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V Nicaud

Publications and source records attributed to V Nicaud.

At least 55 records · Page 3Linked to original sources
PubMed1999

Identification of a genetic risk factor for idiopathic dilated cardiomyopathy. Involvement of a polymorphism in the endothelin receptor type A gene. CARDIGENE group.

BACKGROUND: Idiopathic dilated cardiomyopathy is a frequent cause of heart failure, a major concern of public health. Although idiopathic dilated cardiomyopathy may be familial, most cases are sporadic and the disease is considered to be multifactorial, for which genetic factors may account for a significant part. METHODS AND RESULTS: We hypothesized that genetic abnormalities of the endothelin pathway may be involved in idiopathic dilated cardiomyopathy pathophysiology and therefore examined the possible association between idiopathic dilated cardiomyopathy and polymorphisms in genes encoding endothelin 1, endothelin type A and type B receptors, in a case-control study (433 patients and 400 age- and sex-matched control subjects). Analysis of the Exon 8 C/T polymorphism in the endothelin receptor type A gene indicated that individuals who are homozygote for the T allele were at significantly increased risk for the disease (odds ratio: 1.9; 95% confidence interval: 1.2 to 3. 01;P<0.006). Analysis of the other polymorphisms indicated that no significant difference was observed in genotype or allele frequencies between cases and controls. CONCLUSIONS: The variant in the Exon 8 of the endothelin receptor type A gene appears as a genetic risk factor for idiopathic forms of heart failure. These results provide a new approach to the pathophysiology of idiopathic dilated cardiomyopathy.

Adult↗
PubMed1999

Sequence diversity in 36 candidate genes for cardiovascular disorders.

Two strategies involving whole-genome association studies have been proposed for the identification of genes involved in complex diseases. The first one seeks to characterize all common variants of human genes and to test their association with disease. The second one seeks to develop dense maps of single-nucleotide polymorphisms (SNPs) and to detect susceptibility genes through linkage disequilibrium. We performed a molecular screening of the coding and/or flanking regions of 36 candidate genes for cardiovascular diseases. All polymorphisms identified by this screening were further genotyped in 750 subjects of European descent. In the whole set of genes, the lengths explored spanned 53.8 kb in the 5' regions, 68.4 kb in exonic regions, and 13 kb in the 3' regions. The strength of linkage disequilibrium within candidate regions suggests that genomewide maps of SNPs might be efficient ways to identify new disease-susceptibility genes, provided that the maps are sufficiently dense. However, the relatively large number of polymorphisms within coding and regulatory regions of candidate genes raises the possibility that several of them might be functional and that the pattern of genotype-phenotype association might be more complex than initially envisaged, as actually has been observed in some well-characterized genes. These results argue in favor of both genomewide association studies and detailed studies of the overall sequence variation of candidate genes, as complementary approaches.

Apolipoproteins B↗
PubMed1999

The T allele of the hepatic lipase promoter variant C-480T is associated with increased fasting lipids and HDL and increased preprandial and postprandial LpCIII:B : European Atherosclerosis Research Study (EARS) II.

The common C-480T transition in the hepatic lipase (HL) promoter has been shown to be associated with lower HL activity and increased high density lipoprotein (HDL) cholesterol. We examined the frequency and lipid associations of this HL polymorphism in 385 healthy, young (18- to 28-year-old) men whose fathers had had a premature myocardial infarction (designated cases) and 405 age-matched controls. These individuals were participants in the European Atherosclerosis Research Study II postprandial trial, who had been recruited from 11 European countries in 4 regions (the Baltic; United Kingdom; and central and southern Europe). Overall, the frequency of the T allele was 0.207 in controls and 0.244 in cases (P=0.08). The T allele was associated with higher fasting plasma total cholesterol (P<0.01), triglycerides (P<0.01), and HDL cholesterol (P<0.01). The strongest association was found with apolipoprotein (apo) A-I concentration, which was 10% higher in individuals homozygous for the T allele compared with those homozygous for the C allele (P<0.001). This polymorphism had no effect on the rise in plasma triglyceride levels after a fatty meal. However, before and after the fat load was ingested, levels of particles containing both apoC-III and apoB (LpC-III:B) were higher in carriers of the T allele, with homozygotes having 23% and 27% higher levels preprandially and postprandially, respectively, than those homozygous for the C allele (P<0.05). Thus, our results demonstrate that the C-480T polymorphism in the HL promoter is associated with alterations in plasma lipids and lipoproteins and the accumulation of atherogenic LpC-III:B particles.

Adolescent↗
PubMed1999

Complex association of protein C gene promoter polymorphism with circulating protein C levels and thrombotic risk.

The allele and haplotype frequency of the -1654 C/T and -1641 A/G protein C (PC) gene promoter polymorphisms was determined and analyzed according to circulating PC concentrations in 394 healthy subjects aged 20 to 60 years. The CG haplotype was associated with a lower PC concentration in both homozygous and heterozygous subjects compared with noncarriers. The TA allele had the reverse effect, but only in homozygotes. The distribution of the CG and TA alleles was significantly different in 242 patients, aged 17 to 60 years, with venous thromboembolism. The CG allele increased the risk of thrombosis, with an OR of 1.39 (95% confidence interval (CI), 1.04 to 1.87). The TA allele was protective in subjects aged <45 years, with an OR of 0.68 (95% CI, 0.44 to 1.04). TA was also significantly associated with older age at the first thrombosis. This study confirms the link between the PC gene promoter and circulating PC levels, and suggests a complex effect on the risk of thrombosis.

Adult↗
PubMed1999

The 825C/T polymorphism of the G-protein subunit beta3 is not related to hypertension.

A polymorphism at position 825 (C-->T) of the cDNA that encodes the beta3 subunit (GNB3) of the pertussis toxin-sensitive G protein was recently shown to be associated with human hypertension. To verify this finding and to investigate whether this polymorphism could also be associated with coronary heart disease, we analyzed the GNB3 variant in subjects from 2 previously described studies: Projet d'Etude des Gènes de l'hypertension Artérielle Sévère à modérée Essentielle (PEGASE), a case-control study of moderate to severe hypertension (681 cases and 308 controls), and Etude Cas-Témoins de l'Infarctus du Myocarde (ECTIM), a case-control study of myocardial infarction (MI) (564 cases and 633 controls). Genotyping was performed with allele-specific oligonucleotides. Genotype and allele frequencies were in Hardy-Weinberg equilibrium in all groups. Allele and genotype frequencies did not differ significantly between case patients with essential hypertension or MI and control subjects. In the ECTIM study, the 825T allele frequencies in cases and controls from Belfast, Northern Ireland, were 0.31 and 0.30 (P=0.79), respectively; the corresponding frequencies in cases and controls from France were 0.33 and 0.31 (P=0.30), respectively. In the PEGASE study, the 825T allele frequency was 0.35 in female and male cases and 0.31 in male normotensive controls (P=0.12). The odds ratios for hypertension (PEGASE) and MI (ECTIM) associated with T-allele carrying were 1.23 (95% confidence interval, 0.94 to 1.62; P=0.13) and 1.11 (95% confidence interval, 0.88 to 1.39; P=0.37), respectively. There was no association of the GNB3 polymorphism with early onset of hypertension, familial history of hypertension, or blood pressure level. We conclude that the 825C/T polymorphism of the GNB3 gene did not contribute in any important way to the risk of essential hypertension or MI in these studies.

Adult↗
PubMed1999

A comparison of lifestyle, genetic, bioclinical and biochemical variables of offspring with and without family histories of premature coronary heart disease: the experience of the European Atherosclerosis Research Studies.

BACKGROUND: Lifestyle, genetic, bioclinical and biochemical factors of European university students aged 18-26 years, with and without documented paternal histories of premature coronary heart disease, have been compared in the European Atherosclerosis Research Studies (EARS) I and II. OBJECTIVE: To highlight consistencies and inconsistencies between findings in the two studies. METHODS: All measurements were made according to strict protocols, by trained technicians using validated methods. The results for men in EARS I are compared with those from EARS II which was confined to men. RESULTS: In both studies we found no differences between cases and controls in lifestyle factors and bioclinical factors except that controls were taller. We found inconsistent differences between obesity indices and antecedents of arterial hypertension. In both studies we found consistent differences between cases and controls in levels of total cholesterol and apolipoprotein B, both levels being higher in cases. The lack of any difference between levels of high-density lipoprotein cholesterol and apolipoprotein A1 was also found consistently. Inconsistent differences were found for levels of triglycerides and apolipoprotein E. For most of the candidate genes that were studied, no differences between cases and controls were found, but different polymorphisms were associated with levels of lipids, apoproteins and fibrinogen independently of case-control status. Some of these associations were potentiated by lifestyle factors. The interaction between genetic and environmental factors is further illustrated with results from the association of apolipoprotein E polymorphism with the level of apolipoprotein B and a variety of other determinants of apolipoprotein B level. CONCLUSIONS: In the EARS studies a documented family history of premature coronary heart disease was mainly expressed in terms of biochemical factors that are determined both by nature and by nurture.

Adolescent↗
PubMed1999

The factor V gene A4070G mutation and the risk of venous thrombosis.

The A4070G polymorphism in exon 13 of the factor V (FV) gene, which replaces His by Arg at position 1299 of the B domain, was recently shown to influence circulating FV levels and to contribute to the activated protein C (APC) resistance phenotype. We examined the impact of this polymorphism in a population of unselected patients with venous thromboembolic disease (VTE). The prevalence of the G4070 (R2) allele was determined in 205 patients and 394 healthy subjects of similar age and sex distribution. Thirty-seven patients (18%) were heterozygous for the R2 allele and 1 (0.5%) was homozygous. Forty-four controls (11.2%) were heterozygous for the R2 allele and 1 (0.2%) was homozygous. Thus, the allelic frequency was significantly higher in the patients with VTE than in the healthy controls, with respective values of 9.5% and 5.8%. The odds ratio was 1.8 (95% CI: 1.1-2.8, p = 0.02), pointing to an increased risk of VTE in carriers of the R2 allele. After excluding subjects with putative or confirmed gene defects (mainly the FV R506Q mutation), the R2 allele was still a risk factor for VTE in the remaining patients, with an odds ratio of 2.0 (95% CI: 1.2-3.5, p = 0.01), demonstrating that this polymorphism is itself a risk factor. This study also confirms that the R2 allele influences APC resistance (APCR) in the absence of the FV R506Q mutation.

Activated Protein C Resistance↗
PubMed1999

Venous thromboembolic disease and the prothrombin, methylene tetrahydrofolate reductase and factor V genes.

The prevalence of the A20210 allele of the prothrombin (PT) gene and the T677 allele of the methylene tetrahydrofolate reductase (MTHFR) gene was determined in 205 patients with venous thromboembolism (VTE) and in 398 healthy subjects of similar age and sex distribution. We also determined the frequency of these two candidate risk alleles in subjects carrying the factor V (FV) Q506 allele, to identify a possible interaction. Forty patients (19.5%) and 14 control subjects (3.5%) were heterozygous for the FV R506Q mutation. Twenty-one patients (10.2%) and 11 controls (2.8%) were heterozygous for the PT A20210 allele (odds ratio (OR) 4.02, 95% confidence interval (CI): 1.90-8.50, p <0.001). This confirmed that the PT A20210 allele was a risk factor for VTE in our population. Among the FV Q506 allele carriers, 9 patients (22.5%) and no control also had the PT gene G20210A mutation. The absence of the combined abnormality in the control group made it impossible to calculate the relevant ORs but the lower bound of the 95% CI was 3.94, suggesting that individuals bearing the two mutations have a higher risk than those with a single mutation. Twenty-six patients (12.7%) and 49 controls (12.3%) were homozygous for the MTHFR T677 allele (OR 1.04, 95% CI: 0.62-1.72, not significant). Four patients and 1 control were also heterozygous for the FV R506Q mutation (OR 9.33, 95% CI: 1.03-84.23). However, the ORs for carriers of the FV R506Q mutation were not significantly influenced by MTHFR gene C677T homozygosity.

Alleles↗
PubMed1999

Effect of variation in the apo A-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II. EARS Group.

The aims of the study were to investigate associations of the apolipoprotein (apo) A-IV polymorphisms Thr347Ser and Gln360His with anthropomorphic measurements and fasting and postprandial lipids in subjects participating in the European Atherosclerosis Research Study II (EARS II). The allelic frequencies of Ser347 and His360 were 0.185 and 0.067, respectively, in the sample as a whole. There were no significant differences in rare allele frequency between cases (offspring of fathers who suffered a myocardial infarction before the age of 55 years) and controls. Control subjects who were carriers of Ser347 had significantly higher body mass indices (BMIs), waist:hip ratios, total and low density lipoprotein cholesterol and triacylglycerol (TG) concentrations (all P < or = 0.02) than control subjects who were non-carriers, but these effects were not seen in the cases. Control subjects who were carriers of His360 had lower BMIs (P = 0.04), cholesterol and TG concentrations (both P < or = 0.07) compared to non-carriers, but these effects were not seen in the cases. After consumption of an oral fat load, carriers of His360 who were most obese (subjects in the third tertile of BMI) had significantly reduced postprandial lipemia (P < 0.03, as assessed by area under the curve).-Fisher, R. M., H. Burke, V. Nicaud, C. Ehnholm, and S. E. Humphries. Effect of variation in the apoA-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II.

Adolescent↗
PubMed1998

C677T (thermolabile alanine/valine) polymorphism in methylenetetrahydrofolate reductase (MTHFR): its frequency and impact on plasma homocysteine concentration in different European populations. EARS group.

A common polymorphism has been described in the methylenetetrahydrofolate reductase (MTHFR) gene, substituting an alanine (A) for a valine (V), where the V allele results in a thermolabile enzyme with reduced activity. This polymorphism is easily detectable by PCR amplification and digestion with HinfI restriction enzyme. We describe the use of the MADGE high throughput genotyping system for rapid typing of this polymorphism. Seven hundred and eighty five individuals participating in the European Atherosclerosis Research Study II (EARS II), aged 22-25 from 14 universities in 12 countries across Europe were genotyped for this polymorphism. The frequency of the V allele was 0.32 overall (95% CI; 0.30-0.35), but was significantly lower in the Baltic countries (0.23; 95% CI; 0.19-0.28) compared with the other regions of Europe (0.37; 95% CI; 0.32-0.38) (P < 0.001). Individuals homozygous for the V allele had statistically significant (P < 0.001) higher plasma homocysteine (16.5 micromol/l) compared with those heterozygous for an A allele (10.4 micromol/l) or homozygous for an A allele (10.0 micromol/l). This effect was seen in all countries and regions of Europe. Mean plasma homocysteine levels were significantly higher in the South compared to the Baltic, UK and Middle regions (P = 0.001), but this difference was not explained by the difference in the frequency of the V allele in the samples. This polymorphism explained 12.3% of the total sample variance in plasma homocysteine, other measured factors (smoking, alcohol consumption, systolic blood pressure, physical activity) explained 0.7%. This study demonstrates the large and consistent impact of the thermolabile MTHFR variant on plasma homocysteine levels in different European populations, and shows a regional difference in the levels of homocysteine that must be explained by other genetic or environmental factors.

Adolescent↗
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

Linkage disequilibrium at the cystathionine beta synthase (CBS) locus and the association between genetic variation at the CBS locus and plasma levels of homocysteine. The Ears II Group. European Atherosclerosis Research Study.

Cystathionine beta synthase (CBS) is a key enzyme in homocysteine metabolism. We have examined four apparently non-functional polymorphisms in the CBS gene and have determined their frequency, degree of linkage disequilibrium and association with plasma homocysteine levels. The polymorphisms are a 68 bp insertion in exon 8, C699T in exon 8, C1080T in exon 11 and C1985T in the 3' untranslated region. 785 individuals participating in the European Atherosclerosis Research Study II (EARSII), from 11 countries across Europe were genotyped for these polymorphisms. The 68bp insertion had the highest frequency in the UK and in the Middle region, with a lower frequency in the Baltic and the South (p = 0.01), and the exon 11 polymorphism had the highest frequencies of the rare allele in the Baltic (p < 0.05). There was a high degree of linkage disequilibrium between the polymorphisms (p < 0.001 overall), except between C699T and the C1985T, with three common haplotypes accounting for nearly 80% of chromosomes. Examination of the association between these polymorphisms and plasma homocysteine levels revealed that the carriers of the rare alleles of the C699T, C1080T and C1985T polymorphisms had lower plasma homocysteine concentrations than those homozygous for the common alleles, although these differences were not statistically significant. The thermolabile valine variant caused by a substitution of a C for a T at nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) has previously been shown to have profound effects on plasma levels of homocysteine in this sample, but the homocysteine-raising effect associated with this thermolabile variant was not seen in carriers of the 68 bp insertion, with this interaction being statistically significant (p < 0.001). These data demonstrate that variation in the CBS gene as detected with these four polymorphisms, had no statistically significant effect on plasma homocysteine levels in these healthy young men. However, the presence of the 68 bp insertion, which is found in approximately 7.5% of individuals in the populations of Europe sampled, abolishes the raising effect of thermolabile MTHFR Val/Val genotype, and may be of importance in the situation of high homocysteine.

Alleles↗
PubMed1998

The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction.

P-selectin is an adhesion molecule, expressed at the surface of activated cells, that mediates the interaction of activated endothelial cells or platelets with leukocytes. P-selectin expression is increased in atherosclerotic plaques, and high plasma levels of this molecule have been observed in patients with unstable angina. We investigated the P-selectin gene as a possible candidate for myocardial infarction (MI). The P-selectin gene is situated on chromosome 1q21-q24, spans >50 kb and contains 17 exons. The sequences of the 5'-flanking region and exons of 40 alleles from patients with MI were screened for polymorphisms using polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) and sequencing. Thirteen polymorphisms were identified: five in the 5'-flanking and eight in the exonic sequences. Four polymorphisms (Ser290Asn, Asn562Asp, Leu599Val and Thr715Pro) predicted a change in the amino acid sequence of the P-selectin protein. All P-selectin polymorphisms as well as a common E-selectin polymorphism, Ser128Arg which has been reported as being associated with an increased risk of premature coronary heart disease (CHD), and is in tight linkage disequilibrium with several P-selectin polymorphisms, were investigated in 647 patients with MI and 758 control subjects from four regions of France and Northern Ireland (the ECTIM study). The entire set of P-selectin polymorphisms provided a heterozygosity of 91%. The polymorphisms were tightly associated with one another and displayed patterns of linkage disequilibrium suggesting the existence of highly conserved ancestral haplotypes. The five polymorphisms in the 5'-flanking region of the gene were unrelated to MI or any relevant phenotype measured in the ECTIM study. We inferred that the four missense variants identified in the coding region predicted eight common forms of the P-selectin protein. The Pro715 allele which characterizes one of these forms was less frequent in France than in Northern Ireland ( P < 0.002) and in cases than in controls ( P < 0.002; P < 0.02 after correction for the number of tests). We conclude that the P-selectin gene is highly polymorphic and hypothesize that the Pro715 variant may be protective for MI. Whether this variant affects the properties of the P-selectin protein in a way which is compatible with this hypothesis needs to be checked experimentally.

Adult↗
PubMed1998

Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS).

The H-allele of the intron 8 HindIII polymorphism in the lipoprotein lipase (LPL) gene has been associated with a lower risk of myocardial infarction (MI) and plasma levels of triglycerides (TG). To test whether the HindIII site was in linkage disequilibrium with the functional variant LPL Serine447Stop (S447X), subjects from the European Atherosclerosis Research Study (EARS I) were genotyped for both polymorphic sites. This study included 515 offspring of fathers with a premature (<55 years old) MI, who were designated cases, and 930 age- and sex-matched control subjects from five different regions of Europe. Linkage disequilibrium between the two sites was very strong (>.99), with only three of the four possible haplotypes identified: H+S447, H-S447, and H-X447. The frequency of the H-X447 but not of the H-S447 haplotype was significantly lower in cases than in control subjects (.090 versus .117, P<.01) suggesting a protective effect for MI, with this difference being consistent in all five regions of Europe. Compared with individuals homozygous for the H+S447 haplotype, the odds ratio of having a paternal history of premature MI for H-X447 heterozygotes (approximately 20% of the population) was 0.71 (95% confidence interval, 0.55 to 0.92). In addition, there was an increase of the H-X447 haplotype frequency from north to south in control subjects (0.119 in Finland to 0.143 in the Mediterranean region, P<.01). Compared with the H+S447 haplotype, the H-X447 haplotype was associated with significantly lower concentrations of plasma TGs (5.4% lower, P=.01), with this effect being consistent over the regions of Europe. There was no significant evidence for a heterogeneity of effect between males and females or between cases and control subjects, although the effect on TG levels appeared to be the greatest in male cases (11% lower, P=.05). In a second study (EARS II), of 332 cases and 342 control subjects, postprandial clearance of TGs after a standard fat meal was examined. The H-X447 haplotype was associated with significantly lower postprandial triglyceride levels than was the H+S447 haplotype (9.4% smaller area under the curve, P<.05). Thus, the effects on MI risk and plasma lipids associated with the H allele appeared to be mainly mediated by the X447 mutation, and although the lowering effects associated with the H-X447 haplotype on fasting and postprandial TGs are not large, they are consistent with the lowering effect observed on MI risk throughout Europe.

Adolescent↗
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

Lipoprotein lipase variants D9N and N291S are associated with increased plasma triglyceride and lower high-density lipoprotein cholesterol concentrations: studies in the fasting and postprandial states: the European Atherosclerosis Research Studies.

BACKGROUND: Variations at the DNA level with moderate effects on biochemical variables may be important for the occurrence of disease at the population level, if they are common. Two mutations in the LPL gene, N9 and S291, are associated with variation in fasting plasma concentrations of HDL cholesterol (HDL-C) and triglycerides (TG). We investigated whether these mutants were more frequent in offspring of cases with premature coronary disease and analyzed the effects on fasting plasma lipids and postprandial TG. METHODS AND RESULTS: Students with and without paternal history of myocardial infarction (cases and control subjects [controls]) were studied in the European Atherosclerosis Research Studies I and II (EARS-I and -II). Allelic frequencies for the N9 and S291 mutations did not differ between cases and control subjects. The N9 mutation was identified in 4.2% of all subjects in EARS-I, and carriers had higher fasting TG levels (P<.001) than noncarriers. In an oral fat tolerance test, there were no differences in postprandial TG between carriers and noncarriers of the N9 allele. The S291 mutation was identified in 3.1% of all subjects in EARS-I, and carriers had lower fasting HDL-C levels (P<.005) than noncarriers. There was a significant interaction between S291 genotype and body mass index on fasting TG levels (P<.01). In the cases, carriers of the S291 allele had higher TG levels 6 hours postprandially (P<.04) than did noncarriers. CONCLUSIONS: The two LPL mutations are common and may predispose to elevated TG and decreased HDL-C concentrations, even in young subjects. In the case of the S291 mutation, this effect appears to be mediated via delayed postprandial TG clearance. Moreover, even moderate obesity potentiates the TG-raising and HDL-lowering effects associated with the S291 allele.

Adolescent↗