Hyperlipidemias: Genest J

McPherson R, Frohlich J, Fodor G, Genest J, Canadian Cardiovascular Society. · University of Ottawa Heart Institute, Ottawa, Canada. · Can J Cardiol. · Pubmed #16971976 links to  free full text

Abstract: Since the last publication of the recommendations for the management and treatment of dyslipidemia, new clinical trial data have emerged that support a more vigorous approach to lipid lowering in specific patient groups. The decision was made to update the lipid guidelines in collaboration with the Canadian Cardiovascular Society. A systematic electronic search of medical literature for original research consisting of blinded, randomized controlled trials was performed. Meta-analyses of studies of the efficacy and safety of lipid-lowering therapies, and of the predictive value of established and emerging risk factors were also reviewed. All recommendations are evidence-based, and have been reviewed in detail by primary and secondary review panels. Major changes include a lower low-density lipoprotein cholesterol (LDL-C) treatment target (lower than 2.0 mmol/L) for high-risk patients, a slightly higher intervention point for the initiation of drug therapy in most low-risk individuals (LDL-C of 5.0 mmol/L or a total cholesterol to high-density lipoprotein cholesterol ratio of 6.0) and recommendations regarding additional investigations of potential use in the further evaluation of coronary artery disease risk in subjects in the moderate-risk category.

Alwaili K, Alrasadi K, Awan Z, Genest J. · Cardiovascular Research Laboratories, McGill University Health Center Research Institute, McGill University, Montreal, Quebec, Canada. · Curr Opin Endocrinol Diabetes Obes. · Pubmed #19306526 No free full text.

Abstract: PURPOSE OF REVIEW: Disorders of lipoprotein metabolism are frequently encountered in clinical practice. Although the severe genetic hyperlipidemias are relatively infrequent, prompt recognition and treatment can prevent complications, such as atherosclerosis and pancreatitis. The secondary dyslipidemias, due to medication or other metabolic disorders (hypothyroidism, renal or hepatic diseases), must be identified and treated. With the growing epidemic of obesity, dyslipidemias are a component of the metabolic syndrome. RECENT FINDINGS: The stratification of cardiovascular risk now includes family history and biomarkers of inflammation, especially high-sensitivity C-reactive protein, which enables sound clinical decision making. Lifelong hypercholesterolemia is strongly associated with increasing risk of atherosclerosis and coronary heart disease death, but the decision to treat pharmacologically depends on the absolute cardiovascular risk over the next 10 years. Clinical trial data support intensive treatment of patients at high cardiovascular risk or for the secondary prevention of recurrent coronary heart disease. The recently published JUPITER trial shows that patients with an elevated C-reactive protein benefit from treatment with a statin (rosuvastatin 20 mg) for primary prevention. SUMMARY: The current guidelines for the prevention of coronary artery disease will continue to focus on the determination of global risk, with intensive treatment aimed at the high-risk group. Family history and high-sensitivity C-reactive protein provide additional risk stratification.

Alawadhi M, Thanassoulis G, Marcil M, Genest J. · Division of Cardiology Research, MUHC-Royal Victoria Hospital, 687 Pine Avenue West, Montreal, QC H3A 1A1, Canada. · Curr Atheroscler Rep. · Pubmed #15811253 No free full text.

Abstract: Familial lipoprotein disorders are seen frequently in subjects with premature coronary artery disease. The genetic basis for several dyslipoproteinemias has been elucidated in the past two decades. The majority of lipoprotein disorders result from a combination of polygenic predisposition and poor lifestyle habits, including physical inactivity, increased visceral adipose tissue, increased caloric intake, and cigarette smoking. Monogenic disorders are seen in approximately 5% of premature coronary artery disease cases, and this prevalence is higher in populations with the Founder effect. Unraveling the genetic basis of many lipoprotein disorders has allowed fundamental discoveries in molecular cellular physiology and has paved the way for novel therapeutic approaches.

Genest J. · Cardiovascular Genetics Laboratory, McGill University Health Center, Royal Victoria Hospital, Montreal, Quebec, Canada. · J Inherit Metab Dis. · Pubmed #12889666 No free full text.

Abstract: Disorders of lipoproteins often lead to disease in humans. Most often the sequelae of long-term dyslipoproteinaemia lead to atherosclerotic vascular disease in all arterial beds. Plasma elevation of low-density lipoprotein cholesterol (LDL-C), very low-density lipoproteins (VLDL) and lipoprotein(a), and reduced levels of high-density lipoproteins (HDL-C) are risk factors for coronary artery disease. Severe elevations of plasma triglycerides may lead to acute pancreatitis. In Western societies and in emerging economies, lifestyle contributes to the expression of lipoprotein disorders. Many dyslipoproteinaemias have a genetic aetiology. This review will examine the contribution of genetic lipoprotein disorders in human disease. Emphasis will be placed on monogenic disorders that are associated with coronary artery disease and novel causes of disorders of high-density lipoproteins. The consideration of screening and treatment of affected individuals, especially children, must take into account the severity of the phenotype, the long-term risk of developing vascular disease and available evidence of clinical benefit in a group of diseases that are mostly asymptomatic until manifestations of organ ischaemia in the heart, limbs or brain.

Genest J. · Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, 687 Pine Avenue West, Montreal, Quebec, Canada. · Cardiol Rev. · Pubmed #11790271 No free full text.

Abstract: Plasma level of high-density lipoprotein cholesterol is inversely correlated with coronary artery disease. High-density lipoprotein particles are thought to mediate the uptake of peripheral cholesterol and, through exchange of core lipids with other lipoproteins or selective uptake by specific receptors, return this cholesterol to the liver for bile acid secretion. During the past decade, high-density lipoprotein particles have been found to modulate thrombosis, cell adhesion molecule expression, vasomotor function, platelet function, and endothelial cell apoptosis and proliferation. Many of these effects involve the signal transduction pathway and gene transcription. Genetic disorders of high-density lipoproteins have been characterized at the molecular level. Mutations within the genes involved in the structure and metabolism of high-density lipoproteins can cause high-density lipoprotein deficiency or elevations in high-density lipoprotein cholesterol levels. Some mutations causing high-density lipoprotein deficiency are associated with premature coronary artery disease, whereas others, paradoxically, may be associated with longevity. Modulation of high-density lipoprotein metabolism for therapeutic purposes must take into account not only the cholesterol content of the particle but also its lipid (including phospholipid) composition, apolipoprotein content, size, and charge.

White M, Haddad H, Leblanc MH, Giannetti N, Pflugfelder P, Davies R, Isaac D, Burton J, Chan M, Azevedo E, Howlett J, Ignaszewski A, Busque S, Cantarovich M, Ferguson R, Genest J, Ross H. · Research Center of Montreal Heart Institute, Montreal, Quebec. · J Heart Lung Transplant. · Pubmed #15982605 No free full text.

Abstract: BACKGROUND: Tacrolimus improves lipid profile in renal and liver transplant recipients. The impact of conversion from cyclosporine microemulsion (Neoral) to tacrolimus (Prograf) in a large randomized study of stable heart transplant recipients with treated but persistent mild dyslipidemia is reported. METHODS: One hundred twenty-nine long-term (>or=12 months) cyclosporine microemulsion-treated heart transplant recipients with low-density lipoprotein cholesterol >2.5 mmol/liter and/or a total cholesterol/high-density lipoprotein cholesterol ratio >4 were recruited for the study. Complete lipid profile was assessed before (baseline) and after 6 months of treatment with either cyclosporine microemulsion maintenance (n=64) or tacrolimus conversion (n=65). RESULTS: At 6 months, tacrolimus-converted patients exhibited a greater decrease in total cholesterol (from 5.51 +/- 0.16 to 4.88 +/- 1.22 mmol/liter [tacrolimus], vs 5.61 +/- 1.36 to 5.38 +/- 0.87 mmol/liter [cyclosporine]; p = 0.0078). This decrease in cholesterol was caused largely by a decrease in low-density lipoprotein cholesterol (-0.41 +/- 0.54 [tacrolimus] vs -0.13 +/- 0.55 [cyclosporine]; p=0.0018). There were no changes in high-density lipoprotein cholesterol and triglyceride levels, but apolipoprotein B therapy was reduced in tacrolimus-converted vs cyclosporine-maintained patients (p=0.0003). By 6 months, 23.7% of tacrolimus- vs 6.7% of cyclosporine-treated patients met the target lipid levels for high-risk patients (p=0.0094). Conversion from cyclosporine to tacrolimus resulted in decreases in blood urea nitrogen, creatinine, and uric acid without any changes in glucose, HbA(1C), and insulin levels. CONCLUSIONS: Conversion from cyclosporine microemulsion- to tacrolimus-based immunoprophylaxis resulted in decreased cholesterol, apolipoprotein B, urea, creatinine, and uric acid without any clinically evident perturbation of glucose metabolism in stable heart transplant recipients with treated but persistent mild dyslipidemia.

McPherson R, Angus C, Murray P, Genest J, Anonymous00107. · University of Ottawa Heart Institute, Ottawa, Ontario, Canada. · Am Heart J. · Pubmed #11376309 No free full text.

Abstract: BACKGROUND: Recent studies have demonstrated that women at high risk for cardiovascular disease (CVD) benefit from cholesterol lowering to an extent similar to that of men. The ability to achieve established treatment goals for low-density lipoprotein cholesterol (LDL-C) in women with clearly defined risk factors has not been examined in detail. METHODS AND RESULTS: We have determined the efficacy and frequency of achieving target levels for LDL-C with atorvastatin on the basis of National Cholesterol Education Program Adult Treatment Panel II recommendations in 318 women according to the presence of CVD (198 women) or risk factors for CVD (120 women) and the presence of mixed dyslipidemia with obesity with or without CVD (72 women). Mean baseline LDL-C concentrations for women with established CVD were in the upper 10% of the distribution for age-matched North American women and, for those without CVD, were also extremely elevated and were in the top 5% of the LDL-C distribution for age-matched women in this population. The majority of participants without CVD (63%) reached LDL-C targets (LDL-C <or=160 mg/dL [4.1 mmol/L] if <2 CHD risk factors and LDL-C <or=130 mg/dL [3.4 mmol/L] if >or=2 CVD risk factors) with 10 mg atorvastatin and 79% reached targets with up to 20 mg of atorvastatin. For women with established CVD, 34% achieved an LDL-C <or=100 mg/dL (2.6 mmol/L) with 10 mg and 60% reached this target with up to 20 mg of atorvastatin. With maximal titration to the LDL-C target, up to and including 80 mg atorvastatin, 87% of women without CVD and 80% of women with established CVD achieved LDL-C targets. The presence of mixed dyslipidemia with obesity did not affect the frequency of achieving LDL-C targets. CONCLUSION: Atorvastatin is very effective in achieving National Cholesterol Education Program Adult Treatment Panel II target concentrations for LDL-C in the majority of women with established CVD or CVD risk factors.

Bissonnette R, Treacy E, Rozen R, Boucher B, Cohn JS, Genest J. · Division of Cardiology, McGill University Health Center/Royal Victoria Hospital, Québec, H3A 1A1, Montreal, Canada. · Atherosclerosis. · Pubmed #11254917 No free full text.

Abstract: The effect of fenofibrate (FEN), compared with placebo (PL), on total plasma homocysteine (tHcy) levels in the fasted and fed states has been examined. Twenty men with established coronary artery disease (CAD) or with at least two cardiovascular risk factors, who had elevated plasma triglyceride levels (> 2.3 mmol/l) and reduced HDL-C levels (< 0.91 mmol/l), and in whom a fibric acid derivative was clinically indicated were studied. The study was a randomized, PL controlled, double-blind study designed to test the effect of micronized FEN on postprandial lipemia. Plasma tHcy levels were investigated as a post-hoc analysis. After a 4-week dietary stabilization period, patients were randomized to PL or FEN (200 mg/day) for 8 weeks, followed by an 8-h postprandial study, consisting of 1 g fat/kg body weight (35% cream). The methionine content of cream was approximately 0.53 mg/ml. A 5-week washout period was then followed by a second 8-week treatment period (FEN or PL), at the end of which a second postprandial study was undertaken. Blood was sampled in the fasted state (0 h) and postprandially at 2, 4, 6 and 8 h. Plasma was stored at -80 degrees C for homocysteine, vitamins B(6), B(12) and folate measurements. FEN caused a marked decrease in all triglyceride-rich lipoprotein parameters, no change in LDL-C, and an increase in HDL-C levels. Fen treatment was associated with an increase in fasting tHcy (PL: 10.3+/-3.3 micromol/l to FEN: 14.1+/-3.8 micromol/l, 40.4+/-20.5%, P < 0.001) and fed tHcy levels 6 h post-fat load (PL: 11.6+/-3.3 micromol/l vs. FEN: 17.1+/-5.4 micromol/l, P < 0.001). Homocysteine levels were increased by the fat load; PL: 14% (P < 0.001) and FEN: 21%, P < 0.001 at the 2, 4, 6 and 8 h time points. Change in tHcy level on FEN was not associated with changes in plasma levels of folate, vitamins B(6) or B(12) or creatinine. Amino acid analysis revealed that methionine and cysteine were significantly increased on FEN (P < 0.005). The incidence of hyperhomocysteinemia (defined as tHcy level >14 micromol/l) was PL: 2/20 (10%) and FEN: 9/20 (45%) (chi(2) = 4.51, P = 0.034). There was no correlation between changes in plasma triglyceride levels and tHcy levels. Since tHcy is considered an emerging cardiovascular risk factor, the ability of FEN to increase plasma tHcy levels could potentially mitigate the potential of this drug to protect against cardiovascular disease.

Genest J, Nguyen NH, Theroux P, Davignon J, Cohn JS. · Cardiovascular Genetics Laboratory, and the Hyperlipidemia and Atherosclerosis Research Group, Clinical Research Institute of Montréal, Québec, Canada. · J Cardiovasc Pharmacol. · Pubmed #10630748 No free full text.

Abstract: A randomized, double-blind, placebo-controlled study was undertaken in 20 hypertriglyceridemic men [plasma triglyceride (TG), >2.3 mM] with low levels (<0.9 mM) of high-density lipoprotein cholesterol (HDL-C) to investigate the ability of micronized fenofibrate (Tricor or Lipidil; 200 mg/day) to affect atherogenic and thrombogenic plasma risk factors in the fed and fasted state. Each patient underwent (a) 4 weeks of dietary stabilization, (b) 8 weeks of treatment with fenofibrate or placebo, (c) a 5-week washout period, and (d) 8-weeks of treatment with the alternative medication. An oral fat-loading test (1 g fat/kg body weight) was carried out after both treatment periods. Before treatment, patients had a mean (+/- SD) total plasma TG of 3.31+/-0.93 mM; total C, 5.75+/-0.89 mM; HDL-C, 0.71+/-0.09 mM; and low-density lipoprotein (LDL)-C, 3.40+/-0.68 mM. Compared with placebo, fenofibrate reduced fasting TG levels by 36%, and triglyceride-rich lipoprotein (TRL, d<1.006 g/ml) -TG, and TRL-C levels by approximately 40%. In the postprandial state, fenofibrate reduced total TG, TRL-TG, TRL-C, TRL-apoC-III, and TRL-apoE levels by -35% (all values of p<0.01). Fasted and fed HDL-C and apoA-I levels were increased -10%, and total cholesterol/HDL cholesterol ratios were decreased -15% by fenofibrate. No significant differences were observed in mean LDL-C and LDL-apoB levels. A 6% increase in the LDL-C/LDL-apoB ratio during fenofibrate treatment indicated a shift to larger, more buoyant LDL particles. A small, but statistically significant (p<0.01) increase was observed in fasted and fed Lp(a) levels during fenofibrate treatment. Hemostatic parameters were not significantly affected by fenofibrate, except for a 12-15% decrease (p<0.05) in fibrinogen levels in the fasted and fed state, and a significant increase (43%; p<0.05) in fasting levels of plasminogen activator-inhibitor-1. These data demonstrate that micronized fenofibrate is highly effective, in both the fed and fasted state, in reducing TRL lipids and apolipoproteins, and in reducing plasma fibrinogen levels of men with an atherogenic lipoprotein profile.

Alrasadi K, Alwaili K, Awan Z, Valenti D, Couture P, Genest J. · McGill University Health Center/Royal Victoria Hospital, Montréal, Québec, Canada. · Am Heart J. · Pubmed #19081415 No free full text.

Abstract: BACKGROUND: We have previously reported premature, extensive aortic calcifications in patients with homozygous familial hypercholesterolemia (hmzFH) due to mutations in the low-density lipoprotein receptor gene (LDL-R). The objective of this study was to measure the degree of aortic calcification in heterozygous FH (htzFH) compared to both hmzFH and controls. We hypothesized that the LDL-R gene may contribute to aortic calcifications in a gene-dosage effect. METHOD: Patients with htzFH due to the French Canadian mutation (Delta15 kb del. null allele) were selected. All patients underwent computed tomographic scan to measure vascular calcification. We used 22 hmzFH patients from our previous study and patients undergoing computed tomographic virtual colonoscopy as controls. RESULTS: Mean age for htzFH was 50 +/- 15 years; initial cholesterol level before treatment was 10.45 +/- 1.73 mmol/L. Major cardiovascular events occurred in 9 of 17 patients. A strong correlation between age and calcium score was found (r = 0.72, P = .0016). There was a strong correlation between the cholesterol-year score (an index of lifelong cholesterol burden) and the aortic calcium score (r = 0.62, P = .0105). Aortic calcifications in htzFH subjects occurred later than in hmzFH patients, but much earlier than in controls, suggesting a gene-dosage effect of LDL-R mutations and aortic calcium deposition. CONCLUSION: Aortic calcification was observed in patients with htzFH but presented at a later time and were less extensive than in hmzFH (34 vs 14 years, respectively). Because aortic calcifications may be partly independent of serum cholesterol levels in patients with familial hypercholesterolemia, implications for screening and the timing of treatment initiation may need reassessment.

Awan Z, Alrasadi K, Francis GA, Hegele RA, McPherson R, Frohlich J, Valenti D, de Varennes B, Marcil M, Gagne C, Genest J, Couture P. · McGill University Health Center/Royal Victoria Hospital, 687 Pine avenue West, Montréal, QC H3A 1A1, Canada. · Arterioscler Thromb Vasc Biol. · Pubmed #18239150 links to  free full text

Abstract: BACKGROUND: Patients with homozygous familial hypercholesterolemia (hmzFH) attributable to LDL receptor gene mutations have shown a remarkable increase in survival over the last 20 years. Early onset coronary heart disease (CHD) and calcific aortic valve stenosis are the major complications of this disorder. We now report extensive premature calcification of the aorta in patients with hmzFH. METHODS AND RESULTS: We examined 25 hmzFH patients from Canada; mean age was 32 years (range 5 to 54), and mean baseline cholesterol before treatment was 19+/-5 mmol/L (737+/-206 mg/dL). Aortic calcification was quantified using computed tomography (CT). An elevated mean calcium score was found in patients by age 20 and correlated with age (r(2)=0.53, P=0.001). One quarter (24%) of patients underwent aortic valve surgery. CONCLUSIONS: We document premature severe aortic calcifications in all adult hmzFH patients studied. These presented considerable surgical management challenges. Strategies to identify and monitor aortic calcification in hmzFH by noninvasive techniques are required, as are clinical trials to determine whether additional or more intensive therapies will prevent the progression of such calcifications. Whether vascular calcifications in hmzFH subjects are related to sustained increases in LDL-C levels or to other mechanisms, such as abnormal osteoblast activity, remains to be determined.

Grenon SM, Lachapelle K, Marcil M, Omeroglu A, Genest J, de Varennes B. · Department of Cardial Surgery, McGill University, Royal Victoria Hospital, Montreal, Quebec, Canada. · Can J Cardiol. · Pubmed #18060104 links to  free full text

Abstract: Homozygous familial hypercholesterolemia (HzFH) is a rare genetic defect caused predominantly by mutations at the low-density lipoprotein receptor. Until recent advances in the management of this complex disorder, patients affected by HzFH rarely survived beyond 30 years of age. Two patients with HzFH who survived to adulthood and developed cardiovascular complications requiring surgery are reported. In these patients, a porcelain aorta complicated surgical management. Lipid profile, mutational analysis and pathological assessment of the aorta were performed in two patients referred for cardiac surgery. The first patient was a 46-year-old man with a history of coronary artery bypass grafting (CABG) and recurrent severe angina who, because of a heavily calcified ascending aorta, required a complex repeat CABG. The second patient was a 42-year-old woman who underwent CAGB at 28 years of age and presented 13 years later with aortic stenosis. The extensive calcifications of the whole aortic root required performance of a modified Cabrol procedure. A porcelain aorta appears to be a feature of HzFH. This has an important impact on surgical planning and management and on possible pathophysiological processes related to the cardiovascular complications of HzFH.

Marcil M, Vu H, Cui W, Dastani Z, Engert JC, Gaudet D, Castro-Cabezas M, Sniderman AD, Genest J, Cianflone K. · Centre de Recherche Hôpital Laval, Université Laval, Y2186, 2725 Chemin Ste Foy, Ste Foy, Québec, G1V 4G5. · Arterioscler Thromb Vasc Biol. · Pubmed #16627811 links to  free full text

Abstract: OBJECTIVE: A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASP-responsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects. METHODS AND RESULTS: DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G968-->T) in 1 subject, resulting in Ser323-->Ile substitution in the carboxyl terminal region. This variant was not detected in 2176 additional chromosomes by restriction fragment length polymorphism or fluorescence polarization genotyping. Eight family members of the proband were identified with one altered (+/-)C5L2 allele. Nine other family members had the wild-type (+/+)C5L2 sequence. The abnormal allele was associated with increased plasma triglyceride, plasma cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP. Of 23 subjects tested in cell-based ASP bioactivity assays, those with C5L2(+/-) variant (n = 2) had a 50% reduction in ASP-stimulated triglyceride synthesis, glucose transport and marked reduction in maximal binding (B(max)). By contrast, a C5L2(+/+) family member responded normally, as did hyperapolipoprotein B normal ASP subjects compared with C5L2(+/+) controls (n = 6). CONCLUSIONS: The S323I variant may alter C5L2 function and might be one molecular basis contributing to familial combined hyperlipidemia.

Bourgault C, Davignon J, Fodor G, Gagné C, Gaudet D, Genest J, Lavoie MA, Leiter L, McPherson R, Sénécal M, Marentette M, Sebaldt RJ. · McGill University, Montreal, Canada. · Can J Cardiol. · Pubmed #16308595 links to  free full text

Abstract: 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.

Genest J, McPherson R, Frohlich J, Fodor G. · Division of Cardiology, Royal Victoria Hospital, McGill University, Montréal, Que. · CMAJ. · Pubmed #15824410 links to  free full text

This publication has no abstract.

Genest J, Frohlich J, Fodor G, McPherson R, Anonymous00240. · Royal Victoria Hospital, McGill University, Montréal, Que. · CMAJ. · Pubmed #14581310 links to  free full text

This publication has no abstract.

Yu L, Heere-Ress E, Boucher B, Defesche JC, Kastelein J, Lavoie MA, Genest J. · Cardiovascular Genetics Laboratory, Clinical Research Institute of Montréal, Québec, Canada. · Atherosclerosis. · Pubmed #10487495 No free full text.

Abstract: Familial hypercholesterolemia (FH) is an autosomal dominant lipoprotein disorder caused by defects in the low density lipoprotein (LDL) receptor (R) gene. We report a novel mutation of the LDL-R gene in a 38-year-old man with homozygous FH from the province of Trujilo in Northern Honduras. The patient presented with tendinous xanthomas over the extensor tendons as well as xanthelasmas at sites of surgical scars. He was diagnosed with severe coronary artery disease requiring revascularization at age 29. After an unsuccessful course of treatment with simvastatin, the patient has been treated with plasma apheresis and macromolecular plasma filtration bi-monthly. Haplotyping of the LDL-R gene revealed homozygosity for the rare 'J' allele and a loss of the EcoRV restriction cleavage site in exon 8. Single stranded conformational polymorphism of exons 3, 6, 7, 9, 10 and 8 reveals an abnormal migration pattern in exon 8. Direct sequencing of the promoter region, exons 1, 4, 8 and 13 revealed two RFLP's and a novel mutation in intron 7. This mutation consists of G-->C transposition at the acceptor splice site of exon 8 at the last nucleotide of intron 7 [LDL-R1061(-1)G-->C]. Reverse transcriptase (RT) PCR amplification of RNA from monocytes obtained from the patient reveals a decrease in LDL-R mRNA (52% of control) and skipping of exon 8 (approximately 38%, as assessed by densitometric scanning of the amplified fragments) to form a new RNA transcript that includes exons 7 and 9 without frameshift. Alternative RNA editing leads to a new cryptic acceptor splice site 17 bp downstream in exon 8 producing a frameshift mutation and a predicted premature stop codon 1138 bp from the transcriptional start site (approxiamtely 62%). Western blotting analysis using a monoclonal antibody (C7) directed at the amino terminus of the LDL-R protein reveals a marked reduction in LDL-R protein expressed in monocytes obtained from the patient. We conclude that LDL-R1061(-1)G-->C is a novel mutation of the LDL-R gene that results in marked decrease in LDL-R mRNA levels and protein expression by two alternate RNA editing mechanisms, that cause skipping of exon 8 or the use of a novel cryptic acceptor splice site in exon 8 with a frameshift and premature stop codon. The patient continues to do well on selective plasma filtration but developed bilateral severe carotid artery disease requiring surgical intervention.

Genest J, Lavoie MA. · Clinical Research Institute of Montreal, QC, Canada. · N Engl J Med. · Pubmed #10441605 No free full text.

This publication has no abstract.