G-substrate gene promoter SNP (−1323T>C) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: Intra-familial association study in an eight-generation hyperlipidemic kindred

Background:   Plasma lipid and lipoprotein generally reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity.
Methods:   In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH, to examine possible genetic modification of lipoprotein phenotype by 'modifier locus'. G-substrate (GSBS) is an endogenous substrate for cGMP-dependent protein kinase. We carried out an intrafamilial correlation analysis of modifier effect of −1323T>C substitution in the GSBS gene among 85 LDLR-mutation carriers and 75 non-carriers.
Results:   In the LDLR - mutation carriers, the plasma cholesterol levels were highest among −1323C homozygotes (mean ± SD = 454 ± 101 mg/dL), lowest among −1323T homozygotes (mean ± SD, 307 ± 72 mg/dL) and intermediate among −1323T/C heterozygotes (mean ± SD, 314 ± 62 mg/dL; P  = 0.015). Similarly, in the LDLR-mutation carriers, the plasma triglyceride levels were highest among −1323C homozygotes (mean ± SD, 371 ± 381 mg/dL), lowest among −323T homozygotes (mean ± SD, 171 ± 94 mg/dL), and intermediate among −1323T/C heterozygotes (mean ± SD, 218 ± 130 mg/dL; P  = 0.003). No such gene-interactive effect was observed among non-carriers of the LDLR-mutation.
Conclusion:   These results indicate a significant modification of the phenotype of FH with defective LDLR allele, by GSBS-1323C allele in the kindred studied.     

Plasma Lp(a) values in familial hypercholesterolemia and its relation to coronary heart disease

BACKGROUND AND AIM: To analyze plasma Lp(a) levels and examine different risk factors and coronary heart disease (CHD) in a sample of genetically diagnosed familial hypercholesterolemia (FH) patients. METHODS AND RESULTS: Ninety heterozygous FH patients and 41 non-FH relatives were enrolled in a study to evaluate their plasma and lipoprotein cholesterol, as well as their triglyceride and Lp(a) levels. We found no differences in plasma Lp(a) levels and log transformed values between 90 FH subjects and their 41 unaffected relatives (22.3 mg/dl +/- 19.4 vs 17.7 mg/dl +/- 21.3 and 1.12 +/- 0.5 vs 0.96 +/- 0.54) nor between null allele and defective allele FH subjects (log Lp (a) levels 2.013 +/- 0.282 vs 1.959 +/- 0.151). FH CHD+ were significantly older, and had higher mean systolic and diastolic blood pressure and higher mean plasma triglyceride levels than FH CHD-. No differences in mean and log transformed Lp(a) plasma concentrations were found. CONCLUSIONS: Plasma Lp(a) levels are not related to LDL receptor status and class mutations, nor to the presence of CHD in FH patients.     

Leucine 10 allelic variant in signal peptide of PCSK9 increases the LDL cholesterol-lowering effect of statins in patients with familial hypercholesterolaemia

Background and aimsIn the normal population, carriers of an additional leucine residue in a stretch of nine leucines in the signal peptide of PCSK9 (L10) have lower total (TC) and low-density lipoprotein cholesterol (LDL-C) than homozygotes for the wild-type allele (L9/L9). A similar effect was detected in familial hypercholesterolaemia (FH) patients with the p.C681X mutation of LDL-receptor (LDLR). We investigated the effect of L10 variant on basal lipid profile and response to statins in molecularly characterised FH patients.Methods and resultsPlasma lipids were determined in 322 FH patients screened for the L9/L10/L11 polymorphism and in a subgroup of 54 patients carrying the same LDLR mutation (p.Q474HfsX63). Plasma lipids were also determined in 42 FH patients carrying the L10 variant and in a parallel group of 42 FH patients, L9/L9 homozygotes, matched for gender, age, type of LDLR gene mutation, as well as for type, dose and duration of statin treatment. In FH patients, no difference in the basal plasma TC and LDL-C levels was observed between carriers of L10 variant (L9/L10 + L10/L10) and L9/L9 homozygotes. The same was true in FH patients carrying the p.Q474HfsX63 LDLR mutation. In the subgroups of statin-treated patients, the reduction of TC and LDL-C was greater in carriers of L10 (?34.0% and ?42.5%, respectively) than in L9/L9 homozygotes (?27.5% and ?34.3%, respectively) (P < 0.001).ConclusionThe variant L10 of the leucine repeats in PCSK9 signal peptide is to be considered as a factor capable of modulating the lipid-lowering effects of statins in FH.     

Diagnosis of families with familial hypercholesterolaemia and/or Apo B-100 defect by means of DNA analysis of LDL-receptor gene mutations

BACKGROUND: One major problem of using hypercholesterolaemia alone as a primary criterion for diagnosing familial hypercholesterolaemia (FH) is that 15-40% of relatives may be misdiagnosed because plasma lipid levels in FH heterozygotes overlap with those in the general population. SETTING: General Hospital/University of Vienna, Department of Pediatrics, Outpatient lipid clinic. METHODS: As a part of the MED-PED (make early diagnosis-prevent early death) project we are currently investigating children, adolescents and their relatives who are suspected to be affected with FH in our out-patient clinic for metabolic diseases using MED-PED inclusion criteria and confirming the diagnosis by means of DNA analysis. PATIENTS: 263 patients with premature atherosclerosis and/or hypercholesterolaemia: 116 children (mean age 11.6 +/- 4.1 years; 57 girls and 59 boys) and 147 adults (64 women, mean age 41.5 +/- 13.7 years; 83 men, mean age 42.8 +/- 10.8 years). RESULTS: 119 patients with mutations have been detected; 56 children with either low density lipoprotein receptor (LDLR) and/or ApoB mutations (27 girls and 29 boys; mean total cholesterol (TC) 275 +/- 71 mg/dl, triglycerides (TG) 101 +/- 57 mg/dl, high-density lipoprotein cholesterol (HDL-C) 49 +/- 12 mg/dl, low-density lipoprotein cholesterol (LDL-C) 198 +/- 67 mg/dl) and one boy with a homozygous. LDLR mutation. A further 62 adults with LDLR and/or ApoB mutations were documented; 33 women (mean age 36.9 +/- 11.1 years; mean TC 283 +/- 76 mg/dl, TG 137 +/- 78 mg/dl, HDL-C 55 +/- 17 mg/dl, LDL-C 210 +/- 67 mg/dl) and 29 men (mean age 45.0 +/- 10.6 years; mean TC 301 +/- 87 mg/dl, TG 163 +/- 112 mg/dl, HDL-C 42 +/- 12 mg/dl, LDL-C 233 +/- 83 mg/dl). In 32 of these subjects (11 children (21%), 21 adults (42%)), serum lipid levels were lower than the diagnostic MED-PED limits adopted, so that they might have been misclassified without an additional DNA analysis. CONCLUSION: In our study, diagnosis of FH and related disorders (ApoB-100 defect) by means of conventional laboratory methods missed at least 21% in children and 42% in adults affected with LDLR and/or ApoB gene mutations. Genetic FH diagnosis provides a tool for specific diagnosis of mutation carrier status.     

Genetic variation in apolipoprotein H (beta2-glycoprotein I) affects the occurrence of antiphospholipid antibodies and apolipoprotein H concentrations in systemic lupus erythematosus

Apolipoprotein H (apoH, protein; APOH, gene) is a required cofactor for the production of antiphospholipid antibodies (APA). In this study we have examined whether genetic variation in the APOH gene affects variation in risk for systemic lupus erythematosus (SLE), occurrence of antiphospholipid antibodies (APA), anti-apoH, and plasma apoH concentrations. A total of 222 white SLE women were screened for four APOH polymorphisms (codons 88, 247, 306, and 316) by polymerase chain reaction, and for plasma apoH concentrations by ELISA. Of these, 29.3% were positive for APA (APA-positive group) and 31.1% for anti-apoH. None of the four APOH polymorphisms were significantly associated with variation in risk for SLE. The codons 306 and 316 polymorphisms showed significant, gene-dosage effects on plasma apoH concentrations (P<0.0001) and explained 30% and 13%, respectively, of the residual variation in apoH concentrations. No significant association was observed between anti-apoH status and APOH polymorphisms or plasma apoH levels. However, plasma apoH concentrations were significantly higher in patients positive for APA than in patients negative for APA (18.5+/-4.0 mg/dl vs 17.1+/-3. 8 mg/dl; P=0.02). The distribution of the Trp316Ser polymorphism was significantly different between the APA-positive and APA-negative groups. The frequency of the mutant allele (Ser316) was significantly lower in the APA-positive group than the APA-negative group (3.1% vs 12.1% P<0.04), indicating that the Ser316 mutation is protective against the production of phospholipid-apoH dependent APA. Our data indicate that common genetic variation in the APOH gene is a significant determinant of plasma apoH variation in SLE patients, and the Trp316Ser polymorphism appears to provide protection against the production of APA in SLE patients.     

Effects of CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, on serum lipid and apolipoprotein levels in heterozygous familial hypercholesterolemic patients treated by low density lipoprotein (LDL)-apheresis

Nine heterozygous patients with familial hypercholesterolemia (FH) were treated by low density lipoprotein (LDL)-apheresis using dextran sulfate cellulose columns. After more than 3 procedures of LDL-apheresis without drug therapy, combination therapy with LDL-apheresis and CS-514 (eptastatin), an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme (HMG-CoA) reductase, at a dose of 10 mg twice daily was started. Pre- and post-apheresis serum cholesterol levels were decreased significantly by CS-514, from 289 +/- 24 mg/dl (mean +/- SEM) to 247 +/- 25 mg/dl and from 118 +/- 7 mg/dl to 106 +/- 9 mg/dl, respectively. Pre- and post-apheresis apolipoprotein B levels decreased significantly on CS-514 from 160 +/- 9 mg/dl to 138 +/- 8 mg/dl and from 58 +/- 6 mg/dl to 45 +/- 6 mg/dl, respectively. No adverse effects were observed during the combination therapy. Thus, the addition of an inhibitor of HMG-CoA reductase to LDL-apheresis is a useful method for further reducing serum cholesterol and apolipoprotein B levels in FH heterozygotes.     

北方汉族人载脂蛋白H基因多态性与脑梗死关系的研究

目的探讨中国北方汉族人载脂蛋白H(apoH)基因7号外显子Val247Leu位点多态性与脑梗死的相关性及与血脂代谢的关系。方法采用聚合酶链反应-限制性片段长度多态性分析方法,检测北方汉族急性脑梗死患者320例(脑梗死组)及健康对照者330例(对照组)apoH基因第7外显子Val247Leu位点多态性,并分析不同基因型对血脂代谢的影响。结果 apoH基因Val247Leu位点有TT、GT和GG 3种基因型,以GT型为主。脑梗死组患者TT基因型及T等位基因频率均显著高于对照组(χ~2=53.12,OR=1.672,95%CI:1.332～2.099,P<0.01;χ~2=19.78,OR=3.570.95%CI:2.483～5.134,P<0.01)。不同基因型TC、HDL-C、LDL-C、C反应蛋白、空腹血糖及体重指数比较,差异无统计学意义。与GG型比较,脑梗死患者TT型、GT型TG水平显著增高(P<0.01),TT型与GT型比较差异无统计学意义(P>0.05)。结论 apoH基因7号外显子Val247Leu位点多态性与脑梗死密切相关,T等位基因可能与脑梗死遗传因素有关,并影响TG的代谢。     

Effects of atorvastatin on electrophoretic characteristics of LDL particles among subjects with heterozygous familial hypercholesterolemia

The effects of the HMG CoA reductase inhibitor atorvastatin on electrophoretic characteristics of LDL particles were evaluated in 46 patients (28 males and 18 females) with heterozygous familial hypercholesterolemia (FH) aged 20-61 carrying either a negative or a defective LDL receptor gene mutation. Following a 6 week drug-free baseline period, FH heterozygotes were treated with atorvastatin (median dose: 20 mg/day, range 10-80 mg/day)) for 6 months to maintain their plasma LDL-cholesterol concentrations between 4.0 and 5.0 mmol/l. Atorvastatin treatment significantly reduced plasma total cholesterol, LDL-cholesterol and triglyceride levels and increased plasma HDL-cholesterol. Furthermore, atorvastatin treatment significantly increased LDL peak particle diameter (LDL-PPD) by 0.5% (from 255.0+/-6.2 to 256.4+/-5.5 A, P=0.004) and reduced the absolute concentration of cholesterol among small (<255 A) and large (>260 A) LDL particles by 35% (P<0.001). Changes in LDL-PPD and plasma triglyceride levels were inversely correlated (R=-0.34; P=0.02). Stepwise multiple linear regression analyses showed that 41.6% of the variation in the LDL-PPD response to atorvastatin was attributable to the initial LDL-PPD (14.4%, P=0.003), the apo E polymorphism (12.4%, P=0.02), the nature of the LDL receptor gene mutation (9.6%, P=0.01) and change in triglyceride levels (5.2%, P=0.04). Moreover, the reduction in the cholesterol content of LDL <255 A was directly correlated with the daily dosage of atorvastatin (P=0.05). Results of the present study showed that atorvastatin alters significantly LDL heterogeneity in patients at high risk of coronary heart disease (CHD) such as FH heterozygotes. These results also suggest that genetic and metabolic factors may be important determinants of atorvastatin-induced changes of LDL particle size and distribution among FH heterozygotes.     

Detection of familial hypercholesterolemia in a cohort of children with hypercholesterolemia: results of a family and DNA-based screening

The diagnosis of familial hypercholesterolemia (FH) in unselected children is difficult due to the frequent overlap of cholesterol values in affected and non-affected and the paucity of physical signs. Nevertheless, detection and treatment of FH in childhood has been advocated to prevent atherosclerosis in these patients. Here, we report the results of a screening program in a cohort of 157 unrelated, hypercholesterolemic (HC) children (age range 2-15 years; mean 8.3+/-3.4 years) carried out by a combination of family study and molecular analysis of the LDLR gene. On the basis of the familial phenotype, 27 (17.2%) were classified as probable FH and 49 (31.2%) as affected by FCHL. Among probable FH children, 14 (51.8%) carried mutant LDLR alleles, giving an overall 8.9% prevalence of FH. Most of LDLR variants were already reported, but three new mutations G266C, T368M, and D451Y were identified. Beside increased TC and LDL-C (p<0.001), FH children showed decreased HDL-C (p<0.05) and higher prevalence of family history of CAD when compared to non-FH children. None presented tendon xanthomas. We estimated that LDL-C >3.9 mmol/L was the best cut off value for diagnosing FH in these children, showing 79% sensitivity and 71.0% specificity. We propose the use of a LDL-C cut off level associated with a family study to identify FH among HC children.     

Left atrial endocardial lipid deposits and absent to minimal arterial lipid deposits in familial hyperchylomicronemia

Familial hyperchylomicronemia (type 1 hyperlipoproteinemia) is a rare autosomal recessive disorder characterized by severe chylomicronemia secondary to a congenital deficiency of either lipoprotein lipase or apolipoprotein C-II.¹ In 1983, the presence of a lipoprotein lipase inhibitor (which appears to be inherited as an autosomal dominant disease) as an additional cause of this disease was identified.^1,2 Familial hyperchylomicronemia generally manifests itself in infancy or early childhood as repeated attacks of abdominal pain and as a creamy appearing (lipemic) plasma, both due to ingestion of dietary fats that have delayed clearance from the plasma. Complications due to hyperehylomicronemia include acute pancreatitis, eruptive xanthomas, lipemia retinalis, and hepatosplenomegaly. Plasma triglyceride concentrations generally range from 1,500 to 4,500 mg/ dl, but levels to 25,000 mg/dl have been reported. The plasma total cholesterol generally ranges from 160 to 400 mg/dl, but may be as high as 1,000 mg/dl when the triglyceride levels are severely elevated. Both low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol usually are exceedingly low, in the range of 20 to 40 mg/dl and 5 to 20 mg/dl, respectively. The fasting plasma very low density lipoprotein (VLDL) cholesterol is elevated, and it increases further after a low-fat, high-carbohydrate diet.³

The diagnosis of familial hyperchylomicronemia is based on the presence of a creamy layer (chylomicrons) on the surface of plasma that has been stored in the cold (4 °C), and an elevated plasma triglyceride level. Demonstration of chylomicrons (fasting triglycerides > 1,500 mg/dl) after an overnight fast also may indicate familial hyperchylomicronemia. Analysis of lipoprotein lipase (assay of postheparin plasma) apolipoprotein C-II (gel electrophoresis of VLDL and chylomicron apolipoproteins or lipoprotein lipase activity, or both, in postheparin plasma), and lipoprotein lipase inhibitor activities establish the molecular defect in this disorder.¹ Although many reports have appeared describing clinical and biochemical features of familial hyperchylomicronemia, morphologic features of this condition have received little attention. Some morphologic data have been reported in only 5 such patients.^4–8 The present report describes clinical and necropsy findings in 4 men with familial hyperchylomicronemia with emphasis on cardiovascular observations.     

Comparison of genetic versus clinical diagnosis in familial hypercholesterolemia

Early diagnosis is important in familial hypercholesterolemia (FH), a highly atherogenic condition, but internationally agreed clinical diagnostic criteria are lacking. Genetic testing for low-density lipoprotein (LDL) receptor (LDLR) and apolipoprotein B (APOB) gene defects is the preferable diagnostic method, but the best phenotype indication to proceed with genetic diagnosis has not been established. The aim of this study was to assess the predictive and accuracy values of standard diagnostic criteria for detecting disease-causing mutations in 825 subjects with clinical FH aged > or =14 years from 3 lipid clinics in Spain. All subjects underwent thorough genetic testing for the detection of LDLR and APOB defects using the Lipochip platform. FH-causing mutations were detected in 459 subjects (55.6%). By logistic regression analysis, familial or personal history of tendon xanthoma (TX) and LDL cholesterol were strongly associated with genetic diagnosis (p <0.005, R(2) = 0.41). In subjects without familial or personal histories of TX, the diagnostic criteria for FH of the Make Early Diagnosis to Prevent Early Deaths (MEDPED) project, based on age-specific LDL cholesterol thresholds, showed sensitivity of 72.4%, specificity of 71.1%, and accuracy of 71.6%. LDL cholesterol > or =190 mg/dl in subjects with familial or personal histories of TX and > or =220, > or =225, and > or =235 mg/dl in those without such histories aged <30, 30 to 39, and > or =40 years, respectively, showed sensitivity of 91.1%, specificity of 71.1%, and accuracy of 74.2% for a positive genetic diagnosis. This new set of diagnostic criteria for FH was validated in an independent group of 440 subjects from 6 additional Spanish lipid clinics. In conclusion, TX and age-adjusted LDL cholesterol cut-off values have the highest value for clinical diagnosis and indication of genetic testing in FH.     

The efficacy of cholestyramine as a hypocholesterolemic agent and its tolerance in a Mexican population

The tolerance and efficacy of cholestyramine (12-16 gr/day) was evaluated in 19 patients with primary type-IIa hyperlipoproteinemia. All patients were on an isocaloric low-cholesterol diet that began at least one month before entry, and was continued during the eight weeks of the study. Cholestyramine significantly (p less than 0.001) lowered the plasma levels of cholesterol and of low density lipoprotein cholesterol from means of 288 +/- 46 mg/dl to 244 +/- 44 mg/dl and from 221 +/- 50 mg/dl to 171 +/- 46 mg/dl respectively. These were reductions of 15 and 22%. The magnitude of response to cholestyramine was unrelated to age, sex, cause of the hypercholesterolemia (familial or polygenic) or basal cholesterol levels. The drug was well tolerated. Only one patient was excluded because gastrointestinal discomfort. Because of its safety and efficacy, cholestyramine can be recommended as a first choice drug in the treatment of hypercholesterolemia.     

Hemorrheologic abnormalities in defined primary dyslipoproteinemias with both high and low atherosclerotic risks

Dyslipoproteinemias are associated with hemorrheologic abnormalities (elevated fibrinogen concentration, higher viscosity of plasma and blood). Epidemiologic data suggest that not only elevated lipoprotein concentrations (eg, low-density lipoprotein [LDL] cholesterol), but also hemorrheologic abnormalities could causally be involved in the atherosclerotic process. To elucidate potential effects of hemorrheological disturbances, we investigated patients suffering from primary hyperlipoproteinemias with both low (familial hypertriglyceridemia, n = 25) and high (type III hyperlipoproteinemia, n = 21; familial hypercholesterolemia, n = 19; mixed hyperlipoproteinemia, n = 19) atherosclerotic risk, as well as healthy controls (n = 49) in a cross-sectional design. Dyslipoproteinemias were classified by lipoprotein measurements (using ultracentrifugation), family history, and apolipoprotein E phenotype. Hemorrheology was characterized by the measurement of fibrinogen concentration, viscosity of plasma and blood at different shear rates, and red cell aggregation (RCA) at stasis and low shear. Fibrinogen concentration was lower in controls (2.38 +/- 0.09 g/L) compared with familial hypercholesterolemia (3.19 +/- 0.19 g/L), to type III hyperlipoproteinemia (3.02 +/- 0.12 g/L), to familial hypertriglyceridemia (2.95 +/- 0.21 g/L) and to mixed hyperlipoproteinemia (3.01 +/- 0.12 g/L) (P < .05, respectively) without differences between dyslipoproteinemia groups. Plasma viscosity was higher in patients with type III hyperlipoproteinemia (1.42 +/- 0.03 mPas), with familial hypertriglyceridemia (1.47 +/- 0.04 mPas), and with mixed hyperlipoproteinemia (1.43 +/- 0.02 mPas) compared with controls (1.29 +/- 0.01 mPas) (P < .05, respectively). After including 6 lipoprotein parameters in a general linear model, plasma viscosity, blood viscosity, and RCA were higher in familial hypertriglyceridemia compared with healthy controls and familial hypercholesterolemia (P < .05, respectively). As most of the hemorrheologic abnormalities were still significant after adjusting for lipoprotein concentrations, they seem to be at least partly independent from direct lipoprotein effects. Hemorrheologic abnormalities in familial hypertriglyceridemia (low atherosclerotic risk) were at least as marked as in dyslipoproteinemias with high atherosclerotic risk, suggesting that it might be most important to determine lipoprotein concentrations and to define exactly the type of dyslipoproteinemia for estimating the individual cardiovascular risk in these patients.     

Lipoprotein(a) in homozygous familial hypercholesterolemia

Lipoprotein(a) [Lp(a)] is a quantitative genetic trait that in the general population is largely controlled by 1 major locus-the locus for the apolipoprotein(a) [apo(a)] gene. Sibpair studies in families including familial defective apolipoprotein B or familial hypercholesterolemia (FH) heterozygotes have demonstrated that, in addition, mutations in apolipoprotein B and in the LDL receptor (LDL-R) gene may affect Lp(a) plasma concentrations, but this issue is controversial. Here, we have further investigated the influence of mutations in the LDL-R gene on Lp(a) levels by inclusion of FH homozygotes. Sixty-nine members of 22 families with FH were analyzed for mutations in the LDL-R as well as for apo(a) genotypes, apo(a) isoforms, and Lp(a) plasma levels. Twenty-six individuals were found to be homozygous for FH, and 43 were heterozygous for FH. As in our previous analysis, FH heterozygotes had significantly higher Lp(a) than did non-FH individuals from the same population. FH homozygotes with 2 nonfunctional LDL-R alleles had almost 2-fold higher Lp(a) levels than did FH heterozygotes. This increase was not explained by differences in apo(a) allele frequencies. Phenotyping of apo(a) and quantitative analysis of isoforms in family members allowed the assignment of Lp(a) levels to both isoforms in apo(a) heterozygous individuals. Thus, Lp(a) levels associated with apo(a) alleles that were identical by descent could be compared. In the resulting 40 allele pairs, significantly higher Lp(a) levels were detected in association with apo(a) alleles from individuals with 2 defective LDL-R alleles compared with those with only 1 defective allele. This difference of Lp(a) levels between allele pairs was present across the whole size range of apo(a) alleles. Hence, mutations in the LDL-R demonstrate a clear gene-dosage effect on Lp(a) plasma concentrations.     

Comparison of apolipoprotein B metabolism in familial defective apolipoprotein B and heterogeneous familial hypercholesterolemia

Both defective LDL receptors (familial hypercholesterolaemia, FH) and mutations in apolipoprotein B (apoB) on LDL (familial defective apoB, FDB) give rise to a phenotype of elevated LDL cholesterol. We sought to compare the metabolic basis of the two conditions by examining apoB turnover in FDB and FH subjects. A group comprising three heterozygous and one homozygous FDB subjects were compared with five FH heterozygotes and 17 control subjects using a deuterated leucine tracer. Kinetic parameters were derived by multicompartmental modelling. FH heterozygotes had a reduced delipidation rate for VLDL, which led to a moderate increase in plasma triglyceride. Compared with controls and FH, the FDB subjects converted 44% less IDL to LDL. The LDL FCR was reduced to a similar extent in FDB and FH. In all subjects LDL plasma levels appeared to be regulated by the LDL FCR and the rate of production of small VLDL. We conclude that disturbances in IDL metabolism provide the basis for understanding why FDB is less severe than FH. Our findings suggest that an apoB-LDL receptor interaction is important in the IDL to LDL conversion.     

Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients

Familial hypercholesterolemia (FH) is characterized by an autosomal codominant inheritance, an abnormality in low-density lipoprotein (LDL) receptor function, elevated plasma cholesterol levels and premature atherosclerosis. Sixteen patients with homozygous FH were studied to correlate the extent of their atherosclerotic disease with their lipid levels and receptor function. The age range at initial presentation was 3 to 38 years (mean 12), and at the last examination, 6 to 43 years (mean 20). The mean pretreatment total plasma cholesterol concentration for all patients was 729 +/- 58 mg/dl (+/- standard error of the mean), and the mean LDL cholesterol level was 672 +/- 58 mg/dl (normal 60 to 176). High-density lipoprotein cholesterol was 28 +/- 3 mg/dl (normal 30 to 74). In the 7 patients with FH who had symptoms of myocardial ischemia (Group I), the mean pretreatment LDL cholesterol value (817 +/- 62 mg/dl) was higher than that of the 9 asymptomatic patients (Group II) (560 +/- 74 mg/dl). In Group I, 5 of 7 patients had left or right coronary ostial narrowing and 3 had significant left ventricular outflow obstruction. Most coronary arterial narrowing occurred in the right coronary and left anterior descending arteries and the least amount in the left circumflex coronary artery. A femoral bruit was the physical finding that correlated best with the Group I population; brother:sister pairs revealed a milder clinical course for the female. Seven of the 16 patients have survived into their third decade without symptoms. Comparison of these persons with those in whom angina developed reveals a marked heterogeneity in their clinical course, which appears to be associated with receptor negative/defective status.     

R3531C mutation in the apolipoprotein B gene is not sufficient to cause hypercholesterolemia

Familial hypercholesterolemia and familial ligand-defective apolipoprotein B-100 (FDB) are dominantly inherited disorders leading to impaired low-density lipoprotein receptor (LDLR) and apolipoprotein B-100 (APOB) interaction, plasma LDL elevation, and hypercholesterolemia. We previously identified the first French FDB-R3531C proband, a woman with very high total cholesterol, in a group of type IIa hypercholesterolemic families. We report here the investigation of her family at large that revealed the total absence of cosegregation with hypercholesterolemia. Six of the 10 subjects heterozygous for the R3531C mutation had plasma cholesterol lower than the 97.5th percentile for their age and gender, and mean cholesterol levels were not significantly different between affected and unaffected persons. Furthermore, 2 family members with similar high LDL-cholesterol levels were not carriers of the R3531C substitution, suggesting the implication of another mutation. Segregation analysis of the LDLR gene revealed statistically significant genetic linkage with hypercholesterolemia, and analysis of the proband LDLR gene led to the identification of the 664 proline to leucine defective mutation and its detection in all 6 hypercholesterolemic-related members of this family. Therefore, our results show that the family presents with familial hypercholesterolemia and give evidence that the R3531C substitution in the APOB gene is not an allelic variant leading to FDB. Furthermore, thorough analysis of our data suggests that the APOB-R3531C mutation enhances the hypercholesterolemic effect of the LDLR-P664L defect, suggesting that it is a susceptibility mutation.     

Long-term (14 years) effect of LDL apheresis on obstructive changes in aortocoronary saphenous-vein bypass grafts in a case of heterozygous familial hypercholesterolemia with the LDL receptor proline664 to leucine mutation

A 61-year-old Japanese woman with heterozygous familial hypercholesterolemia (FH), type 2 diabetes mellitus and coronary artery disease underwent coronary artery bypass grafting (CABG) utilizing a saphenous vein graft at the age of 46, in June 1984, 6 months before low density lipoprotein (LDL) apheresis was started. She had received LDL apheresis every two weeks, along with combined drug treatment since the age of 47 (December 1984). She had bilateral xanthelasma and Achilles tendon xanthomas. Her fasting baseline serum total cholesterol and triglyceride level were 464 mg/dl and 57 mg/dl, respectively at the age of 47 when she visited our hospital for the first time. Analysis of the genomic DNA from the patient revealed heterozygous amino acid substitution of Leu for Pro664 in the LDL receptor gene. She was diagnosed as type 2 diabetes mellitus at the age of 53. Combined treatment in the steady state yielded a pretreatment LDL cholesterol level of 230+/-14 mg/dl and a posttreatment level of 57+/-7.6. All grafts were widely patent after as long as 14 years since CABG, suggesting that LDL apheresis combined with drug therapy is highly effective in preventing the occlusion of bypass grafts in a patient with heterozygous FH and type 2 diabetes mellitus.     

Detection of silent coronary artery disease in adolescents and young adults with familial hypercholesterolemia by single-photon emission computed tomography thallium-201 scanning.

Familial hypercholesterolemia (FH), a genetic disease characterized by increased levels of total and low-density lipoprotein cholesterol in the blood, results in a markedly increased incidence of atherosclerosis and coronary artery disease in homozygotes and to a lesser extent in heterozygotes. The purpose of this study was to detect the presence of myocardial ischemia, particularly in heterozygotes, with stress single-photon emission computed tomography thallium-201 scanning and to determine if there were any differentiating variables between heterozygotes with normal and abnormal thallium-201 scans. Fifty-four patients (mean age 16 years; range 8 to 24) with FH were analyzed (4 homozygotes and 50 heterozygotes). Eleven heterozygotes and 3 homozygotes had abnormal thallium-201 scans. Family history, lipid profile, age and sex of heterozygotes with FH did not predict the presence of myocardial ischemia. The mean total cholesterol level in heterozygotes with normal thallium-201 scans was 7.68 +/- 2.29 mmol/liter (297 mg/dl), which was not significantly different from that in heterozygotes with abnormal scans (7.63 +/- 1.07 mmol/liter [295 mg/dl]; p = 0.91). The coronary angiography of 1 homozygote who had an abnormal thallium-201 scan demonstrated a 50% stenosis of the left anterior descending artery. Aggressive, repetitive plasma exchange was then instituted. The 11 heterozygotes with abnormal thallium-201 scans underwent more rigorous dietary and drug therapy. It is concluded that myocardial ischemia with stress in heterozygotes with FH can occur at a young age and that thallium-201 scanning should be performed early as a screening test and to guide patient management.