PubMed Health⌕ Search

Biomedical subjects

O Poirier

Publications and source records attributed to O Poirier.

At least 55 records · Page 3Linked to original sources
PubMed1998

Genetic determination of plasma aldosterone levels in essential hypertension.

The renin-angiotensin-aldosterone system plays an important role in large artery structure and blood pressure homeostasis. Among the genes coding for different components of this system, the aldosterone synthase (CYP11B2) gene could play an important role, but has been less investigated. We examined the role of two variations of the aldosterone synthase gene (CYP11B2), one located in the promoter of the gene, T-344C, the other in the 7th exon, the T4986C (Val/Ala), on plasma levels of renin and aldosterone, blood pressure, and arterial stiffness in subjects with essential hypertension. Subjects of European origin (n = 216) were examined during a 1-day hospitalization. Treatment, if any, was interrupted for at least 21 days before. Arterial stiffness was evaluated by measuring pulse wave velocity. Renin and aldosterone levels were evaluated by using a radioimmunoassay. The two polymorphisms were in complete linkage disequilibrium, as suggested by the presence of only three haplotypes in this population (T-344T4986, T-344C4986, and C-344T4986). The mean age and blood pressure values were similar in the different genotypes. Presence of the -344C allele was associated with elevated levels of plasma aldosterone: 90 +/- 8 pg/mL for TT (n = 67), 110 +/- 6 pg/mL for TC (n = 107), and 129 +/- 10 pg/mL for CC (n = 42) (test of codominant effect, P < .002 after adjustment for age and 24-h Na+ urine excretion). Pulse wave velocity was also increased in the -344C allele carriers: 11.3 +/- 0.4 m/sec, 12.7 +/- 0.3 m/sec, 12.0 +/- 0.5 m/sec in the TT, TC, and CC genotypes, respectively. No association was found between the T4986C polymorphism and the studied variables. In patients with essential hypertension, a variant on the promoter region of the aldosterone synthase gene is associated with significant differences in plasma aldosterone levels and arterial stiffness. These differences are not associated with variations in blood pressure levels.

Age Factors↗
PubMed1998

Polymorphisms of the tumour necrosis factor-alpha gene, coronary heart disease and obesity.

BACKGROUND: Tumour necrosis factor-alpha (TNF-alpha) is a cytokine that has multiple functions. Through its effects on lipid metabolism, coagulation, insulin resistance and endothelial function, TNF-alpha could be involved in cardiovascular pathophysiology. Given this possibility, we hypothesized that polymorphisms of the TNF-alpha gene might be associated with a predisposition to coronary heart disease (CHD). METHODS: The entire coding region and 1053 bp upstream of the transcription start site of the TNF-alpha gene were screened for polymorphisms using polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and sequencing. Five polymorphisms were identified: four were located in the upstream region at positions -857, -851, -308, -238 from the first transcribed nucleotide and one was found in a non-translated region at position +691. Six-hundred and forty-one patients with myocardial infarction (MI) and 710 control subjects from the ECTIM Study were genotyped. RESULTS: The genotype frequencies were similar in cases and control subjects in the high-risk population of Belfast and in France; however, the TNF-alpha/-308A allele was more frequent in Belfast than in France (0.242 vs. 0.157; P < 0.0001), and carriers of this allele were more frequently obese than non-carriers [1.52 (1.15-1.99), P < 0.004]. No associations were found for the other polymorphisms. CONCLUSIONS: These results suggest that polymorphisms of the TNF-alpha gene are unlikely to contribute to CHD risk in an important way, but the TNF-alpha/-308 polymorphism should be investigated further in relation to obesity.

Adult↗
PubMed1998

Nitric oxide synthase gene polymorphisms, blood pressure and aortic stiffness in normotensive and hypertensive subjects.

BACKGROUND: Genetic studies may help us to understand the mechanisms underlying the involvement of various neuro-humoral factors in the regulation of the mechanical properties of large arteries. We have shown previously that the angiotensin II type 1 receptor gene polymorphism was a strong determinant of aortic stiffness in hypertensives. OBJECTIVE: To assess the contribution of two polymorphisms of the endothelial nitric oxide synthase gene to aortic stiffness in normotensive and hypertensive subjects in the same cohort. METHODS: We studied 309 untreated hypertensive and 123 normotensive subjects. Aortic stiffness was evaluated by measuring the carotid-femoral pulse-wave velocity non-invasively. The endothelial nitric oxide synthase gene polymorphisms G10-T at intron 23 (GIN23T) and G298-T at exon 7 (Glu298Asp) were determined in each subject. RESULTS: The distributions of genotypes and allele prevalences of the endothelial nitric-oxide synthase G10-T polymorphisms among hypertensive and normotensive subjects were similar. In contrast, the prevalence of the nitric oxide synthase 298G allele was higher in the hypertensive group than it was among normotensive subjects. We found no association of the endothelial nitric oxide synthase genotypes with blood pressure levels or pulse-wave velocity for either population. CONCLUSIONS: The present results do not suggest that two common polymorphisms of the endothelial nitric oxide synthase gene are involved in the regulation of aortic stiffness in hypertensive and normotensive individuals. The higher prevalence of endothelial nitric oxide synthase 298G allele among hypertensives suggests that this gene is involved in essential hypertension but this observation needs further confirmation.

Adolescent↗
PubMed1998

Gene polymorphisms of the renin-angiotensin system in relation to hypertension and parental history of myocardial infarction and stroke: the PEGASE study. Projet d'Etude des Gènes de l'Hypertension Artérielle Sévère à modérée Essentielle.

OBJECTIVE: To investigate a possible involvement of polymorphisms of the renin-angiotensin system in predisposition to moderate and severe hypertension and their relationship to parental histories of myocardial infarction and stroke. METHODS: Hypertensive cases (453 men, 326 women) were patients followed up by general practitioners for established hypertension. Inclusion criteria were an age of onset of hypertension < or = 60 years and a diastolic blood pressure > or = 105 mmHg without antihypertensive medication or > or = 100 mmHg under treatment. Normotensive controls were selected from population-based samples (362 men) and during a preventative medicine visit (170 women). Polymorphisms of the angiotensinogen gene (AGT M235T and T174M), the angiotensin I converting enzyme gene (ACE I/D), and the angiotensin II type 1 receptor gene (AGT1R A1166C) were investigated. RESULTS: The AGTT235 allele prevalence was higher among male hypertensive cases than it was among controls (0.46 versus 0.40, P = 0.01) and a similar trend was observed with female cases whose hypertension had been diagnosed before they were aged 45 years (0.44 versus 0.38, P = 0.20). The AGT1R C1166 allele prevalence was higher among female hypertensives than it was among controls (0.30 versus 0.23, P = 0.03) but no such difference was observed for men. The AGT T174M and ACE I/D polymorphisms were not associated with hypertension. Hypertensive patients reporting a parental history of myocardial infarction before age 60 years had a higher prevalence of the ACE D allele than did those without such a parental history (0.68 versus 0.56, P = 0.01). The ACE D allele prevalence was also greater among patients reporting a parental history of stroke incidence before age 65 years (0.66 versus 0.57, P = 0.05). CONCLUSIONS: These results support the hypothesis that the AGT gene plays a role in predisposition to hypertension and that the ACE gene plays a role in predisposition to acute ischemic events.

Adult↗
PubMed1998

New polymorphisms of the angiotensin II type 1 receptor gene and their associations with myocardial infarction and blood pressure: the ECTIM study. Etude Cas-Témoin de l'Infarctus du Myocarde.

OBJECTIVE: In an earlier report, we suggested that a polymorphism located in the 3' untranslated region of the angiotensin II type 1 receptor gene (AT1R+1166 A/C) might interact with the angiotensin I converting enzyme (ACE) insertion/deletion (I/D) polymorphism to increase the risk of myocardial infarction. Since the AT1R+1166 A/C polymorphism does not appear to be functional, we postulated that it might be in linkage disequilibrium with an unidentified functional variant which would affect the regulation of the gene in response to angiotensin II. The present study was conducted to identify new polymorphisms of the AT1R gene that might be responsible for this interaction. METHODS: The first four exons, which are untranslated, and 2.2 kb in the 5' flanking region of the AT1R gene were explored by polymerase chain reaction/single-strand conformation polymorphism. Seven polymorphisms were detected in the 5' region at positions -1424, -810, -713, -521, -214, -213 and -153 upstream from the start of transcription. The genotypes of the -810, -713, -214, -213 and -153 polymorphisms were completely concordant. One substitution was detected at the 55th nucleotide of exon 4. These polymorphisms, together with the +1166 A/C polymorphism and a previously described T/C substitution at the 573th nucleotide of exon 5, were genotyped in the Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) study, a multicentre study comparing 651 patients who had survived a myocardial infarction and 728 controls from Belfast (United Kingdom) and Lille, Strasbourg and Toulouse (France). RESULTS: The newly identified polymorphisms were not in linkage disequilibrium with the +1166 A/C polymorphism and therefore could not explain the interaction observed with ACE I/D. None of the polymorphisms was associated with blood pressure levels in control subjects. In the four populations, the A allele of the -810 polymorphism was associated with a lower risk of myocardial infarction (population-adjusted odds ratio of 0.80, confidence interval 0.65-0.97, P< 0.05). CONCLUSIONS: None of the newly identified polymorphisms could account for the previously described interaction between the AT1R+1166 A/C and the ACE I/D polymorphisms affecting the risk of myocardial infarction. However, the present study suggests that AT1R-810 T/A, or other polymorphisms which are in complete association with it, might be associated with the risk of myocardial infarction. Further studies are required to confirm this finding and to identify the functional variants.

Adult↗
PubMed1998

Angiotensin converting enzyme gene polymorphism and ACE inhibition in diabetic nephropathy.

The antiproteinuric effect of angiotensin converting enzyme (ACE) inhibition in insulin-dependent diabetes mellitus (IDDM) patients with diabetic nephropathy varies considerably. Therefore, we tested the potential role of an insertion (I)/deletion (D) polymorphism of the ACE gene on this early antiproteinuric responsiveness in an observational follow-up study. Sixty (II, N = 13; ID, N = 26 and DD, N = 21) young hypertensive IDDM patients suffering from diabetic nephropathy were investigated during three months before and for the initial six month period during ACE inhibition [captopril 44 (SD 22) mg/24 hr, no differences in drug dose between groups]. Blood pressure (MABP) and albuminuria (ELISA) were measured three (1 to 6) times before and three (1 to 13) times during ACE inhibition. At baseline the groups (II/ID/DD) had comparable (1) mean arterial blood pressure (MABP mm Hg) of 113 +/- 10/108 +/- 9/114 +/- 8, (2) albuminuria (geometric mean with 95% CI) 1394 (747 to 2608)/1176 (844 to 1797) and 1261 (827 to 2017) mg/24 hr, and (3) serum creatinine (geometric mean with 95% CI), 80 (68 to 93)/85 (76 to 97)/103 (85 to 119) mumol/liter, respectively. Angiotensin converting enzyme inhibition induced a significant reduction in MABP, albuminuria and kidney function in all three groups (II/ID/DD; P < 0.05): (1) MABP (mean +/- SD) 12 +/- 7/5 +/- 7/8 +/- 9 mm Hg (ANOVA, P = 0.02); (2) albuminuria [mean (95% CI)] 61 (34 to 77)/22 (3 to 37)/31 (13 to 46) %, (ANOVA, P < 0.01); and (3) increasing serum creatinine [mean (95% CI)] 8 (4 to 12)/9 (3 to 16)/8 (0 to 16) % (ANOVA, NS), respectively. Adjusting for differences in reduction in MABP did not change the association between decrease in albuminuria and ACE/ID genotypes (P < 0.01). A multiple linear regression analysis revealed that the ACE/ID polymorphism, albuminuria and MABP at baseline independently influenced the decline in albuminuria after initiation of ACE inhibition (R2 = 0.21, P < 0.01). A significant association between changes in MABP and albuminuria was demonstrated (R2 = 0.16, P < 0.01). Our data show that hypertensive albuminuric IDDM patients with the II genotype are particularly susceptible to commonly advocated renoprotective treatment.

Adult↗
PubMed1998

The histidin-rich glycoprotein Pro186/Ser polymorphism is not related to myocardial infarction in the ECTIM study.

The histidin-rich glycoprotein (HRG) may contribute to coronary heart disease as a consequence of its possible thrombophilic properties. To test this hypothesis we have investigated the Pro186/Ser polymorphism of the HRG gene, which is known to strongly affect plasma HRG levels, in a large multicenter case-control study of myocardial infarction (MI). The results failed to demonstrate any association between the polymorphism and MI or angiographically assessed coronary stenosis.

Adult↗
PubMed1998

Identification of two polymorphisms in the promoter of the microsomal triglyceride transfer protein (MTP) gene: lack of association with lipoprotein profiles.

The microsomal triglyceride transfer protein (MTP) catalyzes the transfer of triglyceride, cholesteryl ester, and phosphatidylcholine between phospholipid surfaces. The 97-kD subunit imparts lipid transfer activity and thus plays a role in the assembly of apolipoprotein B (apoB)-containing lipoproteins. We tested whether polymorphisms in the promoter region of the large subunit of the MTP gene might be related to different plasma lipid variables, atherosclerosis, and the risk of myocardial infarction (MI). We screened 838 bp in the promoter region of the MTP gene by PCR-SSCP and identified two polymorphisms at positions -400 (MTP/-400 (A-->t)) and -164 (MTP/-164 (T-->c)), the latter being situated on a putative sterol responsive element (SRE) consensus sequence. The two polymorphisms, investigated in 622 male patients with MI and in 728 age-matched controls participating in the ECTIM Study, were in nearly complete linkage disequilibrium (|D'| = +0.98, less frequent alleles being preferentially associated, P < 0.001). There were no significant differences in genotype or allele frequencies between patients with MI and controls. Moreover, no significant associations between the two promoter polymorphisms and several lipid variables measured in the control groups of the ECTIM Study or coronary artery stenosis, angiographically assessed in patients with MI, were detected. We conclude that these MTP polymorphisms are unrelated to lipid variables or coronary heart disease in this study. Identification of two polymorphisms in the promoter of the microsomal triglyceride transfer protein (MTP) gene: lack of association with lipoprotein profiles.

Adult↗
PubMed1997

Coronary heart disease and genetics in epidemiologist's view.

We are just beginning to uncover the genetic determinants of coronary heart disease. The genotype-phenotype associations are complex as a consequence of pleiotropy, variation with age, selection owing to the high lethality of the disease, and interactions between genes and with environmental factors. Nevertheless, identification of the gene variants involved in the chronic and acute processes of coronary heart disease appears possible; this could considerably improve our understanding of the aetiology and mechanisms of this disease. Simultaneous analysis of several predisposing alleles should provide the means to identify high-risk individuals and to adapt therapeutic approaches to the genetic make-up of patients.

Coronary Disease↗
PubMed1997

Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population.

The main function of plasminogen activator inhibitor type 1 (PAI-1) is to decrease fibrinolysis, which leads to fibrin accumulation. An elevated plasma PAI-1 concentration has been identified as a risk factor for the development of myocardial infarction, and an association between 1 polymorphism of the PAI-1 promoter and plasma PAI-1 levels has been described. Our aim was to identify new polymorphisms in the PAI-1 gene and to further examine the relationship between PAI-1 genotypes and circulating PAI-1 levels. We report the presence of 4 new polymorphisms that were identified by non-isotopic single-strand conformational polymorphism analysis followed by sequencing. These polymorphisms were investigated in relation to PAI-1 levels in a sample of 256 healthy men, aged 50-59 years, from France and Northern Ireland. Two G/A substitutions were detected at positions -844 and +9785. The former is in strong positive linkage disequilibrium with the previously described 4G/5G polymorphism at position -675. Two polymorphisms in the 3' untranslated region were identified. One corresponds to a T/G substitution at position +11,053 and is in negative linkage disequilibrium with the G/A substitution (+9785). The other is a 9-nucleotide insertion/deletion located between nucleotides +11,320 and +11,345 in a threefold-repeated sequence. This polymorphism is in strong positive linkage disequilibrium with the G/A substitution (+9785). The overall heterozygosity provided by the 5 PAI-1 polymorphisms (including the 4 new variants and the 4G/5G polymorphism) was .77. No significant association was found between PAI activity and genotypes; furthermore, the well known associations between PAI activity and body mass index, serum triglycerides, or insulin were homogeneous according to PAI-1 genotypes.

France↗
PubMed1997

The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l'Infarctus du Myocarde.

The GPIIb/IIIa receptor complex may contribute to acute coronary syndromes by mediating platelet aggregation. The Leu33/Pro polymorphism (PlA1/PlA2) of the GPIIIa has recently been shown to be associated with CHD in a small case-control study. We have investigated this polymorphism in a large multicenter study of patients with myocardial infarction and controls and found no difference in the distribution of allele and genotype frequencies between cases and controls.

Adult↗
PubMed1996

The Gln/Arg polymorphism of human paraoxonase (PON 192) is not related to myocardial infarction in the ECTIM Study.

Paraoxonase is a high-density-lipoprotein associated enzyme capable of hydrolyzing lipid peroxides, which has been suggested to contribute to atherosclerosis and coronary heart disease (CHD). We studied the Gln/Arg polymorphism affecting codon 192 of human paraoxonase (PON 192) to determine whether this polymorphism, which is associated with serum paraoxonase (PON) activity, represents a risk factor for myocardial infarction (MI). The PON 192 polymorphism was analysed in 642 male patients with myocardial infarction and 701 age-matched controls participating in the ECTIM Study (Etude Cas-Témoins de l'Infarctus du Myocarde). The frequency of the Gln allele was 0.69 in cases and 0.70 in controls (ns). The frequency of the PON 192/Arg allele in 405 MI patients who underwent coronary angiography was 0.295, 0.323 and 0.331, respectively in those with 1, 2 or 3 stenosed arteries (stenosis > 50%) (ns). The mean levels of several plasma lipids, lipoproteins and apolipoproteins were compared between the 3 PON genotypes and no difference was observed. The PON 192 polymorphism was unrelated to MI, the severity of coronary atherosclerosis and to plasma levels of several lipid variables.

Adult↗
PubMed1996

Effect of deletion polymorphism of angiotensin converting enzyme gene on progression of diabetic nephropathy during inhibition of angiotensin converting enzyme: observational follow up study.

OBJECTIVE: To evaluate the concept that an insertion/deletion polymorphism of the angiotensin converting enzyme gene predicts the therapeutic efficacy of inhibition of angiotensin converting enzyme on progression of diabetic nephropathy. DESIGN: Observational follow up study of patients with insulin dependent diabetes and nephropathy who had been treated with captopril for a median of 7 years (range 3-9 years). SETTING: Outpatient diabetic clinic in a tertiary referral centre. PATIENTS: 35 patients with insulin dependent diabetes and nephropathy were investigated during captopril treatment (median 75 mg/day (range 12.5 to 150 mg/day)) that was in many cases combined with a loop diuretic, 11 patients were homozygous for the deletion allele and 24 were heterozygous or homozygous for the insertion allele of the angiotensin converting enzyme gene. MAIN OUTCOME MEASURES: Albuminuria, arterial blood pressure, and glomerular filtration rate according to insertion/deletion polymorphism. RESULTS: The two groups had comparable glomerular filtration rate, albuminuria, blood pressure, and haemoglobin A1c concentration at baseline. Captopril induced nearly the same reduction in mean blood pressure in the two groups-to 103 (SD 5) mm Hg in the group with the deletion and 102 (8) mm Hg in the group with the insertion-and in geometric mean albumin excretion-573 (antilog SE 1.3) micrograms/min and 470 (1.2) micrograms/min, respectively. The rate of decline in glomerular filtration rate (linear regression of all glomerular filtration rate measurements during antihypertensive treatment) was significantly steeper in the group homozygous for the double deletion allele than in the other group (mean 5.7 (3.7) ml/min/year and 2.6 (2.8) ml/min/year, respectively; P = 0.01). Multiple linear regression analysis showed that haemoglobin A1c concentration, albuminuria, and the double deletion genotype independently influenced the sustained rate of decline in glomerular filtration rate (R1 (adjusted) = 0.51). CONCLUSION: The deletion polymorphism in the angiotensin converting enzyme gene reduces the long term beneficial effect of angiotensin converting enzyme inhibition on the progression of diabetic nephropathy in patients with insulin dependent diabetes.

Adult↗
PubMed1996

Influence of angiotensin-converting enzyme and angiotensin II type 1 receptor gene polymorphisms on aortic stiffness in normotensive and hypertensive patients.

BACKGROUND: Clinical and experimental studies have demonstrated a major role of the renin-angiotensin system in the functional and structural changes of the large arteries in hypertension. Because genetic studies may help us to understand the mechanisms underlying the involvement of this system in arterial regulation, the present study was designed to assess the contribution of polymorphisms of the ACE insertion/deletion (I/D) and angiotensin II type 1 receptor (AGTR1 A 1166C) genes on aortic stiffness regulation. METHODS AND RESULTS: This study included 311 untreated hypertensive and 128 normotensive subjects. Aortic stiffness was evaluated by measurement of the carotid-femoral pulse-wave velocity (PWV). In normotensive subjects, the two polymorphisms did not influence any of the studied parameters. In hypertensive subjects, there was a decreasing trend of mean PWV with the number of ACE D alleles, but this association became significant only after adjustment for blood pressure (P < .05). Conversely, the AGTR1 A 1166C polymorphism was independently associated with aortic stiffness. Mean values of PWV were 11.6 +/- 2.7 m/s in AGTR1 AA homozygotes, 13.3 +/- 3.3 m/s in AC heterozygotes, and 15.3 +/- 4.3 m/s in CC homozygotes (P < .0001 and P < .00001 after adjustment for age and mean blood pressure, respectively). The percentage of variance of PWV explained by AGTR1 A 1166C polymorphism (11.6%) was much larger than that of ACE I/D polymorphism (1.7%). CONCLUSIONS: These results suggest that in hypertensive but not normotensive subjects, the AGTR1 and ACE genotypes are involved in the regulation of aortic rigidity. The presence of the AGTR1 C allele is a strong independent determinant of aortic stiffness, whereas presence of the ACE 1 allele is weakly associated with increased stiffness.

Adolescent↗
PubMed1996

Association between the LPL-D9N mutation in the lipoprotein lipase gene and plasma lipid traits in myocardial infarction survivors from the ECTIM Study.

Using polymerase chain reaction (PCR) based techniques, we have identified individuals in the ECTIM study of myocardial infarction survivors (cases) and healthy matched controls who are carriers for a mutation of the gene for lipoprotein lipase (LPL) which alters amino acid 9 from aspartic acid to asparagine (LPL-D9N). The frequency of carriers in the cases from Belfast and France (3 separate centres) was 2.5 and 3.7%, respectively (mean 3.3%, 95% CI 1.9-4.7) and in the controls 2.0 and 2.9%, respectively (mean 2.7%, 95% CI 1.6-3.8%), but this difference was not statistically significant. In the cases, carriers of the allele for LPL-N9 had higher levels of several plasma lipid traits including total triglycerides (TG) (30%), very low density lipoprotein (VLDL) cholesterol (19%), apo E (24%), apo C-III (17%), lipoprotein particles (Lp) containing both apo E and apo B (LpE:B) (32%), and particles containing both apo C-III and apo B (LpCIII:B) (39%), and this effect was consistent in cases both from Belfast and from the French centres combined. By contrast, in the controls there were no differences in any lipid trait between carriers and non-carriers of the mutation that was consistent between the French centres and Belfast. There were no significant differences in the levels of any measured factor between cases and controls that could explain the different effect on plasma lipid traits associated with the mutation. However, compared to the non-carriers, in both cases and controls who carried the mutation, plasma TG concentrations were higher in those whose body mass index (BMI) was above the mean of the sample (26.0 kg/m2), with statistically significant interaction seen between BMI and genotype and levels of apo C-III, and lipoprotein particles containing both apo C-III and apo B (P < 0.02). The data suggest that carriers for the LPL-N9 mutation have a mild genetic predisposition to developing hyperlipidaemia and an atherogenic lipid profile, but that this requires the presence of other genetic or environmental factors for full expression, one of which appears to be increasing obesity.

Adult↗
PubMed1996

Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l'Infarctus du Myocarde.

BACKGROUND: Polymorphisms of the beta fibrinogen gene have been shown to affect plasma fibrinogen levels and the risk of peripheral arterial disease. We now present the results of a detailed analysis of the beta fibrinogen gene in relation to plasma fibrinogen and to the severity of coronary artery disease (CAD) in patients with myocardial infarction (MI) in the ECTIM Study. METHODS AND RESULTS: Ten polymorphisms of the beta fibrinogen gene, including five new polymorphisms identified by single-strand conformation polymorphism analysis, and one polymorphism in the 3' flanking region of the alpha fibrinogen gene were investigated in 565 patients with MI and 668 control subjects. The polymorphisms were in tight linkage disequilibrium and the genotype frequencies were similar in patients with MI and control subjects. In the multivariate analysis, only two polymorphisms, beta Hae III (P < .0003) and beta-854 (P < .01), were independently associated with plasma fibrinogen. The significant association between beta fibrinogen polymorphisms and plasma fibrinogen was present in smokers but not in nonsmokers. In French MI patients, the number of coronary arteries with > 50% stenosis was estimated by angiography and used as a criterion for severity of CAD. Presence of the less frequent allele of the beta Bcl I (P < .0003) and of other polymorphisms was positively associated with the severity of CAD. CONCLUSIONS: Genetic variants of the beta fibrinogen gene are associated with an increased plasma level of fibrinogen, especially in smokers. The association with CAD appears to be the consequence of an increased risk of MI in subjects with severe CAD who carry the predisposing beta fibrinogen genotypes.

Adult↗
PubMed1996

Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Témoin de l'Infarctus du Myocarde (ECTIM) Study.

Transforming growth factor-beta 1 (TGF-beta 1) plays an important role in the modulation of cellular growth and differentiation and the production and degradation of the extracellular matrix. A number of experimental results suggest that TGF-beta 1 may be involved in cardiovascular physiopathology. In the present study, we assessed whether the TGF-beta 1 gene is a candidate gene for coronary heart disease or hypertension. We screened the coding region and 2181 bp upstream of the TGF-beta gene for polymorphisms and identified seven polymorphisms: 3 in the upstream region of the gene at positions -988, -800, and -509 from the first transcribed nucleotide; 1 in a nontranslated region at position +72; 2 in the signal peptide sequence Leu10-->Pro, Arg25-->Pro; and 1 in the region of the gene coding for the precursor part of the protein not present in the active form, Thr263-->Ile. We analyzed these TGF-beta 1 polymorphisms in 563 patients with myocardial infarction and 629 control subjects from four regions in Northern Ireland and France. The Pro25 allele was more frequent in patients than in control subjects in Belfast (P < .01) and Strasbourg (P < .05). The TGF-beta 1 polymorphisms were not associated with the degree of angiographically assessed coronary artery disease in patients. The presence of a Pro25 allele was associated with a lower systolic pressure in the four control groups (P < .002), and a history of hypertension was significantly less frequent in homozygotes or heterozygotes for Pro25 than in hormozygotes for Arg25 (odds ratio, 0.43, 95% confidence interval, 0.19 to 0.92; P < .03). Since the Pro25 allele was associated with an increased risk of myocardial infarction and a reduced risk of hypertension, we favor a cautious interpretation of these apparently inconsistent results. Other studies will need to verify whether these associations are real.

Adult↗