢nuclease assay. Genet Anal 1999; 14: 143–9.11 Nickerson D. SeattleSNPs. NHLBI Program for Genomic Applica-tions. [WWW document] UW-FHCRC, Seattle, WA. Available at:http://pga.gs.washington.edu. (accessed 15 April 2003).12 Doggen CJM, Bertina RM, Cats VM, Rosendaal FR. Fibrinogenpolymorphisms are not associated with the risk of myocardial infarc-tion. Br J Haematol 2000; 110: 935–8.13 Atherosclerosis, Thrombosis, and Vascular Biology Italian StudyGroup. No evidence of association between prothrombotic genepolymorphisms and the development of acute myocardial infarction ata young age. Circulation 2003; 107: 1117–22.Statins modulate expression of components of the plasminogenactivator/plasmin system in human cardiac myocytes in vitroS . DEMY ANETS ,* C . KAUN,* G . MAURER ,* K . HUBER and J . WOJTA**Department of Internal Medicine II, Medical University of Vienna, Ludwig Boltzmann Foundation for Cardiovascular Research, Vienna;and 3rd Medical Department for Cardiology and Emergency Medicine, Wilhelminenspital, AustriaTo cite this article: Demyanets S, Kaun C, Maurer G, Huber K, Wojta J. Statins modulate expression of components of the plasminogen activator/plasmin system in human cardiac myocytes in vitro. J Thromb Haemost 2006; 4: 476–79.Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductaseinhibitors or statins represent an established class of drugs forthe treatment of hypercholesterolemia and large-scale clinicaltrials have emphasized their benefits in the primary andsecondary prevention of myocardial infarction (MI) throughtheir positive effects on atherosclerosis and its complications[1–3]. Recent findings that the statins attenuate myocardialhypertrophy in vitro and in vivo provide evidence that theseCorrespondence: Johann Wojta, Department of Internal Medicine II,Medical University of Vienna, A-1090 Vienna, Waehringer Guertel18-20, Austria.Tel.: +43 1 40400; fax: +43 1 40400; e-mail: johann.wojta@meduniwien.ac.atReceived 7 October 2005, accepted 18 October 2005476 Letters to the Editor 2006 International Society on Thrombosis and Haemostasis

Haplotypes of the fibrinogen gamma gene do not affect the risk of myocardial infarction

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Haplotypes of the fibrinogen gamma gene do not affect the risk of myocardial infarction

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