Low-density Lipoprotein Receptor Genotype Research Articles

Efficacy of evinacumab by low-density lipoprotein receptor genotype and function in patients with homozygous familial hypercholesterolaemia: A subanalysis from the ELIPSE open-label extension study

Efficacy of evinacumab by low-density lipoprotein receptor genotype and function in patients with homozygous familial hypercholesterolaemia: A subanalysis from the ELIPSE open-label extension study

Association of LDLR Gene Polymorphism with the Risk of Cardiovascular Disease in End-Stage Kidney Disease Patients on Maintenance Hemodialysis

Background The low-density lipoprotein receptor (LDLR) is essential for regulating intracellular cholesterol levels. Mutations in the LDLR gene can cause a increase in LDL cholesterol levels in the blood, elevating the vulnerability to cardiovascular disease (CVD). This study evaluated the correlation between the LDLR rs688 polymorphism and CVD risk in chronic kidney disease (CKD). Materials and Methods Polymorphism in this case-control study was genotyped using the TaqMan real-time polymerase chain reaction in a cohort of 100 CKD patients (Group I) and 100 healthy controls (Group II). We examined the LDLR rs688 allele and genotype distribution in 50 CKD cases with CVD and 50 cases without CVD. Results There was a significantly greater frequency of CT variant of LDL SNP rs688 in Group I than in Group II (p = 0.006). CT and TT genotypes were significantly higher in CKD patients with CVD, with odds ratios (ORs) (95% CI) of 4.3 (1.6–11.8, p = 0.004) and 7.6 (2.3–24.8, p = 0.001), respectively. Conclusion SNP rs688 C>T detection in the LDLR gene showed that CT and TT genotypes are associated with elevated CVD risk in CKD.

Low-density lipoprotein receptor genotypes modify the sera metabolome of patients with homozygous familial hypercholesterolemia

Homozygous familial hypercholesterolemia (HoFH) is an extremely rare metabolism disorder usually caused by low-density lipoprotein receptor (LDLR) mutations. LDLR genotype is commonly known to determine blood concentrations of LDL cholesterol. However, effects of LDLR genotype on holistic metabolome remain unclear. Herein, we present metabolomic, genetic, and clinical datasets from a large multi-center panel of 142 patients with LDLR-mutated HoFH. Wefound that true homozygotes and compound heterozygotes showed few differences in clinical and metabolomic phenotypes. Compared with defective/defective mutation carriers, patients carrying one or two null mutation showed profound alterations in clinical laboratory lipids and serum cholesterol esters, lysophosphocholines, bile acids, and amino acids. Importantly, these altered metabolites are implicated in multiple biochemical reactions and associated with LDL cholesterol. This study extends the first map of different LDLR genotypes influencing the metabolome and suggests that the small-molecule metabolites serve as potential targets to mitigate the deleterious impact of LDLR mutations on HoFH.

Influence of the LDL-Receptor Genotype on Statin Response in Heterozygous Familial Hypercholesterolemia: Insights From the Canadian FH Registry.

Whether low-density lipoprotein (LDL) receptor (LDLR) residual activity influences the LDL-lowering effect of statins in heterozygous familial hypercholesterolemia (HeFH) remains unclear. The objective of this study was to investigate the relationship between the LDLR genotype and statin-induced LDL cholesterol (LDL-C) reductions in HeFH. A total of 615 individuals with HeFH (receptor-defective [RD] genotype: n= 226; receptor-negative [RN] genotype: n= 389) from 7 lipid clinics across Canada who initiated statin monotherapy were included in this retrospective longitudinal study. Statin-induced reductions in LDL-C among individuals with RD and RN genotypes were compared with the use of linear models. There were 334 women and 281 men with a mean untreated LDL-C concentrations of 6.97 ± 1.65 mmol/L. Untreated and on-statin LDL-C levels where higher among patients with an RN genotype: untreated: RN 7.24 (95% confidence interval [CI] 6.98-7.50) mmol/L vs RD 6.70 (95% CI 6.41-6.98) mmol/L (P= 0.0002); on-statin: RN 4.50 (95% CI 4.31-4.70) vs RD 4.05 (95% CI 3.84-4.26) mmol/L (P= 0.0004). After adjustments for age, sex, smoking status, untreated LDL-C concentrations, statin type and dose, as well as the clinic where the patients were treated, the LDL-C-lowering effect of statins was significantly weaker for individuals with an RN mutation than for individuals with an RD mutation: RN:-31.1% (95% CI-34.7% to-27.4) vs RD-36.5% (95% CI-40.4% to-32.6%); P < 0.0001. The LDLR genotype was the strongest nonmodifiable independent correlate of statin-induced LDL-C reductions (R2= 2.3%; P= 0.0001). The LDLR genotype is significantly associated with statin-induced reductions in LDL-C concentrations in HeFH.

Functional polymorphisms in the LDLR and pharmacokinetics of Factor VIII concentrates

BackgroundOptimization of factor VIII (FVIII) infusion in hemophilia A would benefit from identification of FVIII pharmacokinetics (PK) determinants. The low‐density lipoprotein receptor (LDLR) contains an FVIII‐binding site and might influence FVIII clearance. Consistently, LDLR polymorphisms have been associated with FVIII levels. ObjectiveTo investigate the relationships between individual FVIII PK and functional LDLR polymorphisms. Patients/MethodsThirty‐three hemophilia A patients (FVIII coagulant activity [FVIII:C] ≤2 IU/dL) without inhibitors underwent 85 FVIII single‐dose (21.4‐51.8 IU/kg) PKs with different FVIII concentrates. Twenty patients underwent repeated PKs (2‐6). FVIII:C measured up to 72 hours was analyzed by two‐compartment model. Parameters were evaluated in relation to F8 mutations, ABO blood‐group and LDLR genotypes. ResultsF8 mutation types were not associated with PK parameters. ABO and LDLR c.1773C/T polymorphism were associated with Alpha, Alpha HL, CLD2, K1‐2, and K2‐1 parameters, suggesting an influence on the FVIII initial distribution phase. Regression analysis showed an independent association of both ABO and LDLR c.1773C/T with PK parameters (Alpha, β‐coefficient −0.311 vs 0.348; CLD2, β‐coefficient −0.335 vs 0.318), giving rise to an additive effect in subjects stratified by combined phenotypes. Differently, the LDLR c.81C/T was associated with FVIII clearance and volume of distribution at steady state, which could be related to distinct effects of polymorphisms, potentially linked to LDLR intracellular distribution and FVIII binding behavior. ConclusionsWith the limitation of different FVIII concentrates and low number of patients, our data show plausible associations of LDLR polymorphisms with FVIII PK parameters, thus supporting their investigation as candidate functional determinants of FVIII PK.

Pharmacogenetic analyses of variations of measures of cardiovascular risk in Alzheimer's dementia.

Background & objectives:Neurodegeneration affects blood pressure variations, while renal function and cerebral perfusion are impaired by vascular risk factors. This study was aimed to estimate variations of measures of cardiovascular risk in Alzheimer's dementia by pharmacogenetic analyses of the effects of angiotensin-converting enzyme (ACE) inhibitors and statins.Methods:Consecutive patients were prospectively followed to study variations of creatinine clearance and blood pressure for one year, estimated by correlating the effects of ACE inhibitors with the ACE Alu I/D polymorphism and genotypes or haplotypes of rs1800764 or rs4291, and the effects of statins with LDLR (low-density lipoprotein receptor) genotypes or haplotypes of rs11669576 (exon 8) or rs5930 (exon 10), or genotypes of rs2695121 (liver X receptor β gene). Variations of the coronary heart disease (CHD) risk according to these cardiovascular measures were also explored.Results:All polymorphisms of the 193 patients were in Hardy-Weinberg equilibrium. Genetic determinants of cardiovascular effects affected the individual variability of the response to ACE inhibitors and statins. ACE inhibitors, but not statins, reduced blood pressure for all patients. ACE inhibitors protected carriers of alleles that supposedly decrease serum ACE levels (rs1800764-T, rs4291-A, Alu II) regarding creatinine clearance variations (P<0.005), but carriers of Alu DD (P<0.02), rs1800764-C (P<0.05), or rs4291-AT (P<0.04) showed better blood pressure lowering effects. The presence of rs2695121-T (P=0.007) or rs5930-A (P=0.039) was associated with systolic blood pressure lowering, whereas rs5930-AA was protective against decrease in creatinine clearance (P=0.019). Statins lowered creatinine clearance for carriers of rs2695121-CT (P=0.026).Interpretation & conclusions:Pharmacological response of blood pressure and creatinine clearance to ACE inhibitors and statins may be genetically mediated.

Proprotein-Convertase Subtilisin-Kexin Type 9 and Low-Density Lipoprotein Receptor Genotype Distribution and Statin Association in Filipino American Women

Filipino American women (FAW) have high incidence of coronary heart disease and high low-density lipoprotein cholesterol (LDL-C). The distribution of rs11206510 proprotein-convertase subtilisin-kexin type 9 (PCSK9) and rs1122608 low-density lipoprotein receptor (LDLR) single nucleotide polymorphisms (SNPs), known for genetic influences on LDL-C, is unknown in this population. The objective of this study was to examine the genetic determinants of LDL-C, their association with LDL-C, and effects of statins on LDL-C given the genetic determinants in this high-risk population. Data were obtained from the FAW Cardiovascular Study ( N = 338) of women ages 40 to 65 years from four major U.S. cities between 2011 and 2013. Roche Modular methodology and Luminex-oligonucleotide ligation assay procedure were used for allele frequency, genotype, LDL-C, and lipid analysis. Analysis of variance was used to determine differences between genotype groups. Genotype and statin effect on LDL-C were tested using the generalized linear model procedure of SAS. The distribution of rs11206510 PCSK9 genotypes was 88% TT, 11% TC, and 1% CC, and the rs1122608 LDLR genotype distribution was 83% GG, 17% GT, and 0% TT. These SNPs showed no association with mean LDL-C in this cohort. FAW on statin medications had lower LDL levels regardless of their PCSK9 or LDLR genotypes. Most FAW had a gain-of-function allele of PCSK9 and LDLR. This predominance in FAW cohort may account for the high percentage of subjects with elevated LDL-C. In a population at high risk for hypercholesterolemia, optimal treatment with statins should be considered where appropriate.

Association of low-density lipoprotein receptor genotypes with hepatitis C viral load

Several data suggest that low-density lipoprotein receptor (LDLR) is a co-receptor for hepatitis C virus (HCV). Soluble LDLR can inhibit HCV infectivity; greater plasma low-density lipoprotein levels are associated with treatment success; LDLR genotypes have a synergistic impact on the likelihood of achieving SVR with Peg-IFN plus RBV, as well as on viral kinetics after starting treatment. The objective of this study was to assess the impact of genetic polymorphisms in genes related to cholesterol synthesis and transport pathways on pre-treatment plasma HCV viral load (VL). A total of 442 patients infected with HCV and treatment naive were prospectively recruited. One hundred forty-four SNPs located in 40 genes from the cholesterol synthesis/transport and IL28B were genotyped and analyzed for genetic association with pre-treatment plasma HCV VL. SNPs rs1433099 and rs2569540 of LDLR showed association with plasma HCV VL (P=4 × 10(-4) and P=2 × 10(-3)) in patients infected with genotypes 1 and 4. A haplotype including the last three exons of LDLR showed association with the cutoff level of 600 000 IU ml(-1) VL for genotypes 1 and 4 (OR=0.27; P=8 × 10(-6)), as well as a quantitative VL (mean±s.d.: 6.19±0.9 vs CC+CG 5.58±1.1 logIU ml(-1), P=8 × 10(-5)). LDLR genotypes are a major genetic factor influencing HCV VL in patients infected with genotypes 1 and 4.

Effects of the genetic pattern defined by low-density lipoprotein receptor and IL28B genotypes on the outcome of hepatitis C virus infection

The aim of this study was to assess the impact of the genetic pattern (GP) defined by the single nucleotide polymorphisms (SNPs) rs14158 of low-density lipoprotein receptor (LDLR) and rs12979860 of interleukin-28B (IL28B) genes on the outcome and features of hepatitis C virus (HCV) infection in patients with and without human immunodeficiency virus (HIV) coinfection. 314 HIV/HCV-coinfected and 109 HCV-monoinfected patients treated with pegylated interferon (Peg-IFN) plus ribavirin (RBV), as well as 51 patients with HCV spontaneous clearance (SC), were included. Variations in both SNPs were determined by the TaqMan polymerase chain reaction (PCR) assay. In the 286 patients chronically infected by HCV genotypes 1 or 4, both rs14158 CC and rs12979860 CC were associated with a higher rate of sustained virological response (SVR), and these effects were complementary in both HCV-monoinfected and HIV/HCV-coinfected patients. Thus, 24 % of patients with rs14158/rs12979860 TT-TC/TT-TC, 33 % with TT-TC/CC, 44.2 % with CC/TT-TC, and 75.8 % harboring CC/CC attained SVR (p < 0.001). SC was associated with the IL28B genotype (66.7 % CC in SC vs. 42.6 % among those with chronic infection, p < 0.001) but not with the LDLR genotype. There was no association between GP and the plasma level of alanine aminotransferase (ALT) or the presence of advanced fibrosis. There is a complementary effect between the IL28B and LDLR genotypes on the probability of achieving SVR after Peg-IFN/RBV therapy in patients with HCV 1 or 4. Thus, the predictive value of IL28B genotype is modulated by the LDLR genotype in both HCV-monoinfected and HIV/HCV-coinfected patients. This complementary effect of both genotypes is also observed on the plasma levels of low-density lipoprotein cholesterol (LDL-C).

A DNA Microarray for the Detection of Point Mutations and Copy Number Variation Causing Familial Hypercholesterolemia in Europe

To facilitate genetic cascade screening for familial hypercholesterolemia (FH) in Europe, two versions (7 and 9) of a DNA microarray were developed to detect the most frequent point mutations in the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. The design of these microarrays is based on LIPOchip, version 4, which detects 191 LDLR and APOB mutations identified in Spanish patients with FH. A major improvement of LIPOchip, versions 7 and 9, is the ability to detect copy number variation (deletions or duplications of entire exons) in LDLR, thus abolishing the need to perform multiplex ligase-dependent probe amplification in patients with FH. The aim of this study was to validate a tool capable of detecting point mutations and copy number variations simultaneously and to evaluate its use and the newly developed software for analysis in clinical practice by reanalysis of several patients with known mutations causing FH. With the help of these validations, several aspects were analyzed, improved, and implemented in a newer version, which was evaluated through an internal validation.

The molecular basis of familial hypercholesterolemia in the Czech Republic: Spectrum of LDLR mutations and genotype–phenotype correlations

BackgroundFamilial hypercholesterolemia (FH), a major risk for coronary heart disease, is predominantly associated with mutations in the genes encoding the low-density lipoprotein receptor (LDLR) and its ligand apolipoprotein B (APOB). ResultsIn this study, we characterize the spectrum of mutations causing FH in 2239 Czech probands suspected to have FH. In this set, we found 265 patients (11.8%) with the APOB mutation p.(Arg3527Gln) and 535 patients (23.9%) with a LDLR mutation. In 535 probands carrying the LDLR mutation, 127 unique allelic variants were detected: 70.1% of these variants were DNA substitutions, 16.5% small DNA rearrangements, and 13.4% large DNA rearrangements. Fifty five variants were novel, not described in other FH populations. For lipid profile analyses, FH probands were divided into groups [patients with the LDLR mutation (LDLR+), with the APOB mutation (APOB+), and without a detected mutation (LDLR−/APOB−)], and each group into subgroups according to gender. The statistical analysis of lipid profiles was performed in 1722 probands adjusted for age in which biochemical data were obtained without FH treatment (480 LDLR+ patients, 222 APOB+ patients, and 1020 LDLR−/APOB− patients). Significant gradients in i) total cholesterol (LDLR+ patients > APOB+ patients = LDLR−/APOB− patients) ii) LDL cholesterol (LDLR+ patients > APOB+ patients = LDLR−/APOB− patients in men and LDLR+patients > APOB+ patients >LDLR−/APOB− patients in women), iii) triglycerides (LDLR−/APOB− patients > LDLR+ patients > APOB+ patients), and iv) HDL cholesterol (APOB+ patients > LDLR−/APOB− patients = LDLR+ patients) were shown. ConclusionOur study presents a large set of Czech patients with FH diagnosis in which DNA diagnostics was performed and which allowed statistical analysis of clinical and biochemical data.

LDLr genotype modifies the impact of IL28B on HCV viral kinetics after the first weeks of treatment with PEG-IFN/RBV in HIV/HCV patients

To evaluate the effect of low-density lipoprotein receptor (LDLr) and IL28B genotypes on hepatitis C virus (HCV) viral kinetics in the first 4 weeks of treatment with pegylated-interferon (PEG-IFN)/ribavirin (RBV) in HIV patients co-infected with HCV genotype 1. HIV patients co-infected with HCV genotype 1 and naïve to PEG-IFN/RBV treatment were enrolled in a prospective study. HCV RNA viral loads were measured at baseline and at weeks 1, 2 and 4 after start of therapy. Differences in viral load decline were evaluated for IL28B (CC versus non-CC) and LDLr (CC versus non-CC) genotypes between baseline and weeks 1, 2 and 4. Additionally, the effect of LDLr genotype on HCV viral decline in IL28B CC genotype patients (CC/CC versus CC/non-CC) was analyzed. Eighty-seven HIV/HCV genotype 1 co-infected patients were included in the study. Patients carrying the LDLr-CC or IL28B-CC genotypes showed greater HCV viral decline than those with IL28B non-CC or LDLr non-CC genotypes at every time-point analyzed. CC/CC patients had higher rapid virological response (RVR) rates than CC/non-CC patients (41.2 versus 13.3%; P < 0.001). Moreover, at all time points, the CC/CC pattern was associated with greater HCV viral decline than the CC/non-CC genotype (week 1: 1.18 ± 0.51 versus 0.31 ± 0.29, P = 0.041; week 2: 1.55 ± 0.81 versus 0.93 ± 0.73, P = 0.032; week 4: 2.23 ± 1.1 versus 1.5 ± 0.94, P = 0.039). The LDLr genotype impacts on viral kinetics during the first days of starting treatment with PEG-IFN/RBV in HIV/HCV genotype 1 co-infected patients, and modifies the impact of IL28B on HCV viral decay.

Association of Several Lipid-Related Gene Polymorphisms and Blood Pressure Variation in the Bai Ku Yao Population

Sex differences in hypertension are not well known. The present study was undertaken to detect the association of nine lipid-related gene polymorphisms and blood pressure variation beween men and women in the Bai Ku Yao population. Genotyping of ATP-binding cassette transporter A1 (ABCA-1) V825I, acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) rs1044925, low-density lipoprotein receptor (LDL-R) AvaII, hepatic lipase gene (LIPC) -250G>A, endothelial lipase gene (LIPG) 584C>T, methylenetetrahydrofolate reductase (MTHFR) 677C>T, proprotein convertase subtilisin-like kexin type 9 (PCSK9) E670G, peroxisome proliferator-activated receptor delta (PPARD) +294T>C, and Scavenger receptor class B type 1 (SCARB1) rs5888 was performed in 682 normotensives and 670 hypertensives. The genotypic frequencies of LDL-R and SCARB1 in normotensives and ABCA-1, ACAT-1, LDL-R, LIPC, and MTHFR in hypertensives were different between males and females (P < 0.05-0.001). The genotypic frequencies of ABCA-1, ACAT-1, LDL-R, LIPC, MTHFR, PPARD, and SCARB1 in males and ABCA-1, LDL-R, LIPC, LIPG, and MTHFR in females were different between normotensives and hypertensives (P < 0.05-0.001). Systolic blood pressure (SBP) levels in male hypertensives were different among the LIPC, LIPG, PCSK9, and SCARB1 genotypes (P < 0.05-0.01); and diastolic blood pressure (DBP) levels were different among the ABCA-1, LDL-R, LIPC, LIPG, MTHFR, PCSK9, and PPARD genotypes (P < 0.05-0.001). SBP levels in female hypertensives were different among the LIPC, MTHFR, PCSK9, and PPARD genotypes (P < 0.05-0.01); and DBP levels were different among ABCA-1, ACAT-1, MTHFR, PCSK9, PPARD, and SCARB1 genotypes (P <0.05-0.001). The correlations between these polymorphisms and blood pressure levels were also observed. Sex differences in blood pressure levels in this population may partly attribute to the differences in some lipid-related gene polymorphisms.

Low-density lipoprotein receptor genotyping enhances the predictive value of IL28B genotype in HIV/hepatitis C virus-coinfected patients

The aims of this study were to appraise the predictive value of variations in a single-nucleotide polymorphism (SNP) in the low-density lipoprotein receptor (LDLR) gene for sustained virological response (SVR) to pegylated interferon (Peg-IFN) and ribavirin (RBV), as well as to analyze the relationship between LDLR genotype and other predictors of SVR, particularly IL28B genotype, in patients coinfected with HIV and hepatitis C virus (HCV). One hundred and eighty-four HIV/HCV-coinfected, treatment-naive patients with chronic HCV infection, who received Peg-IFN and RBV, were included. Variations in the SNP rs14158 and rs12979860 were tested by Taqman PCR assay. Twenty-eight (38%) patients with rs14158 TT/TC and 61 (55%) with CC (P = 0.028) achieved SVR. The rates of SVR in patients with rs14158 TT/TC and with CC harboring HCV 1-4 were 20 and 41% (P = 0.020), respectively, and, in those with HCV genotype 2-3, 75 and 84% (P = 0.513), respectively. Patients with rs14158 CC showed less commonly plasma HCV-RNA load at least 600000 IU/ml (57 vs. 71%, P = 0.047) and lower likelihood of relapse (13 vs. 30%, P = 0.023). In patients with HCV genotype 1-4, the rates of SVR according to the combination of IL28B/LDLR genotypes were: CC/CC = 69%; CC/non-CC: 30%; non-CC/CC: 25%; non-CC/non-CC: 14% (P < 0.001). Variations in rs14158 are associated with SVR to Peg-IFN and RBV in HIV/HCV-coinfected patients harboring HCV genotype 1-4. LDLR and IL28B genotypes seem to have a synergistic effect on SVR. The combined use of LDLR and IL28B genotypes in routine clinical practice could enhance the predictive value of IL28B genotype alone.

Diagnosis Scoring for Clinical Identification of Children With Heterozygous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is a frequent monogenic condition characterized by progressive atherosclerosis requiring preventive therapy from childhood. In a pediatric setting, heterozygous FH (hFH) in children may not be identified from common forms of hypercholesterolemia (HC). To elaborate a clinical scoring system for the diagnosis of hFH, defined by the presence of a disease-causing mutation of the gene for the low-density lipoprotein receptor (LDLR). A total of 100 unrelated children (6 +/-3 years old, 43 boys, 57 girls) with type IIa HC (LDLC >130 mg/dL) and complete genetic testing (at loci for genes for LDLR, apolipoprotein B, proprotein convertase subtilisin-like kesin type 9, and apolipoprotein E) were selected for score elaboration. Of 60 criteria from clinical records and family questionnaires, predictors of having hFH were estimated by logistic regression analysis. Scores were validated in 38 other unrelated children with HC. Three independent predictors of hFH were identified according to the LDLR genotype (50 Microt+/50 Microt-): low-density lipoprotein cholesterol before (262 vs 178 mg/dL, P < 0.001) and after (225 vs 142 mg/dL, P < 0.001) 3 months or more of a lipid-lowering diet, combined with parental statin usage (odds ratio 6.2; 95% confidence interval 1.4-28.3; P = 0.018). High precision and accuracy of the scoring system (area under the receiver operating characteristic curve = 0.94; 95% confidence interval 0.91-0.98) were translated into 4 probability classes (definite/probable/possible/improbable hFH) with a false-negative rate of 12%. A score distinguishing hFH from common HC provides a simple tool for appropriate clinical decision and care in high-risk children.

Lipoprotein lipase-facilitated uptake of LDL is mediated by the LDL receptor

LPL mediates the uptake of lipoproteins into different cell types independent of its catalytic activity. The mechanism of this process and its physiological relevance are not clear. Taking into account the importance of the endothelial barrier for lipoprotein uptake, in vitro studies with primary aortic endothelial cells from wild-type and low density lipoprotein receptor (LDLR)-deficient (LDLR(-/-)) mice were performed. Addition of LPL almost doubled the uptake of LDL into wild-type cells. However, there was virtually no LPL-mediated change of LDL uptake into LDLR(-/-) cells. Upregulation of LDLR by lipoprotein-deficient serum/lovastatin in wild-type cells resulted in a 7-fold increase of LPL-mediated LDL uptake. Uptake of chylomicron remnants was not affected by LDLR expression. In proteoglycan-deficient cells, LPL did not increase the uptake of lipoproteins. The physiological relevance of this pathway was studied in mice that were both LDLR(-/-) and transgenic for catalytically inactive LPL in muscle. In the presence of LDLR, inactive LPL reduced LDL cholesterol significantly (13-24%). In the absence of LDLR, LDL cholesterol was not affected by transgenic LPL. Metabolic studies showed that in the presence of LDLR, LPL increased the muscular uptake of LDL by 77%. In the absence of LDLR, transgenic LPL did not augment LDL uptake. Chylomicron uptake was not affected by the LDLR genotype. We conclude that LPL-mediated cellular uptake of LDL, but not of chylomicrons, is dependent on the presence of both LDLR and proteoglycans.

No association between low density lipoprotein receptor genetic variants and Alzheimer's disease risk

A number of studies suggest that brain cholesterol metabolism may play a role in Alzheimer's disease (AD) development, probably through modulation of amyloid beta production. The discovery that apolipoprotein E (APOE) epsilon4 allele is a risk factor for sporadic AD raises the possibility that the receptors to which APOE binds on the surface of neurons are also involved in the neurodegenerative process. To evaluate the relationship between low density lipoprotein receptor (LDLR) genetic variant and AD, independently or in concert with the APOE epsilon4 allele, we examined three LDLR polymorphisms located in exons 8 (rs 11669576), 10 (rs 5930), and 13 (rs 5925), in a large group of 322 Spanish AD patients and 314 controls. The current study does not demonstrate an association between LDLR genotypes or haplotypes and AD, neither in the total sample nor when the populations were stratified for the presence or absence of the APOE epsilon4 allele.

Mutational heterogeneity in low-density lipoprotein receptor gene related to familial hypercholesterolemia in Morocco

Background Familial hypercholesterolemia (FH) is an autosomal dominant disorder caused by mutations in the low-density lipoprotein receptor ( LDLR), apolipoprotein B ( APOB) and proprotein convertase subtilisin/kexin type 9 ( PCSK9) genes. Until now, molecular data concerning FH in Morocco is still limited. To gain more information in this field and to assess the contribution of these three genes in the cause of FH determinism, we analyzed six unrelated Moroccan probands and twenty-five of their family's members. Methods After LDLR and APOB genotype analysis, we screened the LDLR gene for mutations using southern blot and PCR-sequencing analysis. We also screened the APOB gene for the two common mutations R3500Q and R3531C by PCR-mediated site-directed mutagenesis. The PCSK9 gene was analyzed by direct sequencing. Results We identified three novel mutations (C25X, IVS3+5G>T, D558A) and two mutations previously described (D151N, A480E) in the LDLR gene. The R3500Q and R3531C mutations are absent in our probands and for 1 proband, the implication of LDLR, APOB and PCSK9 genes was excluded, supporting the implication of a fourth gene in the determination of FH. Conclusion These data are in agreement with our previous study that suggests a heterogeneous mutational spectrum of FH in Morocco.

Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent–offspring study

Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype–phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76–1.95; p = 0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20–0.78; p = 0.008). We could confirm that children with FH provide a better model to perform genotype–phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk.

Genetic association of low density lipoprotein receptor and Alzheimer's disease

The low density lipoprotein receptor (LDLR) is an attractive candidate gene for genetic association with Alzheimer's disease (AD) because: (i) the LDLR is an apolipoprotein E (apoE) receptor, alleles of which have been associated with AD, (ii) LDLR resides at chromosome 19p13.3 within a region linked to AD, and (iii) LDLR modulates the homeostasis of cholesterol, which itself appears associated with AD. Therefore, we evaluated whether LDLR haplotypes alter the odds of AD by performing an association study examining three LDLR single nucleotide polymorphisms (SNPs) in 118 AD patients and 133 non-AD subjects. LDLR genotypes were obtained by TaqMan allelic discrimination assays. Although individual LDLR SNPs were not associated with AD, analyses of unambiguous haplotypes suggested the hypothesis that the 211 LDLR haplotype was associated with reduced odds of AD. We then evaluated this hypothesis in a second study cohort, i.e., the Religious Orders Study. These results supported the hypothesis that the 211 LDLR haplotype is associated with reduced odds of AD. Moreover, these data suggested further associations between LDLR variants and AD. Thus, LDLR variants appear significantly associated with AD and merit additional study.