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Biomedical subjects

F Cambien

Publications and source records attributed to F Cambien.

At least 37 records · Page 2Linked to original sources
PubMed2001

Polymorphism screening of four genes encoding advanced glycation end-product putative receptors. Association study with nephropathy in type 1 diabetic patients.

Advanced glycation end-products (AGEs) may play an important role in the pathogenesis and progression of cardiovascular and renal complications of diabetes. Four putative AGE receptors (RAGEs), AGE-R1, AGE-R2, and AGE-R3 have been described. In this study, we scanned the sequence of the genes encoding these AGE receptors in 48 patients with type 1 diabetes and investigated the identified polymorphisms (n = 19) in 199 type 1 diabetic patients with nephropathy and 193 type 1 diabetic patients without nephropathy. Overall, none of the polymorphisms was strongly associated with nephropathy. The minor allele of a polymorphism located in the promoter region of the RAGE gene (C-1152A) conferred a weak protective effect (P < 0.05) and was associated with a longer duration of nephropathy-free diabetes (P = 0.08).

5' Untranslated Regions↗
PubMed2000

The association between the Val34Leu polymorphism in the factor XIII gene and brain infarction.

Factor XIII catalyzes the formation of covalent bounds between fibrin monomers, thus stabilizing the fibrin clot and increasing its resistance to fibrinolysis. The frequency of a frequent Val34Leu polymorphism in the FXIII A-subunit gene has been shown to be lower in patients with myocardial infarction or venous thrombosis than in controls, whereas it was higher in patients with hemorrhagic stroke than in controls. Our aim was to study the relation between brain infarction (BI) and the FXIII Val34Leu polymorphism in 456 patients consecutively recruited with a BI confirmed by MRI, and 456 matched controls. The distribution of genotypes was different in cases (63. 2% Val/Val; 30.9% Val/Leu; 5.9% Leu/Leu) compared with controls (49. 8% Val/Val; 42.8% Val/Leu; 7.4% Leu/Leu; P <.001). Carrying the Leu allele was associated with an OR of 0.58 (95% CI = 0.44-0.75). A similar association was observed in cases and controls free of previous cardiovascular or cerebrovascular history (OR = 0.51; 95% CI = 0.36-0.73). No heterogeneity of this association was observed after stratification on the main BI subtypes. Adjustment for traditional vascular risk factors did not modify these findings. In addition, the effect of smoking was modified by the polymorphism (P =.05); the effect of smoking was weaker among Leu carriers than among noncarriers. In conclusion, there was a negative association of the FXIII Val34Leu polymorphism with BI, thus suggesting a protective effect of the Leu allele against thrombotic cerebral artery occlusion. In addition, our results suggest that among Leu carriers, the protective effect of the polymorphism outweighed the effect of smoking. (Blood. 2000;95:586-591)

Adult↗
PubMed2000

Independent association of an APOE gene promoter polymorphism with increased risk of myocardial infarction and decreased APOE plasma concentrations-the ECTIM study.

Apolipoprotein E (APOE) is a major protein in lipid metabolism existing in three common isoforms: APOE2, -3 and -4. The varepsilon4 allele of the APOE gene ( APOE ) coding for the APOE4 isoform is associated with an increased risk of myocardial infarction (MI) and of Alzheimer's disease (AD). Recently, several polymorphisms in the APOE regulatory region have been reported. Some of these have been associated with AD and modified APOE allelic mRNA expression in AD brains. Here, we have investigated whether three of these promoter polymorphisms (-491AT, -427CT and -219GT) can also modify cardiovascular risk. The hypothesis was tested in a large multicentre case-control study of MI, the ECTIM Study, on 567 cases and 678 controls. Among the three APOE promoter polymorphisms tested, only the-219T allele was associated with a significantly increased risk of MI (OR = 1.29, 95% CI: 1.09-1.52, P < 0.003) and the effect was shown to be independent of the presence of the other mutations, including the APOE epsilon2/epsilon3/epsilon4 polymorphism. Moreover, the-219T allele greatly decreased the APOE plasma concentrations in a dose-dependent manner ( P < 0.008). These data indicate that the-219GT polymorphism of the APOE regulatory region emerges as a new genetic susceptibility risk factor for MI and constitutes another common risk factor for both neurodegenerative and cardiovascular diseases.

Adult↗
PubMed2000

Extensive association analysis between the CETP gene and coronary heart disease phenotypes reveals several putative functional polymorphisms and gene-environment interaction.

An extensive association analysis of a candidate gene for coronary heart disease, Cholesteryl Ester Transfer Protein (CETP) gene, was performed. Ten polymorphisms, out of which three were newly identified in regulatory regions, were investigated for association with myocardial infarction (MI) and 2 MI endophenotypes (CETP mass and HDL-cholesterol level) in 568 MI patients and 668 controls. The polymorphisms affecting codon 405 (Ile(405)Val) and the nucleotide 524 downstream from the stop codon (G(+524)T) were almost completely concordant and associated with plasma CETP mass (P < 0.001). The polymorphisms -629 (located in promoter), intron1 (Taq1B) and intron7 were almost completely concordant and associated with plasma CETP mass (P < 0.0001) and HDL-cholesterol levels (P < 0.0001). This latter association was not found in teetotalers and increased with the quantity of alcohol consumed. Heavy drinkers (>75g/day) homozygous for the (-628)A allele had a reduced risk of MI (OR = 0. 33, P < 0.02). Subjects both homozygous for (451)Arg and heterozygous for (373)Pro had decreased plasma HDL-cholesterol levels and this effect increased with alcohol consumption. The results illustrate the complexity of polymorphism-phenotype associations. They suggest that the CETP gene may carry several functional polymorphisms. Observed interactions between alcohol consumption and polymorphisms associated with HDL-cholesterol level constitute concrete examples of gene-environment interactions. Furthermore, the pattern of association between HDL-cholesterol levels and the polymorphisms at codons 373 and 451 illustrated how two polymorphisms may be confounders (in the usual epidemiological sense) one for the other: their marginal effects are neutralized because of linkage disequilibrium and thus are not detectable by standard univariate association analysis.

Adult↗
PubMed2000

Identification of two polymorphisms in the early growth response protein-1 gene: possible association with lipid variables.

Early growth response factor (EGR)-1 may play an important role in the development of atherosclerosis by inducing the expression of several relevant genes which contribute to the complex modulation of vascular structure and function, leading to vascular occlusive lesions. To investigate the possible role of molecular variants in the human EGR-1 gene for the predisposition to atherosclerosis or coronary heart disease we screened the 5'- and 3'- flanking regions and the entire coding sequence for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism analysis and sequencing. Male patients (n=615) with myocardial infarction and 720 age-matched, male control subjects of the Etude Cas-Témoin de l'Infarctus du Myocarde were genotyped for two newly identified polymorphisms in the 5'- (C-151T) and 3'- (T+861C) flanking region of the EGR-1 gene using hybridization with allele-specific oligonucleotides. Allele and genotype frequencies did not significantly differ between patients with myocardial infarction and control subjects without coronary heart disease. In controls not taking hypolipidemic drugs there was a significant association of the -151T allele with lower plasma levels of total cholesterol (P=0.029), low-density lipoprotein cholesterol (P=0.025) and apolipoprotein B (P=0.038) and a higher ratio of high-density to low-density lipoprotein (P=0.049) than with the C-151 allele. We conclude that the C-151T polymorphism of the EGR-1 gene may contribute to modifications of the lipid metabolism. Our findings need to be replicated in independent studies, and in vitro promoter studies should evaluate the functional consequence of the -151T allele, which disrupts a consensus core sequence for the ubiquitous transcription factor activator protein 4.

Adult↗
PubMed2000

Polymorphisms in the genes encoding platelet-derived growth factor A and alpha receptor.

Platelet-derived growth factors (PDGFs) may play an important role in the development of atherosclerosis acting as chemoattractants and mitogens for vascular smooth muscle cells and macrophages. Three dimeric forms of PDGF (AA, AB, BB) have different activities due to distinct binding properties mediated by two types of PDGF receptors (Ralpha, Rbeta). To investigate the possible contribution of molecular variants in the human PDGF-A and PDGF-Ralpha genes to coronary heart disease we screened these genes for polymorphisms by polymerase chain reaction/single-strand conformation polymorphism analysis. A total of 600 men with myocardial infarction and 717 age-matched male controls from four populations in Northern Ireland and France (the ECTIM Study) were gneotyped for newly identified polymorphisms in the genes encoding PDGF-A (C-26IN3T, H69H, C+12IN5T) and PDGF-Ralpha [-1630 I/D (+/-AACTT), A-1506G, C-1390G, G-956A, C-908A, G-793T, +69 I/D (+/-GA)] using allele-specific oligonucleotides. All PDGF-Ralpha polymorphisms, except C-908A, involving a nucleotide change in a common consensus site for GCF and SP-1 transcription factors, were in nearly complete association, generating two major haplotypes. The PDGF-A and PDGF-Ralpha polymorphisms provided a heterozygosity of 0.69 and 0.40, respectively. Genotype and allele frequencies of the PDGF-A and PDGF-Ralpha polymorphisms did not differ between patients with myocardial infarction and controls in either country. None of the polymorphisms investigated was associated with blood pressure, coronary artery stenosis, or any biochemical parameter available in the ECTIM Study.

Adult↗
PubMed2000

The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma2 gene is not associated with postprandial responses to glucose or fat tolerance tests in young healthy subjects: the European Atherosclerosis Research Study II.

This study investigated whether the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma2 (PPARgamma2) gene is associated with glucose and lipid metabolism in young healthy subjects participating in the European Atherosclerosis Research Study II. Men aged 18-28 years (n=675) were recruited from 14 university student populations in 11 European countries. At their first visit subjects had an oral glucose tolerance test and 1 week later an oral fat tolerance test. Lipid variables and genotype were measured centrally. The Ala allele frequency exhibited a clearcut north-to-south gradient through Europe, decreasing from 0.21 in Baltic countries to 0.07 in Mediterranean countries. There was no significant effect of the Pro12Ala polymorphism on fasting lipid, glucose, or insulin levels, nor on the postprandial changes in these variables after glucose and fat tolerance tests. Neither was the Pro12Ala polymorphism associated with body mass index. This study provides no evidence for a major effect of the Pro12Ala polymorphism on glucose and lipid metabolism in young healthy subjects. Since PPARgamma has a major role in adipogenesis, the differential effect of its polymorphism on weight and related metabolic disorders may become apparent only later in life.

Adolescent↗
PubMed2000

Do polymorphisms of apoB, LPL or apoE affect the hypocholesterolemic response to weight loss?

To assess whether there is a differential hypocholesterolemic response to weight loss for subjects carrying polymorphisms of the apolipoprotein B and other genes. A before and after comparison of lipid parameters following a calorie controlled diet for an intervention period of 12 weeks. A lipid clinic based in a large teaching hospital. The difference in slope coefficients relating the percentage change in lipid parameters to the change in body weight (adjusted for age, gender and initial body mass index (BMI)), for genotype subgroups defined by polymorphisms of the 5'VNTR apoB gene, two mutations of the LPL gene and ApoE. One hundred and forty six subjects completed the intervention diet. While, on average, the intervention was successful (mean weight loss 3.9%), there was no statistically significant difference in the slope coefficients relating lipid change to weight loss for most of the genotypes tested. The slope difference for long versus short 5'VNTR alleles of the apoB gene was 0.445 (-1.307, 2.198) for apolipoprotein B and -0. 104 (-1.486, 1.278) for total cholesterol. However, subjects carrying at least one varepsilon4 allele were significantly hypo-responsive to weight loss, difference in slope coefficients -1.087 (-2.09, -0.084) and -1.320 (-2.589, 0.051) for total cholesterol and apoB, respectively. Although, this study is one of the largest of its kind, it has not replicated the findings of other smaller studies. These findings do not provide support for the use of genotype-targeted dietary advice in routine practice.

Adult↗
PubMed2000

Infection with virulent strains of Helicobacter pylori is not associated with ischaemic heart disease: evidence from a population-based case-control study of myocardial infarction.

BACKGROUND: Although the majority of evidence does not support association between Helicobacter pylori infection and ischaemic heart disease, the nature of this relationship may differ when virulence of the infecting strains are examined. METHODS AND RESULTS: The prevalence of IgG antibody evidence of infection with CagA positive stains of H. pylori was investigated in stored plasma samples from 259 cases of myocardial infarction (aged 25-70 years, 74 males) and 259 population based controls from the same area in Northern Ireland. Two-hundred and seventy (52.1%) subjects were seropositive for anti-CagA IgG. CagA seropositivity was more common in cases than in controls: 56.4 vs 47.9%, odds ratio for seropositivity in cases (95% CI) 1.41 (1.00, 1.99). Substantial attenuation of this relationship occurred on adjustment for age, sex, number of siblings, smoking and measures of socio-economic status: odds ratio (95% CI) 1.16 (0.79, 1.70). A similar pattern was seen for seropositivity for all H. pylori strains. CONCLUSION: Infection with the more virulent strains of H. pylori, as with all strains, is not associated with myocardial infarction.

Adult↗
PubMed2000

Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: the CARDIGENE study.

OBJECTIVES: The study investigated the potential role of eight candidate genes in the susceptibility to idiopathic dilated cardiomyopathy (IDC). BACKGROUND: Idiopathic dilated cardiomyopathy has a familial origin in 20% to 25% of cases, and several genetic loci have been identified in rare monogenic forms of the disease. These findings led to the hypothesis that genetic factors might also be involved in sporadic forms of the disease. In complex diseases that do not exhibit a clear pattern of familial aggregation, the candidate gene approach is a strategy widely used to identify susceptibility genes. All genes coding for proteins involved in biochemical or physiological abnormalities of cardiac function are potential candidates for IDC. METHODS: We studied 433 patients with IDC and 401 gender- and age-matched controls. Polymorphisms investigated were the I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene, the T174M and M235T polymorphisms of the angiotensinogen (AGT) gene, the A-153G and A+39C polymorphisms of the angiotensin-II type 1 receptor (AGTR1) gene, the T-344C polymorphism of the aldosterone synthase (CYP11B2) gene, the G-308A polymorphism of the tumor necrosis factor-alpha (TNF) gene, the R25P polymorphism of the transforming growth factor beta1 (TGFB1) gene, the G+11/in23T polymorphism of the endothelial nitric oxide synthase (NOS3) gene and the C-1563T polymorphism of the brain natriuretic peptide (BNP) gene. RESULTS: None of the polymorphisms were significantly associated with the risk or the severity of the disease. CONCLUSIONS: We did not find evidence for an involvement of any of the 10 investigated polymorphisms in the susceptibility to IDC.

Adolescent↗
PubMed2000

Plasminogen activator inhibitor-1 and apolipoprotein E gene polymorphisms and diabetic angiopathy.

BACKGROUND: A point mutation in the plasminogen activator inhibitor-1 (PAI-1) gene and a three-allelic variation in the apolipoprotein-E (ApoE) gene have been suggested as risk factors for the development of diabetic micro- and macrovascular complications. METHODS: We studied 198 type 1 diabetic patients with diabetic nephropathy [121 men, age (mean+/-SD) 41+/-10 years, diabetes duration 28+/-8 years] and 192 patients with persistent normoalbuminuria (118 men, age 43+/-10 years, diabetes duration 27+/-9 years). RESULTS: Male patients with nephropathy had elevated plasma PAI-1 levels [geometric mean (95% CI)], 70 (62-79) ng/ml, compared with normoalbuminuric men, 43 (38-47) ng/ml, P<0.001. Even though nephropathic patients with the 4G4G genotype tended to have higher plasma PAI-1 levels, P=0.06, no difference in allele frequency (4G/5G) was seen between patients with and without nephropathy: 0.538/0.462 vs 0.539/0.461, respectively. Nor did ApoE allele frequencies (epsilon2/epsilon3/epsilon4) differ between nephropathic and normoalbuminuric patients: 0.099/0.749/0. 152 vs 0.081/0.745/0.174, respectively. Genotype distributions were also similar, n.s. Coronary heart disease was more prevalent (36%) among nephropathic patients carrying the atherogenic epsilon4-allele compared with 12% in patients with the epsilon3,epsilon3 genotype, P<0.001. No associations between diabetic retinopathy and PAI-1 or ApoE polymorphisms were observed, n.s. CONCLUSIONS: The ApoE polymorphism may accelerate the development of coronary heart disease often seen in Caucasian patients with type 1 diabetes and diabetic nephropathy, a condition characterized by elevated plasma PAI-1 in men. Neither the PAI-1 nor the ApoE gene polymorphism contributes to the genetic susceptibility to diabetic nephropathy or retinopathy.

Adult↗
PubMed2000

Polymorphisms of the P-selectin gene and risk of myocardial infarction in men and women in the ECTIM extension study. Etude cas-temoin de l'infarctus myocarde.

BACKGROUND AND OBJECTIVE: Studies in animal models and humans implicate cell adhesion molecules in atherogenesis but their role in mediating the risk of myocardial infarction is unclear. The ECTIM (étude cas-temoin de l'infarctus myocarde) extension study was established to determine whether a previously implicated polymorphism of the P-selectin gene was associated with myocardial infarction risk in men and women in Belfast and Glasgow. PATIENTS AND STUDY SETTING: 696 cases with a recent myocardial infarction and 561 age matched controls (both male and female) were recruited into a case-control study in MONICA project areas of Belfast and Glasgow. METHODS: Demographic and lifestyle information was collected by interview administered questionnaire, and each subject was examined and provided a blood sample for DNA extraction. The polymerase chain reaction (PCR) was used to amplify regions encompassing the P-selectin Thr-->Pro (A/C) polymorphism at position 715. Genotype odds ratios for myocardial infarction were estimated by logistic regression adjusted for population, age, and sex. RESULTS: There was no significant association between conventional risk factors (such as hypercholesterolaemia, increased body mass index, or raised blood pressure) and either the rare or the common Pro(715) allele of the P-selectin gene in controls. Overall, comparing Pro(715)/Pro(715) and Pro(715)/Thr(715) with Thr(715)/Thr(715), with adjustment for centre, age, and sex, the odds ratio was 0.78 (95% confidence interval 0.60 to 1.00) (p = 0.054), indicating a "protective" effect of the less common Pro(715) allele. There was no significant heterogeneity in odds ratios between men and women either in this sample or when combined with the original ECTIM subjects. CONCLUSIONS: In a large population based study in two regions of the UK, we have been able to corroborate the earlier ECTIM findings of a lower frequency of the Thr/Pro(715) polymorphism in subjects with myocardial infarction. An apparently "protective effect" of similar magnitude also seems to apply to women.

Case-Control Studies↗
PubMed2000

Polymorphisms of the human matrix gla protein (MGP) gene, vascular calcification, and myocardial infarction.

The matrix Gla protein (MGP) is an important inhibitor of vessel and cartilage calcification that is strongly expressed in human calcified, atherosclerotic plaques and could modulate plaque calcification and coronary heart disease risk. Using a genetic approach, we explored this possibility by identifying polymorphisms of the MGP gene and testing their possible association with myocardial infarction (MI) and plaque calcification. Eight polymorphisms were identified in the coding and 5'-flanking sequences of the MGP gene. All polymorphisms were investigated in 607 patients with MI and 667 control subjects recruited into the ECTIM Study (Etude Cas-Témoins de l'Infarctus du Myocarde) and in 717 healthy individuals with echographically assessed arterial calcification and atherosclerosis who were participating in the AXA Study. In the ECTIM Study, alleles and genotypes were distributed similarly in patients and controls in the whole study group; in only 1 subgroup of subjects defined as being at low risk for MI were the concordant A-7 and Ala 83 alleles more frequent in patients with MI than in controls (P<0.003). In the AXA Study among subjects with femoral atherosclerosis, the same alleles were more common in the presence than the absence of plaque calcification (P<0.025). The other MGP polymorphisms were not associated with any investigated clinical phenotype. Transient transfection experiments with allelic promoter-reporter gene constructs and DNA-protein interaction assays were carried out to assess possible in vitro functionality of the promoter variants detected at positions -814, -138, and -7 relative to the start of transcription. When compared with the -138 T allele, the minor -138 C: allele consistently conferred a reduced promoter activity of -20% (P<0.0001) in rat vascular smooth muscle cells and of -50% (P<0.004) in a human fibroblast cell line, whereas the other polymorphisms, including -7, displayed no evidence of in vitro functionality. We conclude that the A-7 or Ala 83 alleles of the MGP gene may confer an increased risk of plaque calcification and MI; however, the observed relationships are weak or limited to subgroups of patients and therefore need confirmation.

Adolescent↗
PubMed2000

New functional promoter polymorphism, CETP/-629, in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels: role of Sp1/Sp3 in transcriptional regulation.

A new polymorphism located at position -629 (CETP/-629A/C) in the promoter of the cholesteryl ester transfer protein (CETP) gene is described. The -629A allele was associated with lower CETP mass (P<0. 0001) and higher high density lipoprotein cholesterol (P<0.001) than the C allele in a sample of 536 control subjects from the ECTIM study. Transfection studies in HepG2 cells with a luciferase expression vector incorporating a 777-bp fragment of the CETP promoter and containing either A or C at position -629 showed significantly lower luciferase activity with the promoter fragment of the A allele (-25%, P<0.05). By gel-shift assay, DNA-protein interactions were evaluated in nuclear extracts of HepG2 cells with the use of 2 probes (A or C probe) composed of 20 bp of the promoter sequence surrounding the polymorphic site. Two specific complexes of distinct migration rate were identified with the A and the C probe. Competition with an excess of oligonucleotide containing the Sp1 consensus binding site showed that a protein(s) of the Sp transcription factor family was implicated in complex formation with the A probe but not with the C probe. Incubation with specific antibodies indicated that Sp1 and Sp3 bound specifically to the A probe. We introduced mutations in the -629-Sp1 binding site to test its functionality and to define the characteristics of transcription factor binding. We showed, by gel-shift assay, that no nuclear proteins bound to the mutated sequence. Transient transfection of HepG2 cells revealed that the expression of the mutated fragment was significantly increased compared with that of the A promoter fragment (25%, P<0.05). The mutated fragment displayed the same activity as that of the C promoter. These results indicate that Sp1 and/or Sp3 repress CETP promoter activity, whereas nuclear factors binding the C allele are without effect on promoter expression.

Adult↗
PubMed2000

Polymorphisms in the 5' regulatory region of the tissue factor gene and the risk of myocardial infarction and venous thromboembolism: the ECTIM and PATHROS studies. Etude Cas-Témoins de l'Infarctus du Myocarde. Paris Thrombosis case-control Study.

Tissue factor (TF) is a transmembrane protein considered to be responsible for the initiation of coagulation. TF gene expression may be induced in monocytes and endothelial cells and is present in atherosclerotic plaque to initiate thrombus formation. To investigate whether individual differences in TF gene expression could predispose subjects to thrombosis, we sequenced the 5' domain of the gene up to nucleotide 2732 and found 6 different polymorphisms: 4 of them were completely concordant and defined 2 haplotypes with similar frequencies, designated as 1208 D and 1208 I. Genotyping of patients with myocardial infarction in a case-control study involving 2354 subjects showed no association between the polymorphisms and nonfatal coronary thrombosis. In another study involving 255 patients with venous thromboembolism and 1204 controls, allele D was less common in the cases (P=0.022). The odds ratio associated with the presence of at least 1 D allele was 0.72 (P=0. 031). Comparison of subgroups of control subjects who were homozygous for the D or I allele demonstrated a lower plasma TF concentration in DD homozygotes. These results indicate that the TF gene promoter exists in 2 major forms differing at 4 sites. The 1208 D haplotype is not associated with coronary thrombosis but is associated with reduced plasma TF levels and a lower risk of venous thrombosis.

5' Untranslated Regions↗
PubMed2000

Association between the Glu298Asp polymorphism in the endothelial constitutive nitric oxide synthase gene and brain infarction. The GENIC Investigators.

BACKGROUND AND PURPOSE: Nitric oxide (NO) synthesized by endothelial constitutive NO synthase (ecNOS) plays a key role in vascular regulation and atherosclerosis. Little is known concerning the role of the ecNOS gene (NOS3) as a risk factor for brain infarction (BI). Our aim was to investigate the relation between the Glu298Asp polymorphism in exon 7 of NOS3 with BI and its subtypes. METHODS: Patients (n=460; cases) with BI were consecutively recruited and classified into etiological subtypes. Control subjects (n=460; controls) without a history of stroke were recruited among individuals hospitalized at the same institutions and individually matched on age, sex, and center. Genotypes of the polymorphism were determined by polymerase chain reaction. RESULTS: The distribution of genotypes was significantly different between cases and controls (P=0.008); the GG genotype was more frequent in cases (46.1%) than in controls (35.4%; OR, 1.56; 95% CI, 1.19 to 2.04). Among subtypes, the frequency of the GG genotype was significantly higher in cases than in controls in the lacunar subtype (OR, 2.00; 95% CI, 1.05 to 3. 80); in this group, the relation between BI and LDL level was stronger among carriers of the GG genotype than among noncarriers (P for interaction, 0.05). CONCLUSIONS: Homozygosity for the G allele of the Glu298Asp polymorphism in NOS3 was associated with BI, and especially with lacunar stroke. Our findings suggest that genetic susceptibility and LDL cholesterol have a synergistic relation. Although these findings should be replicated in a larger sample of subjects and the functionality of the Glu298Asp polymorphism has not been established, these results may help us to understand the cause of the arteriolopathy underlying lacunae and have future implications in their treatment and prevention.

Adolescent↗
PubMed1999

Functional polymorphism in the regulatory region of gelatinase B gene in relation to severity of coronary atherosclerosis.

BACKGROUND: Gelatinase B, a matrix metalloproteinase that has proteolytic activity against connective tissue proteins, has been suggested to be important in the connective tissue remodeling processes associated with atherogenesis and plaque rupture. This study tested the hypothesis that sequence variation in the promoter region of the gelatinase B gene influences its expression, predisposing individuals carrying certain genetic variants to more severe atherosclerosis. METHODS AND RESULTS: Single-strand conformation polymorphism analysis was carried out to search the promoter region of the gene encoding gelatinase B for naturally occurring genetic variation. As a result, an unreported common polymorphism was detected, which arose from a cytosine (C) to thymidine (T) transition at position -1562 relative to the start of transcription. Transient transfection experiments and DNA-protein interaction assays indicated that the T allele had a higher promoter activity than the C allele, which appeared to be due to preferential binding of a putative transcription repressor protein to the C allelic promoter. A sample of 584 male patients with myocardial infarction and 645 age-matched male healthy control subjects were genotyped. The allele frequencies were not significantly different between the cases and control subjects. However, in 374 patients with available angiographic data, 26% of those carrying 1 or 2 copies of the T allele had >50% stenosis in 3 coronary arteries, whereas only 15% of C/C homozygotes had triple-vessel disease. CONCLUSIONS: These data suggest that this functional genetic variation influences gelatinase B gene promoter activity in an allele-specific manner and has an effect on atherosclerotic phenotype.

Adult↗