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L Tiret

Publications and source records attributed to L Tiret.

At least 73 records · Page 4Linked to original sources
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

Testing association between candidate-gene markers and phenotype in related individuals, by use of estimating equations.

Association studies are one of the major strategies for identifying genetic factors underlying complex traits. In samples of related individuals, conventional statistical procedures are not valid for testing association, and maximum likelihood (ML) methods have to be used, but they are computationally demanding and are not necessarily robust to violations of their assumptions. Estimating equations (EE) offer an alternative to ML methods, for estimating association parameters in correlated data. We studied through simulations the behavior of EE in a large range of practical situations, including samples of nuclear families of varying sizes and mixtures of related and unrelated individuals. For a quantitative phenotype, the power of the EE test was comparable to that of a conventional ML test and close to the power expected in a sample of unrelated individuals. For a binary phenotype, the power of the EE test decreased with the degree of clustering, as did the power of the ML test. This result might be partly explained by a modeling of the correlations between responses that is less efficient than that in the quantitative case. In small samples (< 50 families), the variance of the EE association parameter tended to be underestimated, leading to an inflation of the type I error. The heterogeneity of cluster size induced a slight loss of efficiency of the EE estimator, by comparison with balanced samples. The major advantages of the EE technique are its computational simplicity and its great flexibility, easily allowing investigation of gene-gene and gene-environment interactions. It constitutes a powerful tool for testing genotype-phenotype association in related individuals.

Female↗
PubMed1997

Short stature and heart disease: nature or nurture? The EARS Group.

BACKGROUND: Previous studies have demonstrated that short men are at increased risk of coronary heart disease (CHD). It has been suggested that the inverse relationship between adult height and CHD risk could be attributable to the fetal origins of CHD. METHOD: The hypothesis that transmissible factors could partly explain the association has been tested in the European Atherosclerosis Research Studies (I and II), in which a sample of healthy university students (cases), drawn from 18 European countries (male: n = 721; female: n = 330), whose fathers had had a documented myocardial infarction before the age of 55 years were compared to age- and sex-matched controls (male: n = 1056; female: n = 638). Information about lifestyle and birthweight was collected and a fasting blood sample was obtained from each subject. RESULTS: In females there was no difference in height between cases and controls but male cases were shorter than controls, on average by one cm, both in the EARS I (P = 0.02) and the EARS II studies (P = 0.01) and this difference was independent of reported birthweight and the fathers' educational attainment. In logistic regression the relationship was independent of the subjects' apolipoprotein B level, the other major biological discriminator of case-control status. CONCLUSION: In men at least, height appears to be an independent transmissible risk factor for CHD.

Adolescent↗
PubMed1997

Hepatic lipase gene polymorphisms influence plasma HDL levels. Results from Finnish EARS participants. European Atherosclerosis Research Study.

Hepatic lipase (HL), a triglyceride lipase found in liver, adrenals, testes, and ovaries, takes part in the uptake, remodeling, and function of lipoproteins including HDL, as well as VLDL and chylomicrons. In the present study, the genotype distribution of five HL polymorphisms (-C480T, V133V, T202T, L334F, T457T) and their association to plasma lipid values were investigated. The study participants included 92 students with paternal history of myocardial infarction before the age of 55 and 194 matched control subjects, ie, the Finnish participants of the European Atherosclerosis Research Study (EARS). The allele T of the HL polymorphism -C480T showed an association with elevated HDL, apoA-I, and LpA-I values (ANOVA P < .01). No difference in genotype distribution was observed in the offspring with and without paternal history of myocardial infarction.

Adolescent↗
PubMed1997

Interactions between lifestyle-related factors and the ApoE polymorphism on plasma lipids and apolipoproteins. The EARS Study. European Atherosclerosis Research Study.

To elucidate how the apolipoprotein (apo) E polymorphism and modifiable factors interact in explaining plasma lipid and apolipoprotein levels, we studied 1448 young adults (18 to 26 years old), participating in the European Atherosclerosis Research Study (EARS). Venous blood was collected after an overnight fast. Modifiable factors, eg, body mass index (BMI), waist-to-hip ratio (WHR), tobacco and alcohol consumption, and physical activity, were determined by using standardized protocols. Associations of modifiable factors with apoE levels were homogeneous across apoE phenotypes. In contrast, correlations of BMI with total cholesterol and apoB levels, as well as correlations between WHR and apoB, were significantly (P < .05 to P < .01) stronger in E2 carriers than in subjects with other phenotypes. Total cholesterol and apoB levels were comparable in E2 carriers in the upper tertile of BMI or WHR to those in E3/3 subjects, suggesting that the lowering effect of the E2 allele was no longer present. The inverse association between the plasma cholesteryl linoleate-to-oleate ratio, a marker for the dietary polyunsaturated-to-saturated fatty acid ratio, and triglycerides was also stronger in E2 carriers (-0.33 versus -0.17 in E3/3 and -0.24 in E4 carriers). Associations with other modifiable factors were notably consistent across apoE phenotypes. Gender and modifiable factors explained three times more (31%) of the interindividual variation in apoB levels in E2 carriers than in E3/3 subjects (9%) or E4 carriers (14%), mainly due to a larger variance explained by BMI. Our results suggest that the apoE polymorphism acts in a relatively uniform manner, independently of lifestyle. However, the associations of adiposity to total cholesterol and apoB levels appear to be stronger in apoE2 carriers.

Adolescent↗
PubMed1996

Family study of lipoprotein lipase gene polymorphisms and plasma triglyceride levels.

To better characterize the role of the lipoprotein lipase (LPL) gene in the determination of triglyceride levels in healthy subjects, a study was performed in 193 nuclear families (384 parents, means age = 42.0 +/- 5.2 years; 399 offspring, mean age = 14.6 +/- 4.3 years) volunteering to have a free health checkup examination. The pattern of familial resemblance was compatible with a zero correlation between spouses, a weak father-offspring correlation (0.099 +/- 0.054; P < 0.07), and significant mother-offspring (0.235 +/- 0.053; P < 10(-4)) and sib-sib (0.294 +/- 0.064; P < 10(-4)) correlations. Associations of triglyceride levels with the LPL HindIII and PvuII polymorphisms were investigated by a familial measured genotype analysis, specifying sex- and age-dependent polymorphism effects. The effects associated with both polymorphisms were significant only in fathers, the H+ and P+ alleles being associated with raised triglyceride levels. The HindIII and PvuII polymorphisms explained 3.5% and 3%, respectively, of the variability of triglycerides in fathers. The relationship was weakened after prior adjustment on body mass index, but remained significant for PvuII. Because of the lack of effect in mothers and offspring, the polymorphisms did not contribute to the covariance of triglyceride levels in relatives. In conclusion, this family study showed a weak relationship of the HindIII and PvuII polymorphisms to plasma triglyceride levels in young healthy male subjects. The effects detectable only in fathers suggest a possible modulation of the LPL expression by hormonal or lifestyle factors.

Adolescent↗
PubMed1996

DNA polymorphisms in linkage disequilibrium at the 3' end of the human APO AII gene: relationships with lipids, apolipoproteins and coronary heart disease.

Two investigations were undertaken to analyze the 3' region of the apolipoprotein AII (Apo AII) gene in patients with myocardial infarction (MI) and controls. Previous studies have suggested that a MspI polymorphism in this gene may be associated with hypertriglyceridaemia, high levels of HDL cholesterol and Apo AII. To verify this hypothesis, the distribution of MspI genotypes and their possible associations with several plasma lipid variables were studied in 882 subjects (411 cases with MI and 471 controls) from the ECTIM study. There were no differences in genotype and allele frequencies between cases and controls, and no differences in lipid variable levels in controls carrying the less frequent MspI allele vs other controls. Using single-strand conformation polymorphism (SSCP) analysis, we detected a new polymorphism which caused by a C-to-T transition located in the third intron near the splice junction site (acceptor). This polymorphism modifies a Bst N1 restriction site. The ECTIM population was screened for this new marker, and no significant associations with MI and plasma lipid levels were found. Our results suggest that these two variants located in the coding region of the Apo AII gene are unlikely to contribute significantly to the level of plasma lipid variables and the risk of coronary heart disease (CHD) in the European population.

Adult↗
PubMed1996

Identification of new polymorphisms of the angiotensin I-converting enzyme (ACE) gene, and study of their relationship to plasma ACE levels by two-QTL segregation-linkage analysis.

Plasma angiotensin I-converting enzyme (ACE) levels are highly genetically determined. A previous segregation-linkage analysis suggested the existence of a functional mutation located within or close to the ACE locus, in almost complete linkage desequilibrium (LD) with the ACE insertion/deletion (I/D) polymorphism and accounting for half the ACE variance. In order to identify the functional variant at the molecular level, we compared ACE gene sequences between four subjects selected for having contrasted ACE levels and I/D genotypes. We identified 10 new polymorphisms, among which 8 were genotyped in 95 healthy nuclear families, in addition to the I/D polymorphism. These polymorphisms could be divided into two groups: five polymorphisms in the 5' region and three in the coding sequence and the 3' UTR. Within each group, polymorphisms were in nearly complete association, whereas polymorphisms from the two groups were in strong negative LD. After adjustment for the I/D polymorphism, all polymorphisms of the 5' group remained significantly associated with ACE levels, which suggests the existence of two quantitative trait loci (QTL) acting additively on ACE levels. Segregation-linkage analyses including one or two ACE-linked QTLs in LD with two ACE markers were performed to test this hypothesis. The two QTLs and the two markers were assumed to be in complete LD. Results supported the existence of two ACE-linked QTLs, which would explain 38% and 49% of the ACE variance in parents and offspring, respectively. One of these QTLs might be the I/D polymorphism itself or the newly characterized 4656(CT)2/3 polymorphism. The second QTL would have a frequency of approximately .20, which is incompatible with any of the yet-identified polymorphisms. More extensive sequencing and extended analyses in larger samples and in other populations will be necessary to characterize definitely the functional variants.

Adolescent↗
PubMed1995

DNA polymorphisms of the apoprotein B gene are associated with altered plasma lipoprotein concentrations but not with perceived risk of cardiovascular disease: European Atherosclerosis Research Study.

Three polymorphisms of the apoprotein B gene (XbaI, signal peptide insertion/deletion and the 3'-variable number of tandem repeats) selected on the basis of previously published reports as likely to be the most informative, were investigated in a cross-cultural study in Europe. Students from 14 universities, grouped for analyses into five regions, were recruited as cases (n = 682) if they had a paternal history of premature myocardial infarction. For comparison, twice the number of age- and sex-matched controls (n = 1312) were recruited from the same student populations. There were significant regional differences in allele frequencies of the XbaI and VNTR polymorphisms but not of the signal peptide. There were no significant differences in allele frequencies between cases and controls. Adjusted for age, gender and region, the lipoprotein concentrations differed significantly with genotype. The XbaI polymorphism was associated with differences in plasma cholesterol (P = 0.007), triglyceride (P = 0.050), apo B (P = 0.001) and LDL cholesterol (P = 0.01). An interaction between XbaI genotype and body mass index was observed on plasma triglyceride (P = 0.015) and apo B (P = 0.005) concentrations. The signal peptide deletion allele was associated with increased plasma cholesterol (P = 0.03), apo B (P = 0.04) and LDL cholesterol (P = 0.02). The VNTR was not significantly associated with any of these variables although there was a significant genotype/status interaction in relation to HDL cholesterol (P = 0.001) and apo AI (P = 0.001) concentrations. We conclude that, although they are associated with significant differences in lipoprotein concentrations within- and between-populations, the apo B DNA polymorphisms studied are of less value as indicators of cardiovascular risk-factor status in the offspring of individuals affected by the disease.

Adolescent↗
PubMed1995

European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment interaction.

The European Atherosclerosis Research Study (EARS) compares genetic and environmental factors in the offspring of fathers with myocardial infarction before the age of 55 years (designated cases) and control subjects from five different regions of Europe. Genotype was determined for a G-A polymorphism 455 bp upstream from the start of transcription of the beta-fibrinogen gene. In 585 cases and 1106 control subjects, the relative frequency of the A allele was similar (0.223 and 0.217, respectively), with small and nonsignificant differences in frequency observed among the five regions. Because of evidence for an interaction between a number of factors and genotype in the determination of plasma fibrinogen levels (in particular among female cases who reported use of oral contraceptives), the data were analyzed without adjusting for covariates except for age and region, and analyses were carried out excluding women taking oral contraceptives (n = 297). In agreement with previous reports, in all regions the A allele was associated with elevated plasma fibrinogen levels, with the strongest and most consistent effects being seen in men. In nonsmokers, after adjusting for the effects of age and region, male cases and control subjects with genotype A/A had mean fibrinogen levels 0.49 and 0.33 g/L higher, respectively, than those with genotype G/G, whereas those with genotype G/A had intermediate levels (P < .01). In female nonsmokers there was a similar but smaller and nonsignificant effect (A/A levels higher than G/G by 0.12 and 0.07 g/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Genetic variation at the angiotensinogen locus in relation to high blood pressure and myocardial infarction: the ECTIM Study.

OBJECTIVES: To study the association between polymorphisms of the angiotensinogen (AGT) gene and blood pressure in population-based samples, and to determine whether genetic variation at the AGT locus is involved in the susceptibility to myocardial infarction. METHODS: The study population comprised 630 cases who survived a myocardial infarction, recruited from the World Health Organization Monitoring Cardiovascular Diseases registers in Belfast, Lille, Strasbourg and Toulouse, and 741 controls drawn from the corresponding populations. The AGT polymorphisms investigated were T174M and M235T. High blood pressure was defined as diastolic blood pressure > 100 mmHg or the use of antihypertensive medication, or both. RESULTS: In the controls the mean +/- SEM frequency of the M174 allele was 0.116 +/- 0.008, and that of the T235 allele was 0.401 +/- 0.013. In the whole population blood pressure levels and prevalence of high blood pressure did not vary according to T174M and M235T genotypes. However, obesity appeared as a crucial factor influencing the relationship between high blood pressure and T174M. In subjects with body mass index < 26 kg/m2 there was a 2.4-fold increase of the prevalence of high blood pressure in carriers of the M174 allele compared with in homozygotes for the T174 allele, whereas no association was detected in subjects with body mass index > 26 kg/m2. The association between high blood pressure and M235T was not significant in either group. The T174M and M235T genotype distributions did not differ between survivors of myocardial infarction and controls. CONCLUSIONS: These data suggest that the AGT gene could be involved in the predisposition to high blood pressure in non-overweight, but not in overweight men, possibly reflecting genetically different types of hypertension. No significant impact of the AGT locus in the risk of non-fatal myocardial infarction was detected.

Adult↗
PubMed1994

Synergistic effects of angiotensin-converting enzyme and angiotensin-II type 1 receptor gene polymorphisms on risk of myocardial infarction.

We reported from our previous multicentre case-control study that the deletion (D) polymorphism of the gene encoding angiotensin-converting enzyme (ACE) was associated with increased risk of myocardial infarction. The main function of ACE is to convert angiotensin I into angiotensin II, which exerts its known cellular actions through the angiotensin II AT1 receptor subtype (AGT1R). We have now investigated the role of a common polymorphism of the AT1 receptor gene (an A-->C transversion at position 1166 of AGT1R) and looked for an interaction between ACE and AGT1R gene polymorphisms on the risk of myocardial infarction. We analysed DNA from 613 patients with myocardial infarction and 723 age-matched population controls. We found a significant interaction between ACE and AGT1R gene polymorphisms; the odds ratio for myocardial infarction associated with the ACE DD genotype was 1.05 (95% CI 0.75-1.49) for subjects without the AGT1R C allele, 1.52 (1.06-2.18) in AC heterozygotes, and 3.95 (1.26-12.4) in CC homozygotes (test for trend, p < 0.02). Among patients defined as low risk by traditional risk factors (serum apolipoprotein B < 1.25 g/L, body-mass index < 26 kg/m2) the interaction was even stronger (odds ratios 1.64 [0.68-3.92], 7.03 [2.61-19.0], and 13.3 [p = 0.05], respectively). These findings, if confirmed, could have clinical implications for the prevention and treatment of coronary heart disease.

Adult↗
PubMed1994

Genetic polymorphism of apolipoprotein A-IV in five different regions of Europe. Relations to plasma lipoproteins and to history of myocardial infarction: the EARS study. European Atherosclerosis Research Study.

As a part of the EARS study we assessed the role of the common apo A-IV polymorphism in determining the hereditary predisposition to cardiovascular disease. The study population consisted of 1261 controls and 629 cases (students whose father had MI before 55 years) from five different European regions. The apo A-IV 1-1 phenotype accounted for 85% of the individuals. One per cent of subjects were homozygous for the apo A-IV2 allele. There was significant regional variation in the apo A-IV allele frequencies from North to South in Europe, with the lowest A-IV2 frequency in Finland. The distribution of the apo A-IV phenotypes was similar in cases and controls, as was the regional variation. The apo A-IV polymorphism did not affect HDL cholesterol. There was no correlation between apo A-IV alleles and the plasma concentration of apo A-IV. The plasma concentration of apo A-IV was lower in females than in males; furthermore, there was a significant difference in apo A-IV concentrations between oral contraceptive users and nonusers: users had the lowest values. As no strongly significant genetic difference could be demonstrated between plasma lipid concentration in cases and controls, and as the apo A-IV polymorphism did not significantly influence plasma lipid concentration, we conclude that the apo A-IV gene is not a major determinant of the risk for MI and/or CHD.

Adolescent↗
PubMed1994

ApoE polymorphism and predisposition to coronary heart disease in youths of different European populations. The EARS Study. European Atherosclerosis Research Study.

The European Atherosclerosis Research Study was based on the comparison of offspring having a paternal history of premature myocardial infarction with age- and sex-matched control subjects. Case (n = 635) and control (n = 1259) subjects aged 18 through 26 years were recruited from 14 universities of 11 European countries. The allele distributions of apolipoprotein (apo) E polymorphism differed between populations, with a clear-cut gradient for allele epsilon 4 frequency decreasing from 0.18 in Finland to 0.11 in the south of Europe, following the gradient of coronary heart disease mortality rates. The association of apoE polymorphism with plasma total cholesterol, low-density lipoprotein cholesterol, apoB, and apoE levels was consistent with the now well-identified effects of epsilon 2 and epsilon 4 alleles on these traits. Both epsilon 2 and epsilon 4 alleles equally increased the level of triglycerides, and epsilon 2 had a lowering effect on lipoprotein(a) concentration. There were also weak effects of epsilon 2 and epsilon 4 on high-density lipoprotein cholesterol, apoA-I, and apoA-I-containing lipoprotein levels that paralleled those on apoE levels. The main finding of this study was the significant association of the apoE polymorphism with a paternal history of myocardial infarction. The association was consistent across regions, except in the south. When excluding this region, the population-adjusted odds ratios by reference to phenotype E3/3 were estimated as 0.23, 0.61, 0.78, 1.16, and 1.33 for E2/2, E3/2, E4/2, E4/3, and E4/4, respectively. The apoE locus largely explained the case/control difference of apoB level.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1994

Plasma level and gene polymorphism of angiotensin-converting enzyme in relation to myocardial infarction.

BACKGROUND: The angiotensin-converting enzyme (ACE) plays an important role in the production of angiotensin II and the degradation of bradykinin, two peptides involved in cardiovascular homeostasy. Presence of a polymorphism in the ACE gene (ACE Ss) has been postulated from segregation analysis of plasma ACE in families. This putative polymorphism, which strongly affects the plasma and cellular levels of ACE, probably by modulating ACE gene transcription, has not yet been identified at the molecular level; however, an insertion/deletion polymorphism is present in the 16th intron of the ACE gene (ACE I/D) and appears to be a very good marker for ACE Ss. The biological role of ACE suggests that the ACE gene polymorphism could affect the predisposition to myocardial infarction (MI). METHODS AND RESULTS: We have recently shown, in a large case-control study (ECTIM), that the marker allele D of the ACE gene, which is associated with higher levels of ACE in plasma and cells, was more frequent in male patients with MI than in control subjects, especially in patients considered at low risk. ACE activity has now been measured from frozen aliquots of plasma in a large subsample of the ECTIM study (n = 1086). Plasma ACE level did not differ between patients and control subjects in the older age group (> or = 55 years) but was higher in patients than in control subjects in the younger age group (< 55 years); P < .005 after adjustment on ACE I/D and other risk factors. In patients, plasma ACE levels decreased with age (R = -.225, P < 10(-4)), but in control subjects no such trend was observed. In the low-risk group (ApoB < 1.25 mg/dL, body mass index < 26 kg/m2, and not treated with hypolipidemic drugs), plasma ACE level was increased in patients when compared with control subjects among homozygotes and heterozygotes for the ACE I allele (P < .015). Analysis of the distribution of plasma ACE by using commingling analysis conditional on the marker genotype ACE I/D enabled us to infer the frequencies and effects of the postulated ACE Ss genotypes. The results suggest that the higher plasma ACE levels in patients than in control subjects in the younger age group were due to a difference in frequency of the postulated S allele (.47 versus .36). CONCLUSIONS: These results extend our previous findings and indicate that plasma ACE level may be a risk factor for MI, independent of the ACE I/D polymorphism.

Alleles↗
PubMed1994

Angiotensin II type 1 receptor gene polymorphisms in human essential hypertension.

We conducted the present study to determine whether the angiotensin II type I receptor (AT1) gene might be implicated in human essential hypertension by using case-control and linkage studies. The entire coding and 3' untranslated regions of the AT1 receptor gene (2.2 kb) were amplified by polymerase chain reaction and submitted to single-strand conformation polymorphism in 60 hypertensive subjects with a familial susceptibility. We identified five polymorphisms (T573-->C, A1062-->G, A1166-->C, G1517-->T, and A1878-->G). However, no mutations that alter the encoded amino acid sequence were detected. A case-control study performed on white hypertensive (n = 206; blood pressure, 168 +/- 16/103 +/- 9 mm Hg) and normotensive (n = 298; blood pressure, 122 +/- 10/75 +/- 9 mm Hg) subjects using three of five polymorphisms showed a significant increase in allelic frequency of C1166 in hypertensive subjects (0.36 versus 0.28 for normotensive subjects, chi 2 = 6.8, P < .01). Frequencies for the alleles of the other two polymorphisms (T573-->C, A1878-->G) were similar in both groups. We performed a linkage study using the affected sib pair method and a highly polymorphic marker of the AT1 receptor gene. There was no evidence for linkage in 267 sib pairs analyzed from 138 pedigrees. These findings would be compatible with a common variant of the AT1 receptor imparting a small effect on blood pressure; further studies will be needed to address this possibility.

Adult↗