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Zafer Cengiz Er, , Meral Ekim, Hasan Ekim
Published: 17 January 2022
Egyptian Journal of Medical Human Genetics, Volume 23, pp 1-8;

Background: Hypertension is a serious condition that is spread worldwide and may lead to severe complications such as heart attack, stroke, hypertensive retinopathy, and renal failure. Although some genetic and environmental risk factors are known to play a role in the etiology of hypertension, like most of the other multi-factorial diseases, its etiology is yet to be fully elucidated. Our study aimed to investigate the effects of methylenetetrahydrofolate reductase (MTHFR) C677T (rs1801133) and A1298C (rs1801131), factor V Leiden (FVL) G1691A (rs6025), and prothrombin (PT) G20210A (rs1799963) genetic polymorphisms on the development risk of essential hypertension and level of blood pressure in hypertensive patients. Results: The frequency of the homozygous polymorphic TT genotype for the MTHFR C677T polymorphism was significantly higher in male hypertensive patients than in the male control group (27% vs 6.3%, p = 0.028). The rate of the variant T allele for the MTHFR C677T polymorphism was also significantly higher in male hypertensive patients compared to male healthy controls (51.4% vs 21.9%, p = 0.0004). There was no difference among hypertensive patients and healthy controls regarding the frequencies of MTHFR A1298C, FVL G1691A and PT G20210A polymorphisms. In addition, we found no difference between genotype groups regarding systolic and diastolic blood pressure levels in hypertensive patients. Conclusions: Homozygous polymorphic TT genotype and variant T allele for the MTHFR C677T polymorphism may be considered as a risk factor for the development of essential hypertension in the Turkish male population.
, Recep Eroz
Published: 1 January 2020
Medeniyet Medical Journal, Volume 35, pp 295-303;

The ST- elevation myocardial infarction (STEMI), a serious health care problem, is commonly a thrombotic complication of coronary artery disease. We compare the STEMI patients and control group in terms of the possible causes of inherited thrombophilia including FactorV Cambridge G1091C, FactorV Leiden G1691A, MTHFRC677T, MTHFR A1298C, FactorII G20210A, Factor XIII (V34L), PAI-1, FGB, ITGB3, APOB, FVHR2, ACE gene variants. Fifty-three patients with STEMI and 47 individuals without diagnosis of acute coronary syndrome were included in the study. Percutaneous coronary intervention was performed for patients with STEMI. Echocardiography was performed and inherited thrombophilia genes were evaluated in all subjects. The MTHFR A1298C, Factor XIII (V34L), ITGB, ACE and homozygous or compound heterozygous gene varations of inherited thrombophilia are significantly related with STEMI (p<0.05). Also significantly higher MTHFR A1298C, FactorV Leiden G1691A, PAI and ACE gene variations in MI patients who were smokers; Factor XIII (V34L), PAI and ACE gene variations in MI patients with HT; PAI and ACE gene variation in MI patients with FH and PAI gene variations in MI patients with HL were detected when compared with the control groups with all of the same risk factors (p<0.05). Hereditary thrombophilia factors may show promise in the prevention and management of STEMI when supported studies with larger case series.
Wiam Hmimech, , Brehima Diakite, Dalila Baghdadi, Farah Korchi, Rachida Habbal, Sellama Nadifi
Published: 13 July 2016
Biomedical Reports, Volume 5, pp 361-366;

Myocardial infarction (MI) is a common complex pathology, localized in the main leading causes of mortality worldwide. It is the result of the interaction of genetic and environmental factors. The aim of the present study was to investigate the potential association of C677T 5,10-methylenetetrahydrofolate reductase (MTHFR) (rs1801133) and G20210A factor II prothrombin (FII) (rs1799963) polymorphisms with the susceptibility of MI. Following extraction by the standard salting-out procedure, DNA samples of 100 MI patients and 182 apparently healthy controls were genotyped by polymerase chain reaction‑restriction fragment length polymorphism using HinfI and HindIII restriction enzymes, respectively. The results show a significant association of the G20210T FII polymorphism with the MI risk. The frequencies of the heterozygote genotype GA, homozygous mutated AA and the G20210A allele was higher among patients compared to controls (GA: 59 vs. 5.5%, P Introduction According to the World Health Organization, every year ~50 million people succumb due to ischemic heart diseases, particularly myocardial infarction (MI), which is a worldwide leading cause of fatality (1). In general, MI is a result of myocardium necrosis, which occurs when the latter does not receive enough oxygen, due to a sudden occlusive thrombosis of the coronary artery that irrigates this section of myocardium (2). Several studies have identified that genetic in addition to known risk factors (including age, gender, arterial hypertension, smoking, diabetes and dyslipidemia) strongly increases the risk of MI occurrence (3). Among the numerous genes that were previously found to be in association with MI susceptibility, 5,10-methylenetetrahydrofolate reductase (MTHFR) and factor II prothrombin (FII) genes are the most widely reported. The MTHFR gene is located on chromosome 1 at the ‘Ip36.3’ position; the corresponding cDNA sequence comprises 11 exons spanning 2.2 kb (4). The main product of the MTHFR gene is a protein of 77 kDa with catalytic activity, composed of 656 amino acids (5). It is involved in folate metabolism by catalyzing the irreversible conversion of 5,10-methylenetetrahydrofolate (5,10-CH2-FH4) into 5-methyltetrahydrofolate (5-CH3-FH4), which is the major circulating form of folic acid and the cosubstrate for remethylation of homocysteine to methionine (6,7). In its 5-methyl form, folate participates in single carbon transfers that occur during nucleotide synthesis; S-adenosylmethionine formation; remethylation of homocysteine to methionine; and methylation of DNA, proteins, neurotransmitters and phospholipids (8). The C677T allele of the MTHFR gene is the conversion of cytosine (C) to thymine (T) at position 677, which results in a conversion of alanine to valine at the binding site of the flavin adenine dinucleotide, the cofactor of MTHFR enzyme (9). This allele is commonly known as ‘labile’; it facilitates the separation of the enzyme from its cofactor, reducing the activity of the encoded enzyme at ≥37°C (10,11). Thus, if the folate intake is insufficient, the activity of the homozygote decreases by 50–60% at 37°C, and by 65% at 46°C; heterozygotes are in the intermediate range, and homozygotes tend to have slightly increased plasmatic homocysteine levels (10). Prothrombin is a precursor of thrombin. It has an essential role in fibrin formation and coagulation procedure. Numerous studies have demonstrated that a single base-pair change in the prothrombin gene (G20210A) is associated with increased plasma prothrombin levels (12–15); this has generated significant interest and it has been suggested that this polymorphism may lead to increased risks of arterial and venous thrombosis (16). Located on chromosome 11 (11p11), in a 3′-untranslated region of the prothrombin gene, the G20210A variant replaces a single base of guanine (G) with adenine (A) at position 20210, where the pre-mRNA receives the poly A-tail (17). Patients with one copy of this polymorphism have ~5-fold greater risk of blood clot formation compared to patients without. The risk becomes 50-fold higher among subjects with two copies of the 20210A allele. In such conditions, they become prone to earlier or severe arterial and venous thrombosis, particularly with the addition of a family history of such events (12,18,19). Although mutation in the prothrombin gene has been frequently studied, data regarding this mutation to the risks of MI are limited and their interpretation has been controversial (13–15). In the present study, the main aim was to investigate the association of the C677T and G20210A variants of MTHFR and FII prothrombin genes with MI among Moroccan patients. Materials and methods Patients In the present study, 100 Moroccan MI patients were recruited from the Department of Cardiology (Ibn Rochd University Hospital Center, Casablanca, Morocco), in addition to 184 DNA samples of apparently healthy subjects from the DNA bank of the general population available in the Laboratory of Genetics and Molecular Pathology (Medical School, University Hassan II, Casablanca, Morocco). Written consent was obtained from all participants, and blood samples were collected into 4cc EDTA tubes and were stored at −20°C or treated immediately. For the patients, genomic DNA was extracted from peripheral blood leukocytes using the salting-out procedure (20), and DNA was quantified using spectrophotometry. The study has been performed in accordance with the Declaration of Helsinki and has been approved by the ethics committee of The School of Medicine, Casablanca, Morocco. Polymorphism analysis C677T MTHFR and G20210A FII polymorphisms were analyzed using polymerase chain reaction and restriction fragment length polymorphism techniques, as respectively described by Frosst et al (21) and Danneberg et al (22). Following cleavage of amplified fragments using HinfI and HindIII restriction enzymes, respectively, DNA bands were stained with ethidium bromide and visualized under ultraviolet light. Statistical analysis Statistical analyses were performed using SPSS software 21.0 (IBM Corp., Armonk, NY, USA). χ2 test was used to determine statistical significance of association/non-association between genotypes and clinical parameters. Hardy-Weinberg Equilibrium (HWE) test was performed in the cases and controls groups for the two polymorphisms analyzed. Odds ratio (OR) was calculated to estimate the association between genotypes and risk of MI, using a confidence interval (CI) of 95%, and P<0.05 was considered to indicate a statistically significant difference. Results Patient characteristics The study cohort consisted of 100 MI patients and 182 apparently healthy controls. The distributions of C677T MTHFR and G20210A FII polymorphisms were in HWE in the case and control groups (Table I). The average age of patients was 58.60±2.17 years, and 66% of them were >50 years of age with a male predominance (70 males vs. 30 females). Table I. HWE for the C677T MTHFR and G20210A FII distributions among the cases and controls. Table I. HWE for the C677T MTHFR and G20210A FII distributions among the cases and controls. HWE cases HWE controls Genotypes χ2 P-value (P>0.05) χ2 P-value (P>0.05) C677T MTHFR 1.65 0.43a 0.68 0.457aG20210A FII 5.5 0.06a 0.16 1a a Statistically significant difference. HWE, Hardy-Weinberg Equilibrium; MTHFR, 5,10-methylenetetrahydrofolate reductase; FII, factor II prothrombin. Correlation analysis for the polymorphisms Among the seven risk factors analyzed in the study, C677T MTHFR was positively correlated with obesity (P=0.02). No correlation was observed between G20210A FII with any one of these risk factors (Table II). Table II. Distribution of C677T MTHFR and G20210A FII polymorphisms according to risk factors among MI patients. Table II. Distribution of C677T MTHFR and G20210A FII polymorphisms according to risk factors among MI patients. MTHFR, n (%) FII, n (%) Risk factors Patients, n (n=100) CC CT TT P-value GG GA AA P-value Age, years ≤50 34 13 (38.23) 19 (55.88) 2 (5.89) 0.36 13 (38.23) 18 (52.94) 3 (8.83) 0.53 >50 66 25 (37.87) 33 (50.00) 8 (12.13) 18 (27.27) 41 (62.12) 7 (10.61) Gender Male 70 30 (42.85) 34 (48.57) 6 (8.58) 0.33 22 (31.42) 44 (62.85) 4 (5.73) 0.1 Female 30 8 (26.67) 18 (60.00) 4 (13.33) 9 (30.00) 15 (50.00) 6 (20.00) HTA Presence 44 16 (36.37) 25 (56.81) 3 (6.82) 0.46 11 (25.00) 28 (63.63) 5 (11.37) 0.5 Absence 56 22 (39.28) 27 (48.21) 7 (12.51) 20 (35.71) 31 (55.35) 5 (8.94) Diabetes Presence 39 10 (25.64) 25 (64.10) 4 (10.26) 0.12 8 (20.51) 27 (69.23) 4 (10.26) 0.17 Absence 61 28 (45.90) 27 (44.26) 6 (9.84) 23 (37.70) 32 (52.45) 6 (9.85) Smoking Presence 45 19 (42.22) 22 (48.88) 4 (8.89) 0.49 13 (28.89) 29 (64.44) 3 (6.66) 0.47 Absence 55 19 (34.54) 30 (54.54) 6 (10.92) 18 (32.72) 30 (54.54) 7 (12.74) Obesity Presence 22 8 (36.36) 8 (36.36) 6 (27.28) 0.02a 7 (31.81) 12 (54.54) 3 (13.65) 0.79 Absence 78 30 (38.46) 44 (56.41) 4 (5.13) 24 (30.76) 47 (60.25) 7 (8.99) Dyslipidemia Presence 27 8 (29.63) 16 (59.26) 3 (11.11) 0.59 9 (33.33) 15 (55.55) 3 (11.12) 0.9 Absence 73 30 (41.09) 36 (49.31) 7 (9.59) 22 (30.13) 44 (60.27) 7 (9.59) a P<0.05. MTHFR, 5,10-methylenetetrahydrofolate reductase; FII, factor II prothrombin; HTA, arterial hypertension. For the C677T MTHFR polymorphism, the genotypic and allelic frequencies were 38, 52 and 10%, respectively, for the CC, CT and TT genotypes, and 64 and 36%, respectively, for the 677C and 677T alleles among the cases. In the control group, the frequencies were 52.2, 41.8 and 6%, respectively, for the CC, CT and TT genotypes, and 73.1 and 26.9%, respectively, for the 677C and 677T alleles (Table III). Table III. C677T MTHFR and G20210A FII polymorphism frequencies and genetic distribution among the cases and controls. Table III. C677T MTHFR and G20210A FII polymorphism frequencies and genetic distribution among the cases and controls. Genes Genotypes Cases, n (%) (n=100) Controls, n (%) (n=182) OR (95% CI) P-value (P<0.05) MTHFR CC 38 (38.0) 95 (52.2) Ref CT 52 (52.0) 76 (41.8) 1.71 (1.02–2.84) 0.61 TT 10 (10.0) 11 (6.0) 2.27 (0.88–5.82) 0.64 C 128 (64.0) 171 (73.1) Ref T 72 (36.0) 87 (26.9) 1.35 (0.89–2.03) 0.75 FII GG 31 (31.0) 172 (94.5) Ref GA 59 (59.0) 10 (5.5) 32.73 (15.11–69.71) <0.001a AA 10 (10.0) 0 (0.0) 115 (1.75–7332) 0.003a G 121 (60.5) 182 (97.3) Ref A 79 (39.5) 0 (2.7) 238.83 (4.48–12581.7) <0.001a a P<0.05. MTHFR, 5,10-methylenetetrahydrofolate reductase; FII, factor II prothrombin; OR, odds ratio; CI, confidence interval. For the G20210A FII variant, the genotypic and allelic frequencies among the cases were 31, 59 and 10%, respectively, for the GG, GA and AA genotypes, and 60.5 and 39.5%, respectively, for the 20210G and 20210A alleles. Among the healthy controls, 94.5% were homozygous for the 20210G allele. The 20210A allele was absent in the homozygous form (0% AA), and only 5.5% carried one copy of it (GA). Allelic frequencies were 97.3% for the 20210G allele vs. 2.7% for the 20210A allele (Table III). No statistically significant association was observed between the C677T MTHFR polymorphism and MI risk [CT: OR=1.71 (95% CI, 1.02–2.84), P=0.61; TT: OR=2.27 (95% CI, 0.88–5.82), P=0.64; and 677T: OR=1.35 (95% CI, 0.89–2.03), P=0.75], suggesting that even patients carrying at least one copy of the 677T allele are not protected and this variant may not be a genetic risk factor for MI susceptibility in Morocco. By contrast, the G20210A FII polymorphism was highly associated with MI risk among patients carrying even a single or double copy of the 20210A allele [P-value (GA) <0.001 and P-value (AA)=0.003)] (Table III). These findings suggest that this variant may be a potential genetic marker for MI in Moroccan population. Discussion With a complex pathology, numerous factors are involved in the occurrence of MI. In interaction with environmental factors, the genetic background has an essential role in MI susceptibility. A number of studies began, over the few past years, focusing on the implication of hemostatic markers in MI development, and have suggested that numerous genes affecting coagulation proteins are prothrombotic risk factors (23,24), among which are the FII (G20210A variant) and MTHFR (C677T variant) genes. Several studies have investigated the association of prothrombotic genetic markers, including FII and MTHFR genes with MI risk, but have provided divergent and inconclusive results (5,25,26). To the best of our knowledge, this is the first study to explore the potential association of the G20210A FII and C677T MTHFR polymorphisms with MI risk in the Moroccan population. In the present study sample, the majority of patients were >50 years of age (66%) and were predominantly male (70 vs. 30% who were female). This was in agreement with the Croatian study by Jukic et al (27) regarding the implication of the ABO blood group genotypes and the prothrombotic mutations of factor V Leiden, prothrombin G20210A FII and MTHFR C677T on MI occurrence. The study noted that 75.3% of the patients recruited were >55 years of age, with a male predominance (63.2 male vs. 36.8% female). In addition, the same study reported that males had a 1.5-fold greater risk of developing MI compared to females (P55 years) had >20-fold greater risk (OR=21.1; 95% CI, 12.64–35.23). Hyperhomocysteinemia is known to be an important risk factor for cardiovascular diseases, such as MI. The C677T polymorphism of MTHFR gene has been associated with decreased MTHFR enzyme efficiency and its thermolability (28). Previous studies have reported that individuals carrying a double copy of the 677T allele had significantly increased plasma levels of homocysteine, and suggested that this variant may be a potential genetic risk factor for cardiovascular diseases (29–31). According to the present data, the C677T MTHFR variant was significantly associated to obesity (P=0.02) (Table II). The CT genotype was the most frequent among patients (52%) compared to the other genetic profiles (38% CC and 10% TT). In healthy controls, the CC genotype was the most frequent (52.2%) vs. 41.8 and 6% for the CT and TT genetic profiles, respectively. Similar findings were reported by Spiroski et al (32), which found that the CT genotype was the most frequent genotype among patients (51.3%) vs. 35.5% CC and 13.2% TT. According to this study, the T allele frequency was higher in patients compared to controls, which consists with the present findings (T allele frequency in patients group was 36% compared to 26.9% among healthy controls). Other studies reported that the higher frequency of homozygous mutated genotype TT (18–19%) was found in the Italian population (29,33,34). It was 16.7% in Greece, 6.2% in Germany and 6% in Croatia (35,36). Xuan et al (37) reported that the 677T allele frequency was 28.99% in Caucasian children vs. 42.28% in Asian pediatric patients, and 31.76% in the Caucasian maternal vs. 41.51% in the Asian maternal population. Regarding the present results, no statistically significant association was observed between the C677T MTHFR polymorphism and MI risk in Morocco. Numerous studies have investigated this association among different populations and have noted similar findings (38–43). Other studies suggest a significant association of C677T MTHFR with MI risk (30,37,44,45). The G20210A polymorphism of the FII prothrombin gene is correlated with higher plasma levels of prothrombin among subjects carrying this variant compared to normal subjects, making them prone to blood clots and thrombotic events (13,19,46,47). Regarding the biology, high plasma concentrations of prothrombin associated with the presence of the G20210A FII polymorphism may confer an elevated risk for cardiovascular disease (48). The present results show that no genetic profile was the most frequent in the patient group compared to the controls, and no statistically significant association of the G20210A FII polymorphism with any one of the risk factors analyzed was observed. There was more heterozygote genotype (GA) among patients compared to the healthy controls (59 and 5.5%, respectively). Consistent results were reported by Ercan et al (48) among the Turkish population, and even the heterozygote exhibited a significant association of the G20210A FII polymorphism with coronary artery disease risk. According to the present data, the homozygous mutated genotype (AA) frequency was 10% among patients and 0% among controls. The 20210A allele frequency was higher in the patient group (39.5%) compared to the control group (2.7%). The study performed by Ercan et al (48) reported similar results among healthy controls, signaling that the homozygous mutated profile of G20210A FII polymorphism was absent in the control group. The study also reported that this genotype was not detected among patients. Other similar findings were reported by Doggen et al (14), signaling that the 20210A allele was present in only 2% of healthy controls, and suggesting that the G20210A FII polymorphism is associated with the risk of venous thromboembolism (OR=2.8). In 2009, Gohil et al (49) reported that this variant was correlated the venous thromboembolism risk (OR=3.2), and that the risk associated with the homozygous genetic profile of the polymorphism was 6.7-fold higher. The present results show that the G20210A polymorphism of the FII prothrombin gene was significantly associated with susceptibility to MI. The results of the previous studies regarding this association remain inconsistent (14,15,20,48,50–55). The divergences in results regarding the association of C677T MTHFR and G20210A FII variants with MI risk may be explained by numerous factors, such as differences in genetic background among the studied populations; differences in the selection of patients and controls; studies sample sizes and ethnicity. In conclusion, to the best of our knowledge this is the first study to evaluate the association of C677T MTHFR and G20210A FII prothrombin polymorphisms with MI in Morocco. According to the data, no significant association was observed between the C677T MTHFR variant and MI risk. The heterozygote genetic profile (CT) was more frequent among patients compared to the controls. By contrast, the G20210A FII variant was significantly correlated to MI risk, with a predominance of the heterozygote genotype (GA) and the high frequency of the 20210A allele among patients compared to the controls, thus suggesting that this polymorphism may be a potential genetic marker for MI in Morocco. As a multifactorial disease, the development of MI may be synergistically influenced by numerous factors at different intensities. Thus, further investigations are required to assess these associations in greater detail (gene-gene and gene-environment interactions). Acknowledgements The authors would like to thank all the staff of the Laboratory of Genetic and Molecular Pathology and the Department of Cardiology for their collaboration and help. 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Mohammadali Boroumand, Leila Pourgholi, Shayan Ziaee, Maryam Sotoudeh Anvari, ,
Published: 1 April 2014
Clinical biochemistry, Volume 47, pp 356-360;

The presence of Factor V Leiden (FVL) is proposed to be associated with a higher risk for arterial thrombosis. The aim of this study was to examine a relationship between FVL with the presence and severity of angiographically determined coronary artery disease (CAD). In this case-control study, 1083 patients having angiographic evidence of atherosclerosis with ≥50% luminal stenosis in their epicardial coronary tree were compared with patients with no luminal stenosis (n=320) or with luminal stenosis <50% (n=191) at coronary angiography as reference group. The severity of CAD was determined by vessel score and also a semi-quantitative scoring system (Gensini score). The presence of Factor V polymorphisms was analyzed using polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP). FVL was found to be independently associated with the occurrence of CAD (p=0.020). As compared to wild genotype, heterozygote or homozygote mutant genotypes were more likely associated with a trend towards more severe CAD (adjusted OR=1.85, 95% CI=1.26 to 2.72; p=0.002, and adjusted OR=3.70, 95% CI=1.71 to 8.00; p=0.001; respectively). In addition, the median and inter-quartile range for Gensini score were significantly different among the GG (27.8, 3 to 66.5), GA (53.5, 10 to 104.1), and AA (92.8, 48.1 to 125.9) genotypes (p<0.001). Our results confirmed the hypothesis that FVL mutation is a significant determinant of CAD risk. Furthermore, we observed that FVL is independently associated with increasing CAD severity.
Yeltekin Demirel, Sezai Dogan, Ahmet Uludag, , Sinem Atik, ,
Published: 1 November 2011
Genetic Testing and Molecular Biomarkers, Volume 15, pp 785-791;

Background: Hypertension is one of the leading causes of mortality and morbidity in the world, which is influenced by environmental and genetic factors. The methylenetetrahydrofolate reductase (MTHFR) and angiotensin-converting enzymes (ACE) are possible candidate genes that may influence both body fatness and blood pressure (BP). The purpose of this study was to examine the carriage of gene combinations of the ACE (insertion/deletion [I/D]), MTHFR 677T and 1298C, and lipid profiles in patients with essential hypertension (EH) in Turkey. Methods: A total of 150 adult individuals (50 hypertensive, 50 first-degree relatives, and 50 healthy controls) from Sivas/Turkey with the same age and gender were assessed for body composition, lipid profiles, resting BP, and gene profiles. Additionally, 149 individuals (99 hypertensive, 50 controls) from Canakkale/Turkey had been investigated for ACE I/D polymorphism. Peripheral blood samples were genotyped using strip assay reverse-hybridization multiplex polymerase chain reaction tests for target genes. Results: Heterozygous mutation in FV Leiden was found to be higher in the hypertensive and first-degree relatives when compared with the control group (p<0.05). Homozygous DD alleles of the ACE gene were also higher than the ACE I/D and control groups (p<0.05). The high rates of cholesterol and low-density lipoprotein and low rates of high-density lipoprotein were found in patients with EH when compared with the control. Conclusion: Results show that ACE with DD alleles and mutated alleles of FV Leiden and MTHFR genes were significantly different between genotypes and have a combined effect on EH in Turkish population. Further studies are needed to investigate the genetics of obesity, EH, and BP phenotypes in the current adult population.
, T. T. Keller, E. C. M. Van Gorp, V. E. A. Gerdes, J. C. M. Meijers, G. J. J. Van Doornum, H. R. Büller, D. P. M. Brandjes
Published: 1 July 2011
Journal of Thrombosis and Haemostasis, Volume 9, pp 1432-1434;

Genetic Testing and Molecular Biomarkers, Volume 14, pp 493-498;

Background: Myocardial infarction (MI) can be due to inherited thrombophilia caused by resistance to activated protein C resulting from factor V Leiden (FVL) mutation. Objectives: The objectives of this study were to estimate the frequency of FVL mutation among MI cases in various populations and calculate the overall risk related to it. Subjects and Methods: Subjects comprised 7790 cases with MI and 19,276 healthy controls collected from 41 relevant studies in the search databases. The resulting frequency of FVL mutation among cases and the odds ratio were compared and integrated in a meta-analysis format. Results: Although there was marked variation of the frequency of FVL mutation among different populations including MI and healthy controls, most studies reported a positive risk related to it. Compilation of analyzed studies resulted in an overall frequency of FVL mutation of 6.791% among MI cases, which was significantly higher than that among controls (1.304%, p = 0.0) with an overall odds ratio of 1.608 (95% confidence interval, 1.98–4.44). Conclusion: There is a definite risk related to the carriage of FVL mutation among MI cases. This should have a potential impact on the genetic counseling of family members of affected cases for proper prophylaxis.
, Şenol Coşkun, , Hakan Tkz
Coronary artery disease, Volume 20, pp 435-439;

Atherosclerosis, the major cause of coronary artery disease (CAD), has a very long asymptomatic development phase, which begins in childhood. In this study, we describe the Factor V G1691A, Factor V H1299R and prothrombin G20210A gene polymorphisms in children with a family history of premature CAD. Evidence of these polymorphisms in these children may predict the probability of having atherosclerosis in the future. Our study included a total of 140 children, 72 males and 68 females between the ages of 4.9 and 15.7 years. Among these children, 73 had a parental history of premature CAD and the remaining 67 belonged to our control group. The participants were screened for the mutations Factor V G1691A, Factor V H1299R and prothrombin G20210A by polymerase chain reaction amplified DNA products with specific oligonucleotide probes. Our results suggested that frequencies of the mutated allele of Factor V G1691A and prothrombin G20210A are higher in children with a parental history of premature CAD. In conclusion, Factor V G1691A and prothrombin G20210A polymorphisms which were detected in higher frequencies in children with a parental history of premature CAD may indicate a risk for developing atherosclerosis and might be useful in screening for CAD in children; however, large population-based research is necessary to investigate further genetic risk assessment for CAD.
Georg Benedikt Ehret, Ashley A. O'connor, Alan Weder, Richard S. Cooper,
Published: 17 June 2009
European Journal of Human Genetics, Volume 17, pp 1650-1657;

The publisher has not yet granted permission to display this abstract.
Bahadır Ercan, , Nehir Sucu, Hasan Pekdemir, Ahmet Çamsarı, Uğur Atik
Published: 1 January 2008
Yonsei medical journal, Volume 49, pp 237-243;

The precise molecular mechanisms culminating in coronary artery disease (CAD) are not well understood, despite a wealth of knowledge on predisposing risk factors and pathomechanisms. CAD and myocardial infarction (MI) are complex genetic diseases; neither the environment alone, nor a single gene, cause disease, rather, a mix of environmental and genetic factors lead to atherosclerosis of the coronary arteries. In the present study, our aim was to investigate the roles of prothrombin G20210A mutation and Factor VLeiden mutation in atherosclerotic coronary artery disease. 287 subjects (106 control subjects, who were angiographically normal, and 181 angiographically documented coronary atherosclerotic patients who exhibited coronary artery narrowing to a degree of ≥ 50%) were included in this study. The mutations were assessed with LightCycler Real-Time PCR mutation detection kits (Roche Diagnostics, GmbH, Germany). 6.6% of control subjects, and 6.1% of patients with (50% coronary artery narrowing were determined to have the Factor VLeiden heterozygote mutation. 6.6% of control subjects had the Prothrombin G20210A heterozygote mutation, while 7.7% of patients with (50% coronary artery narrowing had this mutation. The OR for Factor VLeiden was 1.52 (CI: 0.240 - 9.602) and for Prothrombin G20210A mutation, the OR was 1.415 (CI: 0.287 - 6.962). Although both the heterozygote Factor VLeiden and Prothrombin gene mutations were more frequent in patients with CAD than in control subjects, there was no statistical relationship found to exist between coronary artery disease and the Factor VLeiden and Prothrombin G20210A mutations.
Abraham Majluf-Cruz, Manuel Moreno-Hernández, Adriana Ruiz-De-Chávez-Ochoa, Rosario Monroy-García, Karim Majluf-Cruz, , Irma Molina-Ávila, Irma Isordia-Salas, Norma Corona-De la Peña, Florencia Vargas-Vorackova, et al.
Published: 26 December 2007
Clinical and Applied Thrombosis/Hemostasis, Volume 14, pp 428-437;

A common cause of hereditary thrombophilia is activated protein C resistance (APCR), and most cases result from factor V Leiden mutation. An APCR phenotype without association with factor V Leiden has been described. This transversal, observational, nonrandomized study evaluated these 2 phenomena in healthy indigenous and mestizo Mexican subjects (n = 4345), including 600 Mexican natives. No indigenous subjects had APCR, but 82 mestizo subjects did. After retesting, 50 subjects had a negative test. The remaining 32 subjects had factor V Leiden, giving a 0.85% prevalence of factor V Leiden in the mestizo Mexican population. Only 31% of APCR carriers had factor V Leiden. These results show a very low prevalence of APCR and factor V Leiden in Mexico. Except for factor V Leiden, there are no other mutations in the factor V gene responsible for the APCR phenotype. Acquired APCR is nearly twice as prevalent as the inherited variant.
, , Yuechun Shen, Peter F. Bodary, Shufang Gu, Sara L. Manning, Sarah L. Dobies, David Ginsburg, Bsc
Published: 12 April 2005
Journal: Circulation
Circulation, Volume 111, pp 1822-1825;

Background— Activated protein C resistance due to factor V Leiden (FVL) is a common genetic risk factor for venous thrombosis in humans. Although the impact of FVL on the development of venous thrombosis is well established, its effect on arterial thrombosis and atherosclerosis is controversial. Methods and Results— To determine the effect of the FVL mutation on arterial thrombosis in the mouse, wild-type ( Fv+/+ ), heterozygous FVL ( FvQ /+ ), and homozygous FVL ( FvQ/Q ) mice underwent photochemical carotid arterial injury to induce occlusive thrombosis. FvQ/Q mice formed occlusive thromboses 27±3 minutes (n=7) after the onset of injury, which was significantly shorter than that observed for Fv+/+ mice (56±7 minutes, n=9, P<0.01), whereas FvQ /+ mice (41±7 minutes, n=5) were intermediate ( P =0.5, compared with Fv+/+ ). To determine the source of FVL relevant to the enhanced vascular thrombosis, bone marrow transplantation experiments were performed between Fv+/+ and FvQ/Q mice. FvQ/Q mice transplanted with Fv+/+ bone marrow formed occlusive thromboses at 35±5 minutes (n=7, P<0.05 compared with Fv+/+ mice), whereas Fv+/+ mice transplanted with FvQ/Q bone marrow occluded at 59±7 minutes (n=6, P<0.001 compared with FvQ/Q mice). To assess the effect of the FVL mutation on the development of atherosclerosis, FvQ/Q mice were crossed with the atherosclerosis-prone apolipoprotein E (ApoE)–deficient strain ( ApoE−/− ) to generate FvQ/Q,ApoE−/− mice. By 52 weeks of age, FvQ/Q,ApoE−/− mice (n=8) had developed more aortic atherosclerosis (40±6% lesion area) compared with Fv+/+,ApoE−/− mice (15±3% lesion area; n=12, P<0.02). Conclusions— In conclusion, homozygosity for the FVL mutation in mice leads to enhanced arterial thrombosis and atherosclerosis. The source of the FVL leading to accelerated thrombosis appears to be circulating, non–platelet-derived plasma FVL.
, Tilman Kolbe, Christian Faul, Gerhard Steinbeck
Published: 1 March 2004
Journal: Angiology
Angiology, Volume 55, pp 221-225;

The authors report the first case of a patient with a hypereosinophilic syndrome associated with heterozygous factor V gene mutation, resulting in an acute coronary syndrome and recurrent cerebral stroke despite effective anticoagulation. A 40-year-old man presented with an acute coronary syndrome accompanied by a brachiofacial right-sided hemiparesis and dysarthria. Diagnosis of a hypereosinophilic syndrome was established by blood testing, myocardial biopsy, and bone marrow analysis. Eosinophilic infiltration was present in the myocardium, accompanied by proliferation in the endomyocardium and a pneumonic infiltrate. Although effective anticoagulation with heparin was administered, a recurrent stroke occurred while blood eosinophils were being normalized by corticosteroid treatment. A coexisting heterozygosity of the factor V mutation was demonstrated, and it is hypothesized that this might have contributed to the recurrent thromboembolic episodes. In patients with hypereosinophilic syndrome and recurrent thromboembolic episodes, other thrombophilic diseases, including factor V mutations, should be considered, and long-term coagulation should be contemplated.
Robert J Kim,
Published: 31 December 2003
American Heart Journal, Volume 146, pp 948-957;

The association between the inherited gene mutations of factor V, prothrombin, and homocysteine metabolism and venous thromboembolic events is accepted widely; however, their influence on the arterial circulatory system remains controversial.
S Doix, M Mahrousseh, M Jolak, Y Laurent, J.L Lorenzini, C Binquet, M Zeller, Y Cottin, J.E Wolf
Published: 1 June 2003
Annales de cardiologie et d'angeiologie, Volume 52, pp 143-149;

Mutation in blood coagulation factor V Leiden is the most frequently genetic polymorphism implied in venous thrombosis. A 57 year old man was hospitalised for acute myocardial infarction (MI). An emergency coronary angiography was performed, and no significant stenosis was observed. The haematologic check-up showed an heterozygous Leiden mutation of factor V. We report all publications about the relation between factor V Leiden and coronary thrombosis, and we performed a meta-analysis. We analysed the relation in general population and in subgroups, such as, younger and older, and patient with or without coronary stenosis. In global population, the meta-analysis did not found significant association between Factor V Leiden and myocardial infarction (OR = 1.25; IC = 0.97-1.58). In contrast, in patients less than < 55 years old after MI, Factor V Leiden prevalence was significantly higher than in control group (OR = 1.48; IC = 1.05-2.08). In addition, after MI without significant coronary stenosis Factor V Leiden prevalence was significantly higher than in normal patients (OR = 2.84; IC = 1.46-5.51). After MI, in patients without significant coronary stenosis, Factor V Leiden prevalence was significantly higher than in patients with significant coronary stenosis (OR = 3.26; IC = 1.67-6.36). Our study suggests that Factor V Leiden could be search after MI in young subjects and/or without significant stenosis.
Klaus Juul, Anne Tybjærg-Hansen, Rolf Steffensen, Steen Kofoed, Gorm Jensen, Børge Grønne Nordestgaard
Published: 1 July 2002
Journal: Blood
Blood, Volume 100, pp 3-10;

Factor V Leiden (FVL) is associated with venous thrombosis; however, an association between FVL and arterial thrombosis remains controversial. We investigated FVL as a risk factor for myocardial infarction (MI), ischemic stroke (IS), or non-MI ischemic heart disease (non-MI–IHD). The design was 3 case-control studies and 3 prospective studies with 21 years' follow-up. The setting was the general population in Copenhagen, Denmark. The participants for The Copenhagen City Heart Study were 20- to 95-year-old participants without cardiovascular disease (control population, n = 7907) or participants diagnosed with MI (n = 469), IS (n = 231), or non-MI–IHD (n = 365). In addition, 3 independent patient populations from Copenhagen University Hospital with MI (n = 493), IS (n = 231), or non-MI–IHD (n = 448) were included. We measured FVL genotype; major cardiovascular risk factors; and MI, IS, and non-MI–IHD incidence and prevalence. Prevalences of FVL heterozygotes and homozygotes in control subjects from the general population were 7.7% and 0.2%. Odds ratios and relative risks of MI in FVL carriers (heterozygotes + homozygotes) versus noncarriers were 1.24 (95% confidence interval [CI], 0.91-1.69) and 0.83 (0.58-1.20) in case-control and prospective studies, respectively. Corresponding risks for IS were 0.92 (95% CI, 0.56-1.53) and 0.68 (0.45-1.04), and for non-MI–IHD 1.01 (95% CI, 0.71-1.44) and 0.97 (0.66-1.42). Findings from The Copenhagen City Heart Study suggest that FVL is not associated with MI, IS, or non-MI–IHD.
, , Arno H.M. Moons, Marcel Levi, Harry R. Büller,
Published: 17 December 2001
Journal: Circulation
Circulation, Volume 104, pp 3063-3068;

Background — It is pathophysiologically conceivable that genetic variations in coagulation and fibrinolytic proteins are associated with the risk of myocardial infarction. Methods and Results — We performed a literature search to identify published case-control studies correlating the factor V Leiden or prothrombin G20210A mutations or fibrinogen G−455A or plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphisms with the risk of myocardial infarction. Studies were included only if they used solid diagnostic criteria and complied with published methodological criteria. A common OR with corresponding 95% CI was calculated for the risk of myocardial infarction in a fixed-effect model according to Mantel-Haenszel. The factor V Leiden and prothrombin G20201A mutations did not significantly correlate with myocardial infarction (OR 1.26, 95% CI 0.94 to 1.67, P =0.12 and OR 0.89, 95% CI 0.59 to 1.35, P =0.6, respectively). Inclusion of the studies that investigated young patients (<55 years) made the association significant for factor V Leiden (OR 1.29, 95% CI 1.03 to 1.61, P =0.02). Homozygosity for the fibrinogen −455A allele was significantly associated with a decreased risk of myocardial infarction (OR 0.66, 95% CI 0.44 to 0.99, P =0.04), whereas the PAI-1 4G4G genotype was significantly associated with increased risk (OR 1.20, 95% CI 1.04 to 1.39, P =0.04). Conclusions — Associations between these genetic variations and myocardial infarction were weak or absent. In the absence of clinical implications, our results indicate that screening of patients with myocardial infarction for these genetic variations is not warranted.
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