Biomedical subjects

Daniel Gaudet

Publications and source records attributed to Daniel Gaudet.

At least 37 records · Page 2Linked to original sources

PubMed2005

Association of common variation in the HNF1alpha gene region with risk of type 2 diabetes.

It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1alpha with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in >4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.

Case-Control Studies↗

PubMed2005

Genetic aspects of diabetes and its cardiovascular complications: contribution of genetics to risk assessment and clinical management.

Diabetes mellitus is a source of great concern in contemporary cardiology. It is a heterogeneous disease and patients are often characterized by features of the insulin resistance syndrome, also referred to as the metabolic syndrome. The objectives of the present review were to discuss some genes that potentially modulate the risk of coronary artery disease in diabetes mellitus; to address how the genes' respective contributions could possibly influence the global risk assessment of coronary artery disease among diabetic patients; and to present simple clinical markers, such as plasma glycerol concentration and the 'hypertriglyceridemic waist' phenotype, that could help to identify high-risk individuals.

Albuminuria↗

PubMed2005

Statin therapy in Canadian patients with hypercholesterolemia: the Canadian Lipid Study -- Observational (CALIPSO).

BACKGROUND: Although statins are widely used to reduce low density lipoprotein cholesterol (LDL-C), there is little information about patient profiles, treatment patterns and goal achievement among statin-treated patients in Canada. OBJECTIVES: To assess the profile of statin-treated patients and to determine whether they are achieving recommended targets for LDL-C. METHODS: The Canadian Lipid Study -- Observational (CALIPSO) was a cross-sectional study involving Canadian physicians who were among the top statin prescribers. Each physician enrolled up to 15 patients who were at least 18 years of age with a diagnosis of hyper-cholesterolemia and who had been using a statin for at least eight weeks. Sociodemographics, coronary artery disease (CAD) risk factors, pretreatment and current lipid levels, and history of lipid-lowering therapy were reported for 3721 patients. RESULTS: Sixty-eight per cent of statin-treated patients were at high CAD risk according to the 2003 Canadian guidelines, 46.4% had established cardiovascular disease, 33.9% had diabetes and 59.5% had hypertension. Average LDL-C reductions of 32% (37% for high-risk patients) were initially required to reach goal. At the study visit, patients had been treated for an average of 4.3 years and 24.2% were using a high statin dose. Despite statin therapy, 27.2% of all patients and 36.4% of those at high CAD risk had not achieved LDL-C targets. For 67.4% of these patients, the current therapy was not modified at the study visit. CONCLUSIONS: Despite effective therapies, many treated patients are not achieving recommended LDL-C targets. Strategies should be implemented to promote achievement of lipid treatment goals for high-risk patients, thereby reducing the risk of cardiovascular events and their associated clinical and economic burdens.

Aged↗

PubMed2004

Impact of adiponectin gene polymorphisms on plasma lipoprotein and adiponectin concentrations of viscerally obese men.

The aim of this study was first to examine the relationships between adiponectin gene (Apm1) polymorphisms and anthropometric indices as well as plasma adiponectin and lipoprotein/lipid levels, and then to investigate whether the presence of visceral obesity or insulin resistance may modulate the impact of these polymorphisms on metabolic risk variables. Molecular screening of the Apm1 gene was achieved, and a sample of 270 unrelated men recruited from the greater Quebec City area and selected to cover a wide range of body fatness values was genotyped. Sequencing of the Apm1 gene revealed two previously reported polymorphisms (c.45T>G and c.276G>T) as well as two newly identified genetic variations (-13752delT and -13702G>C). Carriers of the c.276T allele had higher LDL-cholesterol and lower HDL-triglyceride concentrations than did 276G/G homozygotes (P=0.02 and P=0.01, respectively). Carriers of the c.45G allele exhibited higher plasma adiponectin concentrations than did 45T/T homozygotes (P=0.04). After dividing each genotype group into subgroups for visceral AT, homozygotes for the normal allele at position -13752delT, carriers of the c.45G allele, and carriers of the c.276T allele had similar total apolipoprotein B (apoB) concentrations, whether they were viscerally obese or not. These results suggest that some Apm1 gene polymorphisms influence plasma adiponectin concentrations and lipoprotein/lipid levels. In addition, the impact of these polymorphisms is modulated by the presence of visceral obesity.

Adiponectin↗

PubMed2004

Molecular screening of the microsomal triglyceride transfer protein: association between polymorphisms and both abdominal obesity and plasma apolipoprotein B concentration.

Microsomal triglyceride transfer protein (MTP) plays a critical role in the assembly of lipoproteins. The aim of this study was first to seek new MTP gene variants and then to verify whether MTP gene polymorphisms were associated with plasma lipoprotein/lipid levels in men with visceral obesity. Molecular screening of the MTP gene revealed 11 polymorphisms. The carriers of the c.933A allele and c.1151C allele or -400A/A homozygotes were characterized by increased levels of abdominal visceral adipose tissue (AT) measured by computed tomography (P=0.02, P=0.04, P=0.03, respectively). After dividing each genotype group into subgroups using 130 cm(2) as a cutoff point for visceral AT, significantly higher low-density lipoprotein (LDL)-apolipoprotein B (apoB) concentrations were found in obese men bearing the c.891G allele, the -400 T allele, as well as for 282G/G homozygotes, 933C/C homozygotes, and 1151A/A homozygotes when compared to their lean counterparts. Haplotypes were not associated with phenotypes under study. In conclusion, some MTP gene polymorphisms in the French Canadian population are associated with the amount of abdominal visceral AT and plasma LDL-apoB concentrations.

Adipose Tissue↗

PubMed2004

Association between the PPARalpha-L162V polymorphism and components of the metabolic syndrome.

Genetic factors, alone or in interaction with components of the diet, are thought to be involved in the development of the metabolic syndrome. The objective of our study was first to compare the frequency of the peroxisome proliferator-activated receptor (PPAR)alpha-L162V polymorphism in a sample of men with and without the metabolic syndrome as defined by the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) guidelines, and secondly, to evaluate gene-diet interaction effects on features of the metabolic syndrome. The PPARalpha-L162V genotype was determined in a sample of 632 men by a polymerase chain reaction-restriction length polymorphism (PCR-RFLP)-based method; fat as well as saturated fat intakes were evaluated by a dietitian-administered food frequency questionnaire. The frequency of the V162 allele was similar in men with ( n=281) and without ( n=351) the metabolic syndrome ( chi(2)=0.03, p=0.84) but was higher in subjects having simultaneously abdominal obesity, hypertriglyceridemia, and low high-density lipoprotein cholesterol (HDL-C) levels ( chi(2)=3.73, p=0.05). Carriers of the V162 were characterized by higher plasma apolipoprotein B and triglyceride (TG) levels ( p=0.10, p=0.004). In a model including the PPARalpha-L162V polymorphism, fat or saturated fat, its interaction, and covariates (smoking habits, and energy and alcohol intake), the interaction explained a significant percentage of the variance observed in waist circumference ( p<0.05). In conclusion, the PPARalpha-L162V polymorphism alone or in interaction with dietary fat intake is associated with components of the metabolic syndrome.

Adult↗

PubMed2004

Effect of liver fatty acid binding protein (FABP) T94A missense mutation on plasma lipoprotein responsiveness to treatment with fenofibrate.

Fenofibrate, a peroxisome proliferated activated receptor alpha (PPARalpha) agonist, has been shown to decrease plasma triglyceride (TG) and increase plasma high-density lipoprotein (HDL) cholesterol levels despite a large interindividual variation in the response. Fenofibrate-activated PPARalpha binds to a DNA sequence element termed PPAR response element (PPRE) present in regulatory regions of target genes. A PPRE has been identified in the proximal 5' flanking region of the gene encoding the liver fatty acid binding protein (LFABP). LFABP is a small cytosolic protein of 14 kDa present in the liver and the intestine and is a member of the superfamily of the fatty acid binding proteins (FABPs). FABPs play a role in the solubilization of long-chain fatty acids (LCFAs) and their CoA-ester to various intracellular organelles. FABPs serves as intracellular acceptors of LCFAs, and they may also have an impact in ligand-dependent transactivation of PPARs in trafficking LCFAs to the nucleus. Since PPARs are known to regulate the transcription of many genes involved in lipid metabolism, the importance of LFABP in fatty acid uptake has to be considered. The aim of this study was to verify whether genetic variations in the LFABP gene may impact on plasma lipoprotein/lipid levels in the fasting state as well as on the response to a lipid-lowering therapy with fenofibrate on plasma lipids and obesity variables. We also wanted to verify whether the presence of the PPARalpha L162V mutation interacts with genetic variants in LFABP gene. To achieve this goal, we first determined the genomic structure of the human LFABP gene and then designed intronic primers to sequence the coding regions, all exon-intron splicing boundaries, and the promoter region of the gene in 24 patients showing divergent plasma lipoprotein/lipid response to fenofibrate. Sequence analysis revealed the presence of a T94A missense mutation in exon 3. Interspecies comparison revealed that threonine 94 is conserved among species. We subsequently screened another sample of 130 French Canadian subjects treated with fenofibrate for the presence of the LFABP T94A mutation. Carriers of the A94 allele were at increased risk to exhibit plasma TG levels above 2.00 mmol/l after treatment with fenofibrate [2.75 (1.03-7.34); OR 95% confidence interval (CI)]. In addition, carriers of the A94 allele were characterized by higher baseline plasma-free fatty acid levels (FFA) ( p=0.01) and by a lower body mass index (BMI) ( p=0.05) and waist circumference ( p=0.005) than T94 homozygotes. Moreover, PPARalpha L162V and LFABP T94A showed to have a synergistic effect on BMI ( p interaction = 0.03). These results suggest that the LFABP T94A missense mutation could influence obesity indices as well as the risk to exhibit residual hypertriglyceridmia following a lipid-lowering therapy with fenofibrate.

Adult↗

PubMed2004

Relationship between cholesteryl ester transfer protein and LDL heterogeneity in familial hypercholesterolemia.

Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 +/- 4.8 vs. 259.2 +/- 4.1 A; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = -0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations. These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis.

Adolescent↗

PubMed2004

The c.419-420insA in the MTP gene is associated with abetalipoproteinemia among French-Canadians.

Abetalipoproteinemia (ABL) is a rare autosomal recessive disease characterised by the absence of apolipoprotein B (apoB) containing lipoproteins and, in consequence, very low triglyceride and cholesterol levels. Microsomal triglyceride transfer protein (MTP) has been associated with ABL. A search for sequence variants in the large subunit of MTP in a kindred of 10 individuals from Saguenay-Lac-St Jean area with a propositus exhibiting ABL as well as in four independent patients from the greater Quebec city area and exhibiting very low apoB and LDL-cholesterol levels identified 12 variations. Only one sequence variation, the c.419-420insA, was observed, in the homozygous form, in the abetalipoproteinemic patient. The -493G/-400A/-164T/282G/383T/419-420insA/453T/891C/969T/1151A/2884G haplotype carries the insertion and was found in all members of the family studied. In conclusion, the present study showed that the c.419-420insA alone, in the homozygous form, is a cause of classical recessive inherited ABL in the French-Canadian population.

Abetalipoproteinemia↗

PubMed2004

Diet-induced obesity delays cardiovascular recovery from stress in spontaneously hypertensive rats.

OBJECTIVE: Blood pressure (BP) and heart rate (HR) responses to stress are significant predictors of cardiovascular morbidity and mortality. Because obesity is a major risk factor for cardiovascular disease, we examined whether diet-induced obesity alters the BP and HR responses to stress and whether these alterations are associated with augmented cardiovascular morbidity in the rat. RESEARCH METHODS AND PROCEDURES: Adult male spontaneously hypertensive rats were fed either a normal diet or high-fat diet (HFD) for 12 weeks. At weeks 0 and 12, body weight was measured, and BP and HR were recorded by radiotelemetry throughout three consecutive day and night periods and in response to 30-minute immobilization stress. At the end of the 12-week intervention, the rats were sacrificed, and their organs and sera were collected. RESULTS: With the intervention, HFD rats showed a significantly greater increase in body weight (as expected) and circulating leptin and free fatty acid levels compared with normal diet rats. In addition, they showed similar increases in BP and HR elevations during stress but significantly slower BP and HR decreases after stress. These HFD-induced delays in stress recovery were associated with BP and HR elevations during the night (behaviorally active) period and with augmentations in cardiac mass. DISCUSSION: The results of this study indicate that, in spontaneously hypertensive rats, dietary obesity delays cardiovascular recovery from stress, and, in parallel, it promotes the development of nocturnal hypertension as well as cardiac hypertrophy. This suggests that dietary obesity may significantly potentiate the impact of daily stressful experiences on the cardiovascular system.

Animals↗

PubMed2004

Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes.

The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P < 0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.

Amino Acid Substitution↗

PubMed2004

Haplotype structure and genotype-phenotype correlations of the sulfonylurea receptor and the islet ATP-sensitive potassium channel gene region.

The genes for the sulfonylurea receptor (SUR1; encoded by ABCC8) and its associated islet ATP-sensitive potassium channel (Kir6.2; encoded by KCNJ11) are adjacent to one another on human chromosome 11. Multiple studies have reported association of the E23K variant of Kir6.2 with risk of type 2 diabetes. Whether and how E23K itself-or other variant(s) in either of these two closely linked genes-influences type 2 diabetes remains to be fully determined. To better understand genotype-phenotype correlation at this important candidate gene locus, we 1) characterized haplotype structures across the gene region by typing 77 working, high-frequency markers spanning 207 kb and both genes; 2) performed association studies of E23K and nearby markers in >3,400 patients (type 2 diabetes and control) not previously reported in the literature; and 3) analyzed the resulting data for measures of insulin secretion. These data independently replicate the association of E23K with type 2 diabetes with an odds ratio (OR) in the new data of 1.17 (P = 0.003) as compared with an OR of 1.14 provided by meta-analysis of previously published, nonoverlapping data (P = 0.0002). We find that the E23K variant in Kir6.2 demonstrates very strong allelic association with a coding variant (A1369S) in the neighboring SUR1 gene (r(2) > 0.9) across a range of population samples, making it difficult to distinguish which gene and polymorphism in this region are most likely responsible for the reported association. We show that E23K is also associated with decreased insulin secretion in glucose-tolerant control subjects, supporting a mechanism whereby beta-cell dysfunction contributes to the common form of type 2 diabetes. Like peroxisome proliferator-activated receptor gamma, the SUR1/Kir6.2 gene region both contributes to the inherited risk of type 2 diabetes and encodes proteins that are targets for hypoglycemic medications, providing an intriguing link between the underlying mechanism of disease and validated targets for pharmacological treatment.

ATP-Binding Cassette Transporters↗

PubMed2003

Segment of rat chromosome 20 regulates diet-induced augmentations in adiposity, glucose intolerance, and blood pressure.

Previous linkage and association studies have suggested that a region of human chromosome 6 containing the tumor necrosis factor (TNF)-alpha gene is involved in the pathogenesis of obesity and obesity-associated hypertension. The aim of the present investigation was to establish whether a segment of rat chromosome 20 (RNO20), which also contains the TNF-alpha gene, determines diet-induced changes in adiposity and blood pressure (BP). The results showed that a transfer of the RNO20 segment from the normotensive Brown Norway (BN) rat onto the background of the spontaneously hypertensive rat (SHR) is associated with a significantly greater increase in adiposity, glucose intolerance, circulating leptin levels, and BP during 12-week, high-fat-diet feeding. In contrast, the transfer is not associated with significant changes in these variables during 12-week, normal-diet feeding. In addition, sequencing of the TNF-alpha gene revealed differences between SHR and BN in the 5'- and 3'-regulatory regions of the gene. Subsequent analyses of TNF-alpha gene expression in fat, muscle, and liver, however, did not provide support for the functional involvement of these differences. In summary, the investigated RNO20 segment contains 1 or more gene variants that affect adiposity, glucose tolerance, serum leptin levels, and BP, but only when the animals are exposed to a particular environment, ie, high-fat-diet feeding. Further studies are needed to identify genes mediating these effects. Considering current changes in our lifestyle involving an increased calorie and fat intake, we believe that gene-environment interactions, such as those described here, play an important role in the current epidemic of obesity and obesity-associated hypertension.

Adipose Tissue↗

PubMed2003

Visceral obesity attenuates the effect of the hepatic lipase -514C>T polymorphism on plasma HDL-cholesterol levels in French-Canadian men.

UNLABELLED: The dyslipidemic state of visceral obesity is characterized by increased plasma triglyceride (TG) levels, low HDL-cholesterol concentrations and alterations in LDL composition and concentration. A functional, non-coding -514C>T single nucleotide polymorphism (SNP) of the hepatic lipase gene (LIPC) has been related to variation in HDL-cholesterol concentrations. OBJECTIVES: To investigate the hypotheses that the LIPC -514C>T polymorphism may be associated with a deteriorated lipoprotein-lipid profile and that environmental factor, such as abdominal obesity, alters this association. METHODS: A total of 235 French-Canadian men from the greater Quebec City area were assigned into three groups on the basis of their LIPC -514C>T SNP, including 149 CC homozygotes, 75 CT heterozygotes, and 11 TT homozygotes. RESULTS: In the present study, the highest values of BMI, waist circumference, and accumulation of visceral adipose tissue (VAT) were observed among TT homozygotes (p<0.05). After adjustment for age and BMI, TT homozygotes still showed higher plasma apolipoprotein (apo) AI and HDL-TG concentrations than the two other groups (p<0.05). When the two genotype groups (CC vs CT/TT) were further divided on the basis of VAT accumulation using a cut-off point of 130 cm(2) (high vs low) it appears that irrespective of the genotype subjects with low VAT had higher HDL(2)-cholesterol concentrations (p<0.0001). However, lean carriers of the T allele had higher plasma HDL(2)-cholesterol levels than lean CC homozygotes. The beneficial effect of the T allele on plasma HDL(2)-cholesterol levels was abolished in the presence of visceral obesity (VAT>130 cm(2)). CONCLUSION: In summary, the presence of visceral obesity attenuates the impact of the LIPC -514C>T polymorphism on plasma HDL(2)-cholesterol levels.

Adult↗

PubMed2002

Contribution of abdominal obesity and hypertriglyceridemia to impaired fasting glucose and coronary artery disease.

Multiple logistic regression models were used in a cross-sectional study to determine the relation of fasting glycemia to angiographically assessed coronary artery disease (CAD) in 569 men (aged 18 to 69 years) who were stratified according to fasting blood glucose concentrations (<6.1 mmol/L, and 6.1 to 6.9 mmol/L or 110 to 124 mg/dl), waist circumference (<90 vs >or=90 cm), and fasting triglyceridemia (<2.0 vs >or=2.0 mmol/L or <177 vs >or=177 mg/dl). For this purpose, nondiabetic impaired fasting glucose was defined as from 6.1 to 6.9 mmol/L (110 to 124 mg/dl) compared with 250 normoglycemic controls (fasting glycemia <6.1 mmol/L or <124 mg/dl) without history of CAD. In the absence of "hypertriglyceridemic waist," impaired fasting glucose was not predictive of CAD. However, the risk of CAD was markedly higher among subjects characterized by both the hypertriglyceridemic waist phenotype and the presence of impaired fasting glucose (odds ratio 8.5, 95% confidence intervals 3.5 to 20.4; p <0.05) compared with the normoglycemic group with low waist circumferences and triglyceride levels. Thus, the results of the present study emphasizes the importance of other underlying metabolic abnormalities, such as abdominal obesity and related atherogenic dyslipidemia, in the modulation of the CAD risk associated with hyperglycemia.

Abdomen↗

PubMed2002

Characterization of LDL particle size among carriers of a defective or a null mutation in the lipoprotein lipase gene: the Québec LIPD Study.

OBJECTIVE: The objective of the present study was to compare the impact of the null P207L and defective D9N mutations in the LPL gene on LDL particle size among heterozygous carriers. METHODS AND RESULTS: LDL particle size was measured on whole plasma by 2% to 16% non-denaturing polyacrylamide gradient gel electrophoresis in a cohort of 206 heterozygous carriers of either the P207L or the D9N mutation. The P207L carriers (N=88) presented with a more atherogenic lipoprotein-lipid profile compared with the D9N carriers (N=118). Accordingly, LDL particle size was smaller in the P207L carriers than in the D9N subjects (248.8+/- 1.0 vs 254.5+/-1.0 A, P< 0.001), and the difference remained significant after adjustment for plasma triglyceride (TG) levels. The difference in LDL diameter between the P207L and the D9N carriers was 3-fold greater in individuals with plasma TG levels >3.5 mmol/L than in subjects with TG < or =3.5 mmol/L. The factors that statistically contributed to LDL particle size variation in multivariate analyses were plasma TG levels (11.6%) and age (6.4%) in subjects with TG levels < or =3.5 mmol/L and HDL cholesterol levels (15.5%) and the LPL gene mutation (null versus defective, 7.0%) in patients with TG levels >3.5 mmol/L. CONCLUSIONS: These results suggest that the null P207L mutation in the LPL gene has a greater impact on LDL particle size than the defective D9N mutation and that this mutation-specific effect is amplified at greater plasma TG concentrations.

Cohort Studies↗

PubMed2002

Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia.

BACKGROUND: Patients with homozygous familial hypercholesterolemia (HoFH) have a high incidence of cardiovascular morbidity and mortality from premature atherosclerosis, and the efficacy of pharmacological therapy has been limited. We evaluated the efficacy, safety, and tolerability of ezetimibe, a novel cholesterol absorption inhibitor, in a multicenter, double-blind, randomized trial of HoFH patients receiving atorvastatin or simvastatin. Methods and Results- Fifty patients with a diagnosis of HoFH on the National Cholesterol Education Program Step 1 or stricter diet and taking open-label atorvastatin 40 mg/d or simvastatin 40 mg/d (statin-40) with (n=25) or without (n=25) concomitant LDL apheresis were randomized to 1 of 3 double-blind treatments: atorvastatin or simvastatin 80 mg/d (statin-80, n=17); ezetimibe 10 mg/d plus atorvastatin or simvastatin 40 mg/d (n=16); or ezetimibe 10 mg/d plus atorvastatin or simvastatin 80 mg/d (n=17) for 12 weeks. The primary end point was mean percentage change in LDL cholesterol (LDL-C) from statin-40 baseline to the end point for patients receiving statins alone (statin-80) versus patients receiving ezetimibe plus atorvastatin or simvastatin at either dose (ezetimibe plus statin-40/80). Ezetimibe plus statin-40/80 significantly reduced LDL-C levels compared with statin-80 (-20.7% versus -6.7%, P=0.007). In the high-dose statin cohorts, ezetimibe plus statin-80 reduced LDL-C by an additional 20.5% (P=0.0001) versus statin-80. Similar significant reductions in LDL-C concentrations were observed for patients with genotype-confirmed HoFH (n=35). Ezetimibe was safe and well tolerated. CONCLUSIONS: Ezetimibe coadministered with atorvastatin or simvastatin in patients with HoFH produced clinically important LDL-C reductions compared with best current therapy. Ezetimibe provides a new, complementary pharmacological approach for this high-risk population.

Adolescent↗

PubMed2002

Visceral obesity and hyperinsulinemia modulate the impact of the microsomal triglyceride transfer protein -493G/T polymorphism on plasma lipoprotein levels in men.

The dyslipidemic state of visceral obesity is characterized by increased plasma triglyceride levels, low high-density lipoprotein-cholesterol concentration and alterations in low-density lipoprotein (LDL) composition and concentration. A functional, non-coding microsomal triglyceride transfer protein (MTP) -493G/T polymorphism of the microsomal triglyceride transfer protein gene has been related to variations in LDL-cholesterol levels. To study the effect of the MTP -493G/T polymorphism on lipoprotein levels in visceral obesity and hyperinsulinemia, a total of 227 men were assigned into two groups on the basis of their MTP -493G/T polymorphism, including 121 GG homozygotes and 105 carriers of the T allele (92 GT and 13 TT). The two genotypic groups did not differ for their physiological characteristics nor for lipoprotein--lipid profiles, before and after adjustment for age. However, GG homozygotes were characterized by higher fasting insulin levels than carriers of the T allele (P<0.05). When the two genotypic groups were further divided on the basis of their visceral adipose tissue (AT) accumulation, assessed by computed tomography, we observed that T allele carriers with low levels of visceral AT (<130 cm(2)) had decreased plasma total cholesterol and LDL-apolipoprotein B (LDL-apoB) levels compared to viscerally obese men (P=0.035 and P=0.0001, respectively). Among GG homozygotes, no significant difference were observed. Although not significant, T allele carriers characterized by visceral obesity tended to have smaller, denser LDL particles than T allele carriers characterized by a low accumulation of visceral AT. When subjects were divided on the basis of their fasting insulin levels, it appears that hyperinsulinemic men were characterized by a deteriorated lipoprotein--lipid profile when they were carriers of the T allele compared to normoinsulinemic men. In summary, visceral obesity and hyperinsulinemia modulate the impact of the MTP -493G/T polymorphism on plasma total cholesterol and LDL-apoB levels, as well as on LDL peak particle diameter.

Abdomen↗