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Lack of association between factor V Leiden and prothrombin G20210A polymorphisms in Tunisian subjects with a history of myocardial infarction
Cardiovascular Pathology 22 (2013) 39–41
Contents lists available at SciVerse ScienceDirect
Cardiovascular Pathology
Original Article
Lack of association between factor V Leiden and prothrombin G20210A polymorphisms in Tunisian subjects with a history of myocardial infarction Dhouha Berredjeb Ben Slama a,⁎, Najiba Fekih-Mrissa a, Abdeddayem Haggui b, Brahim Nsiri a, Nadia Baraket b, Habib Haouala b, Nasreddine Gritli a a b
Laboratory of Molecular Biology, Department of Hematology, Military Hospital of Tunis, Tunis, Tunisia Department of Cardiology, Military Hospital of Tunis, Tunis, Tunisia
a r t i c l e
i n f o
Article history: Received 25 August 2011 Received in revised form 11 February 2012 Accepted 5 March 2012 Keywords: Factor V Leiden FII G20210A Myocardial infarction Risk factors
a b s t r a c t Background: Myocardial infarction is a multifactorial disease. It is provoked by occlusions in the coronary arteries resulting from exposure to multiple risk factors. Objective: To study the risk of myocardial infarction associated with the gene polymorphisms of factor V Leiden and factor II (G20210A). Materials and methods: Cases consisted of 100 myocardial infarction patients who were hospitalized in the Principal Military Hospital of Tunis and 200 control subjects with no history of myocardial infarction. Results: The prevalence of the factor V Leiden was higher in myocardial infarction patients (9%) than in control subjects (6%) with an OR=1.55 (95% CI=0.58–4.12), whereas the prevalence of prothrombin G20210A mutation was 3% and 2.5% in the patient and control groups, respectively [OR=1.21 (95% CI=0.22–5.94)]. Conclusion: Our results indicate that neither factor V Leiden nor the prothrombin G20210A contributed to the risk factors for myocardial infarction. © 2013 Elsevier Inc. All rights reserved.
1. Introduction A diagnosis of myocardial infarction (MI) was considered to be confirmed if the reported event met the World Health Organization criteria of symptoms supported by either elevations of cardiac enzyme levels or diagnostic changes on the electrocardiogram or both [1]. Several studies have examined the relationship between MI and prothrombotic genetic markers such as the G1691A mutation in the factor V gene and the G20210A mutation in the prothrombin gene [2,3]. We chose to investigate the association of these genetic factors, known to be related with an increased thrombotic tendency, to the occurrence of MI in a selected group of Tunisian subjects. The interaction between genetic prothrombotic risk factors and traditional risk factors was also evaluated. 2. Material and methods 2.1. Selection of case patients and control subjects This case-control study included 100 patients who had MI before the age of 60 years (mean age 46.92±7.627). They had been admitted ⁎ Corresponding author. Laboratory of Molecular Biology, Department of Hematology, Military Hospital, 1008 Mont Fleury Tunis, Tunisia. Tel.: +216 22526904. E-mail address: [email protected] (D. Berredjeb Ben Slama). 1054-8807/$ – see front matter © 2013 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2012.03.002
to the Cardiology Department of the Military Hospital of Tunis between January 2009 and June 2010. Control subjects were healthy individuals with no history of MI or thromboembolic disease (mean age 31±9.6). The study protocol was approved by the ethics committee of the hospital. All persons completed a questionnaire concerning the presence of cardiovascular risk factors such as smoking habits and alcohol consumption. Medication use and history of diabetes were ascertained through an interview with control subjects and retrieved from discharge letters for the patients. A person was classified as hypertensive if drugs were prescribed for this condition. The variables of obesity, diabetes, hypertension, and dyslipidemia were classified together as “metabolic risk factors.” 2.2. Blood collection and DNA analysis Peripheral blood from all individuals in the study was collected in EDTA-containing tubes. DNA was extracted from the white blood cells according to a salting-out method, and the DNA was stored at 4°C until amplification [4]. A multiplex amplification with biotinylated primers was used to amplify the genomic DNA. The PCR products then underwent a reverse hybridization by the use of a commercial kit (ThromboType plus, Hain Lifescience, Nehren, Germany). This test was based on the DNA.STRIP technology and permits the combined molecular genetic characterization of position 1691 in the human factor V gene and position 20210 in the human prothrombin gene.
40
D. Berredjeb Ben Slama et al. / Cardiovascular Pathology 22 (2013) 39–41
Table 1 Characteristics of risk factors among MI patients and control subjects
Sex (male/female) Age (years), mean±S.D. Obesity Diabetes Hypertension Dyslipidemia Smoker
Patients (n=100)
Control subjects (n=200)
OR (95%CI)
P value
84:16 (84%/16%) 46.92±7.62 17 (17%) 41 (41%) 38 (38%) 49 (49%) 73 (73%)
129:71 (64.5%/35.5%) 31±9.6 12 (6%) 15 (7.5%) 18 (9%) 21(10%) 79 (39.5%)
– – 3.21 8.57 6.20 8.19 4.14
– – b.05 b.05 b.05 b.05 b.05
2.3. Statistical analysis Descriptive statistics included mean values and standard deviations for continuous variables and proportions for categorical data. The strength of the association between traditional and prothrombotic genetic risk factors and MI in patients was estimated by calculating the odds ratios (OR) and 95% confidence intervals (CI). The presence of interactions between traditional and prothrombotic genetic risk factors was estimated by calculating “the attributable proportion of the disease” caused by the interaction with 95% CI [5]. The demographic characteristics of and prevalence of traditional risk factors in the 100 patients with MI and 200 control subjects are shown in Table 1. The two groups were sex matched; the vast majority of patients and control subjects were men with 84 male patients (84%) and 129 male controls (64.5%). There was a significantly higher prevalence of smoking in patients (73%) than in controls (39.5%). All metabolic risk factors and obesity were vastly more prevalent among the patients than among controls: dyslipidemia (49% vs. 10%), diabetes (41% vs. 7.5%), hypertension (38% vs. 9%), and obesity (17% vs. 6%). 2.4. Genetic risk factors Among the 100 patients with MI, there were 9 (9%) who were heterozygous for the factor V Leiden G1691A mutation and 3 (3%) heterozygous for the prothrombin G20210A mutation. There were no homozygous patients for either polymorphism. In contrast, in the controls, the distribution of the factor V Leiden G1691A and prothrombin G20210A was 12 (6%) and 5 (2.5%) respectively. Eleven (5.5%) controls were heterozygous for the factor V Leiden and only one (0.5%) control subject was homozygous. There were no homozygous carriers of the prothrombin G20210A polymorphism in the control group (Table 2). 2.5. Interaction between traditional and genetic prothrombotic risk factors Current smoking and the presence of metabolic risk factors were strong risk factors for MI. Smokers (73%) comprised the majority of those with MI. There was a concomitant risk with smoking and the presence of the factor V Leiden mutation: among nine patients who carried this mutation, seven patients were smokers. Similarly, there
(1.38–7.53) (4.24–17.54) (3.16–12.24) (4.33–15.61) (2.38–7.25)
were two patients who smoked from the three patients who carried the prothrombin G20210A mutation. The risk of MI was higher in smokers who carried either of these mutations (Table 3). The results shown in Table 3 indicate that the presence of factor V Leiden or the prothrombin G20210A and one or more of the metabolic risk factors increased the risk of MI. Obesity was not a significant risk factor.
3. Discussion Myocardial infarction (MI) usually occurs because an occlusive acute thrombus develops at the site of a ruptured atheromatous plaque in an epicardial coronary artery [6,7]. Both atherosclerosis and thrombosis therefore do contribute toward the occurrence of MI, although the relative importance of these two processes varies from patient to patient and is different at different ages [8,9]. In this study, we postulated that there was not an increased procoagulant tendency mediated by the factor V Leiden mutation or the prothrombin G20210A variant. However, either mutation concomitant with other factors (particularly smoking) can perhaps induce the development of MI in a selected group. Indeed, like this study, the US Physicians' Health Study reported no association between factor V Leiden and MI [10]. The US Physicians' Health Study also reported a lack of association between the prothrombin G20210A variant and MI [11]. As well as these results, Gupta et al. [12] indicated that factor V Leiden and factor II G20210A mutations were totally absent in their study among cases and controls from North India. Moreover, Eikelboom et al. [13] had shown that, in young survivors of MI, predominantly men, the prothrombin mutation was not associated with an increased risk. However, in others studies, there were conflicting results as to whether factor V Leiden and factor II G20210A mutation increased the risk of MI. Van de Water et al. [14] investigated the prevalence of prothrombin 20210GA and factor V Leiden mutations in 271 patients with MI. The prevalence of factor V Leiden mutation was determined to be 14.6% and 3.6% in the patient and control groups, respectively [OR=4.7 (95% CI=1.3–17.7), P=.04]. Similarly, the prevalence of the prothrombin 20210GA mutation was determined to be 7.3% and 1.8% in the patient and control groups, respectively [OR=4.9 (95% CI=1.1– 22.8), P=.04] [14]. Two other studies had also identified an increased frequency of factor V Leiden in selected subgroups of survivors of MI [15,16]. However, limitations of our study were due to the relatively small number of patients and the lack of a healthy control group.
Table 2 Distribution of genetic polymorphisms in MI patients and control subjects
FVL
Prothrombin (FII)
Genotypes
Patients (n=100)
Control subjects (n=200)
OR (95% CI)
1691GG 1691AG 1691AA 20210GG 20210AG 20210AA
91 9 0 97 3 0
188 11 1 195 5 0
1.55 (0.58–4.12)
OR=Odds ratio of AG and AA genotypes vs. the GG genotype.
P value .49N.05
1.21 (0.22–5.94)
1N.05
D. Berredjeb Ben Slama et al. / Cardiovascular Pathology 22 (2013) 39–41
41
Table 3 Risk effect of cardiovascular risk factor with and without a coagulation defect Cardiovascular risk factor
Presence or absence of coagulation defect
Patients (n=200)
Control subjects (n=100)
Odds ratio (95% CI)
P value
Smoking
Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎
64 9 24 3 36 5 52 7 31 7 57 5 15 2 73 10
77 2 106 15 15 0 168 17 18 0 165 17 12 0 171 17
5.41 (1.04–37.73)
.04
0.88 (0.19–3.63)
1
–
.30
1.33 (0.47–3.65)
.72
–
.08
0.85 (0.26–2.60)
.96
–
.49
1.38 (0.56–3.37)
.58
No smoking Diabetic Nondiabetic Hypertensive Nonhypertensive Obese Nonobese ⁎ Absence of coagulation defect. ⁎⁎ Presence of FVL or G20210A.
4. Conclusion Based on the results of our study, we surmise that, in a complex, polygenic, and multifactorial disorder such as MI, the role of an inherited predisposition to thrombosis is relatively weak in itself and weaker than the role of traditional risk factors. Yet some prothrombotic genetic factors may be important contributors in combination with environmental factors or acquired prothrombotic stimuli, particularly with smoking. Prospective studies are needed to examine the clinical value of the interaction between environmental factors and the prothrombotic genotypes. Acknowledgments We would like to thank Dr. Christian Winchell for his precious help in correcting this manuscript and Ghaya Bouaicha for her technical support. References [1] World Health Organization. Ischemic heart disease registers: report of the fifth work group (including a second revision of the operating protocol): Copenhagen, Denmark, April 26–29, 1971. Copenhagen, Denmark: World Health Organization, Regional office for Europe; 1971. [2] Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–7. [3] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88: 3698–703.
[4] Miller SA, Dykes DD, Polesky HF. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215. [5] Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology 1992;3:452–6. [6] Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992;326: 242–50. [7] Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992;326: 310–8. [8] Zimmerman FH, Cameron A, Fisher LD, Ng G. Myocardial infarction in young adults: angiographic characterization, risk factors and prognosis (coronary artery surgery registry). J Am Coll Cardiol 1995;26:654–61. [9] Kanitz MG, Giovannucci SI, Jones JS, Molt M. Myocardial infarction in young adults: risk factors and clinical features. J Emerg Med 1996;14:139–45. [10] Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke and venous thrombosis in apparently healthy men. N Engl J Med 1995;332:912–7. [11] Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke and venous thrombosis in a large cohort of U.S. men. Circulation 1999;99:999–1004. [12] Gupta N, Khan F, Tripathi M, Singh VP, Tewari S, Ramesh V, et al. Absence of factor V Leiden (G1691A) mutation, FII G20210A allele in coronary artery disease in North India. Indian J Med Sci 2003;57:535–42. [13] Eikelboom JW, Baker RI, Parsons R, Taylor RR, van Bockxmeer FM. No association between the 20210G/A prothrombin gene mutation and premature coronary artery disease. Thromb Haemost 1998;80:878–80. [14] Van de Water NS, French JK, Lund M, Hyde TA, White HD, Browett PJ. Prevalence no significant stenoses at angiography three to four weeks after myocardial infarction. J Am Coll Cardiol 2000;36:717–22. [15] Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817–21. [16] Doggen CJM, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998;97:1037–41.
Contents lists available at SciVerse ScienceDirect
Cardiovascular Pathology
Original Article
Lack of association between factor V Leiden and prothrombin G20210A polymorphisms in Tunisian subjects with a history of myocardial infarction Dhouha Berredjeb Ben Slama a,⁎, Najiba Fekih-Mrissa a, Abdeddayem Haggui b, Brahim Nsiri a, Nadia Baraket b, Habib Haouala b, Nasreddine Gritli a a b
Laboratory of Molecular Biology, Department of Hematology, Military Hospital of Tunis, Tunis, Tunisia Department of Cardiology, Military Hospital of Tunis, Tunis, Tunisia
a r t i c l e
i n f o
Article history: Received 25 August 2011 Received in revised form 11 February 2012 Accepted 5 March 2012 Keywords: Factor V Leiden FII G20210A Myocardial infarction Risk factors
a b s t r a c t Background: Myocardial infarction is a multifactorial disease. It is provoked by occlusions in the coronary arteries resulting from exposure to multiple risk factors. Objective: To study the risk of myocardial infarction associated with the gene polymorphisms of factor V Leiden and factor II (G20210A). Materials and methods: Cases consisted of 100 myocardial infarction patients who were hospitalized in the Principal Military Hospital of Tunis and 200 control subjects with no history of myocardial infarction. Results: The prevalence of the factor V Leiden was higher in myocardial infarction patients (9%) than in control subjects (6%) with an OR=1.55 (95% CI=0.58–4.12), whereas the prevalence of prothrombin G20210A mutation was 3% and 2.5% in the patient and control groups, respectively [OR=1.21 (95% CI=0.22–5.94)]. Conclusion: Our results indicate that neither factor V Leiden nor the prothrombin G20210A contributed to the risk factors for myocardial infarction. © 2013 Elsevier Inc. All rights reserved.
1. Introduction A diagnosis of myocardial infarction (MI) was considered to be confirmed if the reported event met the World Health Organization criteria of symptoms supported by either elevations of cardiac enzyme levels or diagnostic changes on the electrocardiogram or both [1]. Several studies have examined the relationship between MI and prothrombotic genetic markers such as the G1691A mutation in the factor V gene and the G20210A mutation in the prothrombin gene [2,3]. We chose to investigate the association of these genetic factors, known to be related with an increased thrombotic tendency, to the occurrence of MI in a selected group of Tunisian subjects. The interaction between genetic prothrombotic risk factors and traditional risk factors was also evaluated. 2. Material and methods 2.1. Selection of case patients and control subjects This case-control study included 100 patients who had MI before the age of 60 years (mean age 46.92±7.627). They had been admitted ⁎ Corresponding author. Laboratory of Molecular Biology, Department of Hematology, Military Hospital, 1008 Mont Fleury Tunis, Tunisia. Tel.: +216 22526904. E-mail address: [email protected] (D. Berredjeb Ben Slama). 1054-8807/$ – see front matter © 2013 Elsevier Inc. All rights reserved. doi:10.1016/j.carpath.2012.03.002
to the Cardiology Department of the Military Hospital of Tunis between January 2009 and June 2010. Control subjects were healthy individuals with no history of MI or thromboembolic disease (mean age 31±9.6). The study protocol was approved by the ethics committee of the hospital. All persons completed a questionnaire concerning the presence of cardiovascular risk factors such as smoking habits and alcohol consumption. Medication use and history of diabetes were ascertained through an interview with control subjects and retrieved from discharge letters for the patients. A person was classified as hypertensive if drugs were prescribed for this condition. The variables of obesity, diabetes, hypertension, and dyslipidemia were classified together as “metabolic risk factors.” 2.2. Blood collection and DNA analysis Peripheral blood from all individuals in the study was collected in EDTA-containing tubes. DNA was extracted from the white blood cells according to a salting-out method, and the DNA was stored at 4°C until amplification [4]. A multiplex amplification with biotinylated primers was used to amplify the genomic DNA. The PCR products then underwent a reverse hybridization by the use of a commercial kit (ThromboType plus, Hain Lifescience, Nehren, Germany). This test was based on the DNA.STRIP technology and permits the combined molecular genetic characterization of position 1691 in the human factor V gene and position 20210 in the human prothrombin gene.
40
D. Berredjeb Ben Slama et al. / Cardiovascular Pathology 22 (2013) 39–41
Table 1 Characteristics of risk factors among MI patients and control subjects
Sex (male/female) Age (years), mean±S.D. Obesity Diabetes Hypertension Dyslipidemia Smoker
Patients (n=100)
Control subjects (n=200)
OR (95%CI)
P value
84:16 (84%/16%) 46.92±7.62 17 (17%) 41 (41%) 38 (38%) 49 (49%) 73 (73%)
129:71 (64.5%/35.5%) 31±9.6 12 (6%) 15 (7.5%) 18 (9%) 21(10%) 79 (39.5%)
– – 3.21 8.57 6.20 8.19 4.14
– – b.05 b.05 b.05 b.05 b.05
2.3. Statistical analysis Descriptive statistics included mean values and standard deviations for continuous variables and proportions for categorical data. The strength of the association between traditional and prothrombotic genetic risk factors and MI in patients was estimated by calculating the odds ratios (OR) and 95% confidence intervals (CI). The presence of interactions between traditional and prothrombotic genetic risk factors was estimated by calculating “the attributable proportion of the disease” caused by the interaction with 95% CI [5]. The demographic characteristics of and prevalence of traditional risk factors in the 100 patients with MI and 200 control subjects are shown in Table 1. The two groups were sex matched; the vast majority of patients and control subjects were men with 84 male patients (84%) and 129 male controls (64.5%). There was a significantly higher prevalence of smoking in patients (73%) than in controls (39.5%). All metabolic risk factors and obesity were vastly more prevalent among the patients than among controls: dyslipidemia (49% vs. 10%), diabetes (41% vs. 7.5%), hypertension (38% vs. 9%), and obesity (17% vs. 6%). 2.4. Genetic risk factors Among the 100 patients with MI, there were 9 (9%) who were heterozygous for the factor V Leiden G1691A mutation and 3 (3%) heterozygous for the prothrombin G20210A mutation. There were no homozygous patients for either polymorphism. In contrast, in the controls, the distribution of the factor V Leiden G1691A and prothrombin G20210A was 12 (6%) and 5 (2.5%) respectively. Eleven (5.5%) controls were heterozygous for the factor V Leiden and only one (0.5%) control subject was homozygous. There were no homozygous carriers of the prothrombin G20210A polymorphism in the control group (Table 2). 2.5. Interaction between traditional and genetic prothrombotic risk factors Current smoking and the presence of metabolic risk factors were strong risk factors for MI. Smokers (73%) comprised the majority of those with MI. There was a concomitant risk with smoking and the presence of the factor V Leiden mutation: among nine patients who carried this mutation, seven patients were smokers. Similarly, there
(1.38–7.53) (4.24–17.54) (3.16–12.24) (4.33–15.61) (2.38–7.25)
were two patients who smoked from the three patients who carried the prothrombin G20210A mutation. The risk of MI was higher in smokers who carried either of these mutations (Table 3). The results shown in Table 3 indicate that the presence of factor V Leiden or the prothrombin G20210A and one or more of the metabolic risk factors increased the risk of MI. Obesity was not a significant risk factor.
3. Discussion Myocardial infarction (MI) usually occurs because an occlusive acute thrombus develops at the site of a ruptured atheromatous plaque in an epicardial coronary artery [6,7]. Both atherosclerosis and thrombosis therefore do contribute toward the occurrence of MI, although the relative importance of these two processes varies from patient to patient and is different at different ages [8,9]. In this study, we postulated that there was not an increased procoagulant tendency mediated by the factor V Leiden mutation or the prothrombin G20210A variant. However, either mutation concomitant with other factors (particularly smoking) can perhaps induce the development of MI in a selected group. Indeed, like this study, the US Physicians' Health Study reported no association between factor V Leiden and MI [10]. The US Physicians' Health Study also reported a lack of association between the prothrombin G20210A variant and MI [11]. As well as these results, Gupta et al. [12] indicated that factor V Leiden and factor II G20210A mutations were totally absent in their study among cases and controls from North India. Moreover, Eikelboom et al. [13] had shown that, in young survivors of MI, predominantly men, the prothrombin mutation was not associated with an increased risk. However, in others studies, there were conflicting results as to whether factor V Leiden and factor II G20210A mutation increased the risk of MI. Van de Water et al. [14] investigated the prevalence of prothrombin 20210GA and factor V Leiden mutations in 271 patients with MI. The prevalence of factor V Leiden mutation was determined to be 14.6% and 3.6% in the patient and control groups, respectively [OR=4.7 (95% CI=1.3–17.7), P=.04]. Similarly, the prevalence of the prothrombin 20210GA mutation was determined to be 7.3% and 1.8% in the patient and control groups, respectively [OR=4.9 (95% CI=1.1– 22.8), P=.04] [14]. Two other studies had also identified an increased frequency of factor V Leiden in selected subgroups of survivors of MI [15,16]. However, limitations of our study were due to the relatively small number of patients and the lack of a healthy control group.
Table 2 Distribution of genetic polymorphisms in MI patients and control subjects
FVL
Prothrombin (FII)
Genotypes
Patients (n=100)
Control subjects (n=200)
OR (95% CI)
1691GG 1691AG 1691AA 20210GG 20210AG 20210AA
91 9 0 97 3 0
188 11 1 195 5 0
1.55 (0.58–4.12)
OR=Odds ratio of AG and AA genotypes vs. the GG genotype.
P value .49N.05
1.21 (0.22–5.94)
1N.05
D. Berredjeb Ben Slama et al. / Cardiovascular Pathology 22 (2013) 39–41
41
Table 3 Risk effect of cardiovascular risk factor with and without a coagulation defect Cardiovascular risk factor
Presence or absence of coagulation defect
Patients (n=200)
Control subjects (n=100)
Odds ratio (95% CI)
P value
Smoking
Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎ Absence⁎⁎ Presence⁎⁎ Absence⁎ Presence⁎⁎
64 9 24 3 36 5 52 7 31 7 57 5 15 2 73 10
77 2 106 15 15 0 168 17 18 0 165 17 12 0 171 17
5.41 (1.04–37.73)
.04
0.88 (0.19–3.63)
1
–
.30
1.33 (0.47–3.65)
.72
–
.08
0.85 (0.26–2.60)
.96
–
.49
1.38 (0.56–3.37)
.58
No smoking Diabetic Nondiabetic Hypertensive Nonhypertensive Obese Nonobese ⁎ Absence of coagulation defect. ⁎⁎ Presence of FVL or G20210A.
4. Conclusion Based on the results of our study, we surmise that, in a complex, polygenic, and multifactorial disorder such as MI, the role of an inherited predisposition to thrombosis is relatively weak in itself and weaker than the role of traditional risk factors. Yet some prothrombotic genetic factors may be important contributors in combination with environmental factors or acquired prothrombotic stimuli, particularly with smoking. Prospective studies are needed to examine the clinical value of the interaction between environmental factors and the prothrombotic genotypes. Acknowledgments We would like to thank Dr. Christian Winchell for his precious help in correcting this manuscript and Ghaya Bouaicha for her technical support. References [1] World Health Organization. Ischemic heart disease registers: report of the fifth work group (including a second revision of the operating protocol): Copenhagen, Denmark, April 26–29, 1971. Copenhagen, Denmark: World Health Organization, Regional office for Europe; 1971. [2] Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994;369:64–7. [3] Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88: 3698–703.
[4] Miller SA, Dykes DD, Polesky HF. A simple salting-out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215. [5] Hosmer DW, Lemeshow S. Confidence interval estimation of interaction. Epidemiology 1992;3:452–6. [6] Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (1). N Engl J Med 1992;326: 242–50. [7] Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992;326: 310–8. [8] Zimmerman FH, Cameron A, Fisher LD, Ng G. Myocardial infarction in young adults: angiographic characterization, risk factors and prognosis (coronary artery surgery registry). J Am Coll Cardiol 1995;26:654–61. [9] Kanitz MG, Giovannucci SI, Jones JS, Molt M. Myocardial infarction in young adults: risk factors and clinical features. J Emerg Med 1996;14:139–45. [10] Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke and venous thrombosis in apparently healthy men. N Engl J Med 1995;332:912–7. [11] Ridker PM, Hennekens CH, Miletich JP. G20210A mutation in prothrombin gene and risk of myocardial infarction, stroke and venous thrombosis in a large cohort of U.S. men. Circulation 1999;99:999–1004. [12] Gupta N, Khan F, Tripathi M, Singh VP, Tewari S, Ramesh V, et al. Absence of factor V Leiden (G1691A) mutation, FII G20210A allele in coronary artery disease in North India. Indian J Med Sci 2003;57:535–42. [13] Eikelboom JW, Baker RI, Parsons R, Taylor RR, van Bockxmeer FM. No association between the 20210G/A prothrombin gene mutation and premature coronary artery disease. Thromb Haemost 1998;80:878–80. [14] Van de Water NS, French JK, Lund M, Hyde TA, White HD, Browett PJ. Prevalence no significant stenoses at angiography three to four weeks after myocardial infarction. J Am Coll Cardiol 2000;36:717–22. [15] Rosendaal FR, Siscovick DS, Schwartz SM, Beverly RK, Psaty BM, Longstreth WT, et al. Factor V Leiden (resistance to activated protein C) increases the risk of myocardial infarction in young women. Blood 1997;89:2817–21. [16] Doggen CJM, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation 1998;97:1037–41.