Biomedical subjects

J Genest

Publications and source records attributed to J Genest.

At least 55 records · Page 3Linked to original sources

PubMed1998

Plasma acylation stimulating protein (ASP) as a predictor of impaired cellular biological response to ASP in patients with hyperapoB.

BACKGROUND: The objective of this study was to examine specific membrane binding of [125I]-acylation stimulating protein (ASP) in cultured human skin fibroblasts obtained from normal subjects and patients with hyperapoB. ASP is a small basic protein isolated from human plasma that stimulates triglyceride synthesis (TGS) and glucose transport (GT) in human skin fibroblasts and adipocytes. DESIGN: In the present study, three groups were studied: normal (NASP-NB) subjects, hyperapoB subjects with normal plasma ASP (NASP-HB) and hyperapoB subjects with high plasma ASP (HASP-HB). RESULTS: ASP-induced TGS in fibroblasts from HASP-HB subjects was significantly less than in the two control groups with normal plasma ASP (NASP-NB and NASP-HB). Similarly, ASP stimulation of GT was less in HASP-HB fibroblasts than in the NASP-HB fibroblasts or the NASP-NB subjects. Insulin-induced TGS was similar in all three groups as was insulin-stimulated GT. As well, protein kinase C-mediated stimulation was equivalent among the three groups both for GT and for TGS. There was no significant difference in the binding affinity (Kd) of [125I]-ASP to intact cells in any group. By contrast, binding of [125I]-ASP revealed a significantly lower Bmax of the HASP-HB cell lines than the NASP-NB cells and the NASP-HB cells. CONCLUSION: A decrease in the ASP cell-surface receptor concentration is responsible for decreased ASP stimulation of TGS, and GT and may contribute to the inefficient postprandial triglyceride (TG) clearance in HASP-HB subjects.

Adult↗

PubMed1998

Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I.

We have previously described patients with familial high density lipoprotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations of Tangier disease or evidence of other known causes of HDL deficiency. To determine whether FHD in these individuals was associated with impaired HDL production or increased HDL catabolism, we investigated the kinetics of plasma apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL) and four control subjects (apoA-I, 126+/-18 mg/dL, mean+/-SD) by using a primed constant infusion of deuterated leucine. Kinetic analysis of plasma apolipoprotein enrichment curves demonstrated that mature plasma apoA-I production rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5+/-1.7 mg x kg[-1] x d[-1]). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0.79 and 1.66 days) compared with controls (5.32+/-1.05 days). Essentially normal levels of plasma proapoA-I (the precursor protein of apoA-I) in FHD patients were associated with normal plasma proapoA-I PRs (7.8 and 10.4 versus 10.9+/-2.6 mg x kg[-1] x d[-1]) and proapoA-I RTs (0.18 and 0.15 versus 0.16+/-0.03 day). The RTs of apoA-II were, however, less in patients (3.17 and 2.92 days) than control subjects (7.24+/-0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7+/-0.2 mg x kg[-1] x d[-1]). Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I). These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier disease, by essentially normal plasma catabolism and concentration of proapoA-I.

Apolipoprotein A-I↗

PubMed1998

Rationale for and outline of the recommendations of the Working Group on Hypercholesterolemia and Other Dyslipidemias: interim report. Dyslipidemia Working Group of Health Canada.

A panel consisting of lipidologists, epidemiologists, cardiologists, internists, general practitioners, and public health and government representatives used the evidence-based approach to examine the rationale for a draft of recommendations for medical management of lipid disorders. The proposed recommendations deal with assessment of cardiovascular risk based on history, physical examination and laboratory findings; assessment of the fasting lipid profile; diagnosis and treatment of secondary risk factors; calculation of the 10-year risk of a cardiac event; initiation of lifestyle modifications in patients in whom low density lipoprotein cholesterol (LDL-C), total:high density lipoprotein cholesterol (HDL-C) ratio or triglycerides exceeds target values based on a patient's risk category; follow-up; treatment with drugs; and choices of drugs. In contrast to previous recommendations, there are new, considerably lower, cholesterol level targets for secondary prevention, with a less important emphasis on total cholesterol value than on LDL-C or total:HDL-C ratio and triglyceride levels, and an emphasis on determining the likelihood of a cardiac event by evaluating all relevant risk factors and sharpening the focus on nondrug treatment, which should result in treating a greater percentage of at-risk patients.

Anticholesteremic Agents↗

PubMed1998

Lipoprotein lipase gene mutations in coronary artery disease.

BACKGROUND: Genetic lipoprotein disorders are frequently associated with premature coronary artery disease (CAD). Functional mutations of the lipoprotein lipase (LPL) gene are associated with altered plasma lipoprotein profiles and are relatively common in French Canadians. OBJECTIVE: To investigate the prevalence of LPL gene mutations in a group of patients with premature CAD and in a healthy control group. METHODS: A total of 636 subjects (337 [82% men] with angiographically documented CAD and 299 controls [63% men]) were examined for the presence of mutations LPL(Gly188-->Glu), LPL(Pro207-->Leu), LPL(Asp250-->Asn) and LPL(Asn291-->Ser) of the LPL gene. These mutations represent over 97% of LPL mutations in familial hyperchylomicronemia in Quebec. RESULTS: The prevalence of heterozygosity for defective LPL alleles was eight of 337 (2.4%) in the CAD group and five of 299 (1.7%) in the control group (chi(2) = 0.118, P = 0.73; power [P] for alpha = 0.05, P = 0.60). In the six CAD patients heterozygous for LPL(Asn291-->Ser), fasting plasma lipoprotein lipid levels did not differ significantly from those of the rest of the CAD group or markedly from those of control subjects. The two CAD patients heterozygous for the LPL(Gly188-->Glu) mutation, however, had hypertriglyceridemia and low plasma high density lipoprotein levels. No CAD or control subjects were identified with the LPL(Pro207-->Leu) or LPL(Asp250-->Asn) alleles. CONCLUSIONS: In this selected population of premature CAD subjects, the prevalence of heterozygosity for defective LPL alleles was slightly higher (but not significantly so) than that in a group of healthy subjects. The LPL(Gly188-->Glu) and LPL(Asn291-->Ser) mutations may confer genetic susceptibility to premature CAD in a small number (approximately 2.4%) of patients; overall these four LPL alleles do not appear to contribute significantly to CAD risk in French Canadians.

Adult↗

PubMed1998

Angiotensin converting enzyme insertion/deletion polymorphism in French Canadian subjects with premature coronary artery disease.

The insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene has been postulated to be associated with CAD in some populations of European descent. As part of a study investigating metabolic and genetic factors in subjects with premature coronary artery disease (CAD), we examined the I/D polymorphism of the ACE gene in 134 subjects with premature CAD (105 men and 29 women, mean age 49 +/- 6 years) and 116 control subjects selected for health (71 men, 45 women; mean age 39 +/- 7 years). Both patients and controls were of French Canadian descent. As expected, significant differences were found between cases and controls with respect to age, plasma lipoprotein cholesterol, presence of smoking, diabetes and high blood pressure after correction for age. Multivariate analysis confirms the importance of age, HDL-C levels, smoking and apo B levels as determinants of CAD. Allele frequencies of the I and D polymorphism were 43.1% and 57.9% in controls, and 48.5% and 51.5% in CAD cases (chi 2 = 0.622, p = 0.430). No significant association between the I/D polymorphism and conventional cardiovascular risk factors, including plasma levels of lipids, lipoprotein cholesterol, diabetes or smoking, was found in cases or controls. Furthermore, the presence of the I/D polymorphism did not correlate with a history of hypertension or a family history of premature CAD in CAD patients. We conclude that, in our selected population, the I/D polymorphism of the ACE gene is not associated with CAD, conventional risk factors, or a family history of CAD. Although our sample size does not allow sufficient power to ascertain that the ACE I/D polymorphism is not associated with CAD, we do not recommend the routine measurement of the ACE polymorphism in our population to determine cardiovascular risk.

Adult↗

PubMed1998

Plasma triglyceride-rich lipoprotein and high density lipoproteins disorders associated with atherosclerosis.

The aforementioned epidemiological studies have played a central role in defining the importance of plasma lipoprotein disorders in the pathogenesis of atherosclerosis. More specifically, they have been instrumental in establishing plasma lipid and lipoprotein levels such as the plasma concentration of triglyceride, LDL, HDL, and Lp(a), as indicators of CAD risk. The challenge for future epidemiological studies will be to better define the link between CAD and a) the level of particular lipoprotein subfractions, b) factors affecting lipoprotein metabolism, and c) factors affecting the atherogenicity of plasma lipoproteins. For example, it is important to define which triglyceride-rich lipoprotein subfractions are most strongly associated with risk of CAD (e.g., intestinal vs hepatic TRL, large TRL vs smaller TRL remnants) or which subfractions of HDL are most protective (e.g., large vs small HDL, apoE-containing HDL vs apoAI- and All-containing HDL). The relationship between CAD and plasma levels of lipoprotein enzymes and co-factors (e.g., cholesterol ester transfer protein, LCAT), and also compounds that can potentially affect the oxidizability of lipoproteins (e.g., vitamins, paraoxanase) needs to be more clearly defined. Finally, future studies will need to focus not just on the relationship between plasma lipid disorders and atherosclerosis, but between plasma lipids and plaque stability and risk of thrombosis.

Arteriosclerosis↗

PubMed1997

Correlation of a common mutation in the methylenetetrahydrofolate reductase gene with plasma homocysteine in patients with premature coronary artery disease.

Mild hyperhomocysteinemia, a risk factor for occlusive arterial disease, can be caused by disruptions of homocysteine metabolism. Methylenetetrahydrofolate reductase (MTHFR) catalyzes the synthesis of 5-methyltetrahydrofolate, the methyl donor for homocysteine remethylation to methionine. A common mutation in MTHFR, an alanine-to-valine substitution, may contribute to mild hyperhomocysteinemia in coronary artery disease (CAD). To test this hypothesis, we studied 152 patients with CAD by mutation analysis, MTHFR enzymatic assays, and measurements of plasma homocysteine and several vitamins. The MTHFR mutation was associated with reduced enzymatic activity and increased enzyme thermo-lability in these patients. The difference in the prevalence of the homozygous mutant genotype between the CAD patients (14%) and an unmatched group of healthy subjects (10%) was not significant. However, individuals with the homozygous mutant genotype had higher plasma homocysteine, particularly when plasma folate was below the median value. This genetic-environmental interaction is proposed to be a risk factor for CAD.

Adult↗

PubMed1997

Metabolic factors clustering, lipoprotein cholesterol, apolipoprotein B, lipoprotein (a) and apolipoprotein E phenotypes in premature coronary artery disease in French Canadians.

Plasma lipoprotein cholesterol abnormalities, diabetes, hypertension and smoking have all been identified as independent predictors of cardiovascular events. Clustering of multiple risk factors suggests a common metabolic link among high blood pressure, insulin resistance, plasma lipoprotein abnormalities and obesity. New guidelines for the management of dyslipidemias target patients with established coronary artery disease (CAD), and high risk patients with multiple risk factors and severe genetic lipoprotein disorders, such as familial hypercholesterolemia. To determine the prevalence of lipoprotein, apolipoprotein and metabolic disorders in premature CAD, 243 men and 61 women with premature CAD (occurring before age 60 years) and 203 age- and sex-matched controls (152 men, 61 women) were studied. After correcting for beta-blocker use (40% of men and 54% of women), hypertension and diabetes were seen more frequently in CAD patients than in controls. In men and women, cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) were significantly higher, and high density lipoprotein (HDL) cholesterol was lower, in CAD patients than in controls. By stratifying patients according to LDL cholesterol: HDL cholesterol ratio (5 or less, or greater than 5) and by triglyceride levels (less than 2.3 mmol/L, or 2.3 mmol/L or greater), significantly more men and women with CAD were found to have an elevated LDL cholesterol:HDL cholesterol ratio and elevated triglycerides (13.8% versus 1.9%, men and women combined, CAD versus controls, P < 0.0001). A metabolic factor index was devised, assigning a score of 1 each for presence of hypertension, lipoprotein abnormalities, diabetes or fasting blood glucose above 7.0 mmol/L, and a body mass index of 27 or greater. The prevalence of a metabolic factor index of 3 or more was 29.2% in CAD men versus 6.7% in controls (P < 0.0001) and 38.3% in CAD women versus 11.7% in controls (P < 0.01). Familial hypercholesterolemia was seen in fewer than 5% of patients with premature CAD and type III dyslipoproteinemia in one of 343 CAD patients. The distribution of apolipoprotein E phenotypes was the same in CAD patients and controls. Multivariate analysis revealed that in men, HDL cholesterol, lipoprotein (a) levels and smoking were the best predictors of risk. In men, plasma levels of LDL cholesterol, triglycerides or body mass index did not enter the model at the P < 0.05 level. In women, low HDL cholesterol, lipoprotein (a), the presence of diabetes, smoking and apolipoprotein B levels were all predictors of risk (P < 0.05). However, the clustering of risk factors may be the best predictor of risk. In this selected population, HDL and lipoprotein (a) are the best metabolic markers of premature CAD; metabolic factor clustering is common in patients with premature CAD.

Adult↗

PubMed1997

Percutaneous transluminal angioplasty in coronary-internal thoracic-subclavian steal syndrome.

Internal thoracic artery implants are widely used as conduits in coronary artery bypass surgery because of their resistance to the development of atherosclerosis. Two cases are reported of subclavian artery stenosis proximal to the internal mammary artery in patients who had undergone coronary bypass surgery. In both cases, an atypical pattern of postsurgical angina developed, with retrosternal chest pain occurring specifically with upper extremities exercise. Coronary and graft angiography revealed retrograde flow in the left internal thoracic artery during injection of the grafted coronary. Severe stenosis was identified in the subclavian artery. Treatment consisted of dilation of the subclavian artery stenosis with stent placement in one patient. Both patients had marked symptomatic improvement after the procedure.

Angiography, Digital Subtraction↗

PubMed1997

Plasma acylation-stimulating protein in coronary artery disease.

To date, plasma levels of acylation-stimulating protein (ASP) have been determined only in normal and obese individuals. Accordingly. ASP was measured in fasting samples obtained from 59 age-matched controls and 208 patients with documented coronary artery disease (CAD). Overall, plasma ASP was significantly higher in the CAD subjects compared to the control subjects (55.3 +/- 1.8 nmol/L CAD versus 32.0 +/- 2.6 nmol/L control, P < .0005). In the control group, the distribution of plasma ASP values was unimodal whereas in the coronary group it was significantly skewed to the right. The coronary group was subdivided into those with pronounced elevation of apoB (a marked type II phenotype, n = 13), those with hypertriglyceridemia with a normal apoB (n = 17), and the remaining CAD subjects (n = 178). In the first two groups, ASP did not differ significantly from control subjects (43 +/- 2.8 nmol/L and 49 +/- 4.4 nmol/L respectively). By contrast, in the remaining CAD subjects, both the mean ASP level (56.8 +/- 2.0 nmol/L, P < .001 by ANOVA) and the proportion of patients with a markedly elevated ASP (25.3% were > 95th percentile, P < .005 versus control by X2) were significantly increased. When this third group was divided into tertiles by plasma apoB and triglyceride there was a direct relationship between plasma ASP and these two parameters. Linear regression analysis demonstrated an association between plasma ASP and plasma triglyceride (P < .05), VLDL cholesterol (P < .025), and VLDL apoB (P < .05). Finally, when all of the CAD subjects were divided by apoE phenotype, there appeared to be a relationship between plasma ASP and apoE phenotype such that ASP was higher in E2 subjects, intermediate in E3 subjects, and lower in E4 subjects. The present data document plasma ASP levels in a number of dyslipoproteinemic states and suggest a relation between the adipsin-ASP pathway and other metabolic determinants of lipoprotein metabolism.

Acylation↗

PubMed1996

Biomedical research in Quebec: the history of the Fonds de la recherche en santé du Québec.

The author describes the history of the Fonds de la recherche en santé du Québec, from after World War II to the present day. The Conseil de la recherche médicale du Québec (Quebec Medical Research Council) was created in 1964 to bring Quebec up to speed in biomedical research through programs that complemented those of the Medical Research Council of Canada. The council progressively evolved, becoming the Conseil de la recherche en santé du Québec (Quebec Health Research Council) in 1974 and the Fonds de la recherche en santé du Québec (FRSQ) in 1982. The FRSQ covers all aspects of medical research, in its broadest sense. Quebec's progress in biomedical research has been spectacular and has had direct and considerable influence on the quality of medical education and patient care. From 1982 to 1996, various Quebec governments have devoted more than +500 million to the FRSQ, a testimony to their comprehension of the importance of this area and to their farsightedness. The FRSQ and its predecessor organizations have been a major force in improving and maintaining the quality of medical teaching and care in Quebec during the last three decades.

Academies and Institutes↗

PubMed1996

Abnormal regulation of the LDL-R and HMG CoA reductase genes in subjects with familial hypercholesterolemia with the "French Canadian mutation".

Familial hypercholesterolemia (FH) is seen with high frequency in the province of Québec, Canada. A large deletion (> 10 kb) of the 5'-end of the low density lipoprotein receptor (LDL-R) gene is the major mutation of the LDL-R in FH subjects in Québec (approximately 60% of FH subjects). No mRNA is produced from the allele bearing the mutation, and cellular cholesterol obtained by receptor-mediated endocytosis is under the control of the non-deletion allele. We have previously reported that some patients with the 10-kb deletion (approximately 9%) fail to respond to the hydroxymethylglutaryl coenzyme A reductase (HMG CoA reductase) inhibitor class of medications. We studied mRNA levels of the LDL-R and HMG CoA reductase genes in response to the HMG CoA reductase inhibitor lovastatin in a time- and dose-dependent fashion in cultured human skin fibroblasts and we devised an in vitro model to study the response to drug therapy in subjects with FH. We determined mRNA levels by RNase protection assay in skin fibroblasts obtained from controls (n = 3) and FH subjects with the > 10-kb deletion (responders, n = 3; non responders, n = 3; to drug therapy). We measured 125I-LDL binding on skin fibroblasts grown in the presence of lipoprotein-deficient serum with or without 1 microM lovastatin, using 10 micrograms/mL of 125I-LDL protein. Control subjects exhibited coordinate regulation of the LDL-R and HMG CoA reductase genes in response to lovastatin, 0.1-25 microM, for 0-24 h. Correlation coefficients between mRNA levels of both genes were > 0.9 in controls and FH subjects. However, by linear regression analysis, the corresponding slopes for the correlation between both genes were 0.98 (controls), 3.36 and 3.63 (FH responders and non-responders), indicating a pattern of dissociated but still coordinate regulation in FH subjects. The magnitude of increase of mRNA levels of the LDL-R gene was approximately five-fold over LPDS in controls, two-fold in FH responders and two-fold in non-responders. Binding studies using 125I-LDL reveal that a control subject and all responders had a 2-2.5-fold increase in binding to cell surface receptors but two out of three FH non-responders showed no increase in binding in response to 1 microM lovastatin. The LDL-R and HMG CoA reductase genes are expressed in coordinate regulation in fibroblasts from subjects with FH due to the > 10-kb deletion, but with a proportionately greater up-regulation of the HMG CoA reductase gene. Some subjects, with FH caused by the > 10-kb deletion of the LDL-R gene, who fail to respond to HMG CoA reductase inhibitors have abnormal LDL receptor binding activity at the cell surface in response to lovastatin in vitro.

Anticholesteremic Agents↗

PubMed1996

Plasma total homocysteine in healthy subjects: sex-specific relation with biological traits.

Fasting plasma total homocysteine (tHcy) concentration was measured in 380 men and 204 women selected for health on the basis of clinical history, physical examination, and normal results of a biochemical profile. We sought to define tHcy reference values in healthy individuals and to determine relations between tHcy and plasma folic acid, vitamin B-12, and pyridoxal phosphate (vitamin B-6) concentrations. Men had significantly higher plasma tHcy than women (9.7 +/- 4.9 compared with 7.6 +/- 4.1 mumol/L, x +/- SD) and lower folate concentrations (8.6 +/- 5.2 compared with 9.8 +/- 6.6 nmol/L, P < 0.05). Significant correlations were found between tHcy and uric acid, creatinine, albumin, folate, and vitamin B-12 concentrations. There was no correlation with age, body mass index, blood pressure, glucose, and total and lipoprotein lipids. When divided in quartiles of vitamin concentrations, subjects with the lowest vitamin B-12 and folate values had significantly higher tHcy concentrations than those in the other three quartiles. Interestingly, after exclusion of subjects in the lowest quartiles of folate and vitamin B-12 concentration, correlations between tHcy and vitamin concentrations were no longer observed, except for vitamin B-12 in men. Stepwise-multiple-regression analyses showed that the sex-specific influence of biological variables on tHcy concentrations was twice as important in healthy women than in healthy men. This study emphasizes the significance of sex-associated differences in the biology of homocysteine and underlines the importance of considering these in the determination of threshold values.

Adult↗

PubMed1996

Plasma concentration of apolipoprotein E in intermediate-sized remnant-like lipoproteins in normolipidemic and hyperlipidemic subjects.

Triglyceride-rich lipoprotein (TRL) remnants have been strongly implicated in the pathogenesis of atherosclerosis. To further investigate plasma remnant lipoprotein metabolism, we have determined the plasma concentration of apolipoprotein (apo) E (by polyclonal enzyme-linked immunoassay) in remnant-like lipoproteins, isolated by automated gel filtration chromatography as a fraction intermediate in size between VLDL and HDL. In normolipidemic subjects (n = 12), 1.2 +/- 0.11 mg/dL (33 +/- 2%, mean +/- SE) of total plasma apoE was associated with this fraction (termed ISL apoE). In hypercholesterolemic (type IIa, n = 12), hypertriglyceridemic (type IV, n = 12), and mixed hyperlipidemic (type IIb, n = 12) subjects, mean ISL apoE concentrations were 2.1 +/- 0.2, 2.5 +/- 0.2, and 3.8 +/- 0.4 mg/dL, respectively (P < .001 versus normal values) (45 +/- 2%, 32 +/- 2%, and 44 +/- 2% of total). ISL apoE was 8.7 +/- 1.4 mg/dL (42 +/- 3%) in type III dyslipidemic subjects (apoE2/2, n = 8). ISL apoE was positively correlated with plasma triglyceride (r = .41, P < .01), and at any given level of plasma triglyceride, subjects with an apoE2/2 or apoE3/2 phenotype tended to have a higher concentration of ISL apoE (P < .01) than apoE3/3 or E4/3 individuals. ISL apoE was also correlated (P < .001) with total plasma cholesterol (r = .66), TRL cholesterol (r = .49), TRL apoE (r = .47), LDL apoB (r = .42), and LDL+HDL triglyceride (r = .74). These results suggest that (1) a significant proportion of plasma apoE resides within an intermediate-sized remnant-like lipoprotein fraction in both normolipidemic and hyperlipidemic subjects; (2) plasma remnant lipoprotein accumulation is associated with an elevation in ISL apoE concentration; and (3) ISL apoE concentration is significantly correlated with various proatherogenic lipid parameters and may itself be a potentially important atherogenic index.

Adult↗

PubMed1996

Lack of association of the apolipoprotein A-I-C-III-A-IV gene XmnI and SstI polymorphisms and of the lipoprotein lipase gene mutations in familial combined hyperlipoproteinemia in French Canadian subjects.

Familial combined hyperlipoproteinemia (FCH) is a common familial lipoprotein disorder characterized by elevated plasma cholesterol and triglyceride levels with segregation in first-degree relatives. Most affected subjects with FCH have elevated plasma levels of apolipoprotein (apo) B. The disorder results from oversecretion of hepatic apoB-containing lipoprotein particles. The genetic defect(s) are unknown. Previous work has suggested that genetic polymorphisms of the apoA-I gene and functional abnormalities of the lipoprotein lipase (LPL) gene are associated with FCH. We investigated the XmnI and SstI restriction fragment length polymorphisms (RFLP) of the apoA-I gene in FCH subjects of French Canadian descent. We also investigated three common functional mutations of the lipoprotein lipase (LPL) gene (LPLGly188Glu, LPLPro207Leu, and LPLAsp250Asn) in French Canadians that account for approximately 97% of cases of complete LPL deficiency in the province of Québec, Canada. We identified and characterized 54 FCH probands in lipid clinics and examined at least one first-degree relative. There were 37 men and 17 women (mean age 48 +/- 9 and 58 +/- 8 years, respectively). None of the probands had diabetes mellitus; mean plasma glucose was 5.5 mmol/L. High blood pressure was diagnosed in 32% of men and 29% of women. The body mass index (weight (kg)/height(m2)) was elevated in probands (27 +/- 4 for men and 26 +/- 4 for women). Mean plasma levels of cholesterol (C) was 7.6 +/- 1.5 mmol/L, triglycerides 3.5 +/- 1.6 mmol/L, LDL-C 4.9 +/- 1.2 mmol/L, HDL-C 1.0 +/- 0.3 mmol/L, and apoB 1.83 +/- 0.67 g/L in the probands. Allele frequency of the rare alleles of the XmnI and SstI RFLP was not significantly different from a healthy reference group. In several families studied, the XmnI and SstI RFLP did not unequivocally segregate with the FCH phenotype. There was no significant effect of the presence or absence of the XmnI or SstI RFLP's on plasma lipids, lipoprotein cholesterol or apoB levels. Only one FCH proband was found to have a mutation of the LPL gene (Gly188Glu), and this did not segregate with the FCH phenotype in the family. We conclude that in our highly selected group of FCH subjects of French Canadian descent, the XmnI and SstI RFLPs of the apoA-I gene and common functional mutations of the LPL gene resulting in complete LPL deficiency are not associated with FCH.

Adult↗

PubMed1995

Clustering of cardiovascular risk factors: targeting high-risk individuals.

Cardiovascular risk factors have traditionally been divided into 2 categories: modifiable risk factors (smoking, hypertension, elevated cholesterol, reduced high density lipoprotein cholesterol, and diabetes), and nonmodifiable risk factors (age, gender, and hereditary factors). However, more recent data indicate clustering of several metabolic and familial factors that are often related to each other. A pattern of lipoprotein abnormalities characterized by increased hepatic production of apolipoprotein B-containing lipoprotein particles, high blood pressure, visceral obesity, and peripheral insulin resistance are identified with increasing frequency in subjects with premature coronary artery disease (CAD). The metabolic substrates for many such disorders are being uncovered, and genetic analysis of affected kindred have, often with conflicting results, suggested associations with candidate genes. In the context of a multifactorial approach, aggressive treatment of lipoprotein disorders in high-risk individuals, or in the secondary prevention of cardiovascular diseases, has resulted in a decreased rate of progression of CAD and a marked reduction in clinical events. Further work in the field of hemostatic factors has shown that fibrinogen, activated coagulation factor VII, spontaneous platelet aggregation, and elevated levels of plasminogen activator inhibitor-1 (PAI-1), are all associated with CAD. There is a strong association between lipids (especially triglyceride-rich lipoproteins) and fibrinogen, PAI-1, and activation of factor VII. In addition, vascular function, especially endothelial cell physiology, has been shown to be compromised in the presence of multiple risk factors and to be improved with intensive therapy aimed at reducing risk factors, especially plasma lipoprotein levels. The implications for clinical practice are important. In the primary prevention of cardiovascular disease, proper risk stratification must be carried out with specific attention given to lifestyle changes. Cessation of smoking and changes in diet (both qualitative and quantitative), exercise, and serenity are often required. In the prevention of cardiovascular disease in subjects at high risk, or in the secondary prevention of CAD, a clear justification exists for aggressive lifestyle changes, often coupled with lipid-lowering therapy and adequate blood pressure control. Basic research is providing us with a better understanding of the molecular interactions between lipoproteins and hemostatic factors. It is becoming increasingly necessary to develop novel pharmaceutical agents with the combined ability to reduce atherogenic lipoprotein levels while also reducing susceptibility to thrombosis.

Adult↗

PubMed1995

Homocysteine and coronary artery disease in French Canadian subjects: relation with vitamins B12, B6, pyridoxal phosphate, and folate.

We determined plasma levels of homocysteine in 584 healthy subjects (380 men and 204 women) from a major utility company in the province of Québec, Canada, and in 150 subjects (123 men and 27 women) with angiographically documented coronary artery disease (CAD) (age < 60 years). Plasma levels of vitamins B12, B6, pyridoxal phosphate (a vitamin B6 derivative), and folate were also determined. Mean homocysteine levels were higher (p < 0.05) in the bottom quartiles for folate, vitamin B12, and pyridoxal phosphate. A significant correlation was noted between homocysteine levels and folate and vitamin B12 levels. No significant correlation was found between plasma homocysteine levels and age, lipids and lipoprotein cholesterol, glucose, and the presence of hypertension or cigarette smoking in healthy subjects or in patients with CAD. Control men had higher homocysteine levels than control women (p < 0.005). Men and women with CAD had higher levels of homocysteine than controls (11.7 +/- 5.8 vs 9.7 +/- 4.9 nmol/ml [p < 0.001] and 12.0 +/- 6.3 vs 7.6 +/- 4.1 nmol/ml, p < 0.01, respectively). Women and men with CAD had similar homocysteine levels. The proportion of patients with CAD having homocysteine levels > 90th percentile of controls was 18.1% for men and 44.4% for women (both p < 0.01). Significantly lower pyridoxal phosphate levels were seen in subjects with CAD, men and women combined (27.7 +/- 29.5 vs 42.1 +/- 38.4 ng/ml, p < 0.005). No significant differences were observed for B12, folate, or total B6.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Measurement of homocyst(e)ine in the prediction of arteriosclerosis.

Homocyst(e)ine [H(e)], the sum of homocysteine, homocystine, and the homocysteine-cysteine mixed disulfide, free and protein-bound, has been shown to be associated in retrospective case control studies, and in one prospective study, with vascular disease, including coronary artery disease (CAD), cerebrovascular disease, and peripheral vascular disease. Elevated levels of homocyst(e)ine severe enough to cause homocystinuria are seen in severe nutritional deficiencies of vitamin B12, folic acid and vitamin B6. Rare genetic disorders of vitamin B12 synthesis of 5'-10'-methylene tetrahydrofolate reductase, or the pyridoxal phosphate-dependent enzyme cystathionine beta-synthase may cause severe hyperhomocyst(e)inemia and homocystinuria. The clinical manifestation of these disorders are mental retardation, neurological disorders, and widespread thromboembolic phenomena. The measurement of H(e) is currently performed using high-pressure liquid chromatography with fluorescence detection. Other methods, especially mass spectroscopy, are also used. Internal standards using increasing concentrations of homocystine and acetylcysteine and several external standards are used to ensure accuracy of the assay. Milder elevations of H(e) have recently been associated with vascular disease, in both men and women. The strength of this association appears to be stronger for peripheral and cerebrovascular disease than for CAD. Nevertheless, several case control studies in Europe, Canada, and the United States have shown that H(e) levels are elevated in CAD patients compared with controls, and H(e) levels are independent of the conventional cardiovascular risk factors (age, gender, lipid and lipoprotein cholesterol levels, hypertension, or cigarette smoking). One prospective study, the Physicians' Health Study, has shown that H(e) levels are slightly but significantly higher in CAD cases vs controls in a population of US physicians.(ABSTRACT TRUNCATED AT 250 WORDS)

Arteriosclerosis↗