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Joep C Defesche

Publications and source records attributed to Joep C Defesche.

At least 19 recordsLinked to original sources
PubMed2006

Influence of LDL-receptor mutation type on age at first cardiovascular event in patients with familial hypercholesterolaemia.

AIMS: To investigate the influence of different LDL-receptor (LDLR) gene mutations on age at first cardiovascular event in familial hypercholesterolaemia (FH) patients. METHODS AND RESULTS: Dutch FH patients (n = 862) with known LDLR mutations from a retrospective cohort study were included. A gamma frailty Cox model was used. An event was defined as the first cardiovascular event. Gender, hypertension, smoking, diabetes, HDL cholesterol, LDL cholesterol (LDL-C), or triglycerides were included as covariates. Furthermore, the effect of LDLR mutation type on LDL and HDL cholesterol levels was investigated using mixed effects models, including gender, smoking, body mass index, and age at time of lipid measurement as covariates. A total of 86 different LDLR mutations were present in this cohort. Twenty-two percent of patients experienced an event (median age: 47.1 year; range: 25.6-85.8 years). The effect of LDLR mutation type on event-free survival is only significant in the models without LDL-C levels. Also, LDLR mutation type was significantly associated with LDL-C levels (P = 0.007), but not with HDL cholesterol levels (P = 0.12). CONCLUSION: In the present study, LDL-C levels are a more important risk factor of event-free survival than the type of LDLR mutation.

Adult↗
PubMed2006

Lipoprotein lipase gene analyses in one Turkish family and three different Chinese families with severe hypertriglyceridaemia: one novel and several established mutations.

Lipoprotein lipase (LPL, triacylglycerol acylhydrolase; EC 3.1.1.3) deficiency (OMIM 238600) is an autosomal recessive inherited condition caused by mutations in the LPL gene, either in a homozygous or in a compound heterozygous state, leading to loss of lipolytic activity and resulting in severe hypertriglyceridaemia and subsequent risk for developing pancreatitis. Numerous LPL gene mutations leading to loss of catalytic function have been described. In this present study, we describe full clinical, biochemical and molecular analyses of severe hypertriglyceridaemic individuals in one Turkish and three Chinese families. We established one novel mutation (delCT1312-1313), a new combination of mutations (S193R and I194T) and four previously reported mutations (L252R, L252V, S193R and I194T) of the LPL gene and report phenotypes for these and four previously described mutations. Finally, we show that two patients homozygous for the LPL gene delCT1312-1313 mutations are characterized by absence of LPL activity that coincides with absence of LPL protein.

Catalysis↗
PubMed2006

A functional polymorphism in the glucocorticoid receptor gene and its relation to cardiovascular disease risk in familial hypercholesterolemia.

CONTEXT: Individuals with the functional ER22/23EK variant in the glucocorticoid receptor gene are relatively resistant to the downstream consequences of glucocorticoids. Evidence suggests that carriers have a more favorable cardiovascular risk profile, but the relationship between this ER22/23EK variant and cardiovascular disease has not been hitherto assessed. OBJECTIVE: We, therefore, determined whether carriership of the ER22/23EK improves cardiovascular disease risk in patients with severe hypercholesterolemia. DESIGN, SETTING, AND PARTICIPANTS: In a multicenter cohort study, 2024 patients with heterozygous familial hypercholesterolemia, aged 18 yr and older, were genotyped for the ER22/23EK polymorphism. Patients were identified at lipid clinics throughout The Netherlands between 1989 and 2002. MAIN OUTCOME MEASURES: The primary outcome measure was cardiovascular disease. RESULTS: Seventy-six (7.8%) of 977 men and 72 (6.9%) of 1047 women were carriers of the ER22/23EK variant. A total of 395 men and 247 women had a cardiovascular event. In contrast to expected results, we observed no significant association of the ER22/23EK variant with cardiovascular disease risk (men: relative risk, 0.75; 95% confidence interval, 0.50-1.14; P = 0.2; women: relative risk, 1.37; 95% confidence interval, 0.82-2.28; P = 0.2). However, we found a significant interaction between gender and the polymorphism on cardiovascular disease (P = 0.02). CONCLUSIONS: In this large cohort of individuals with very high risk of cardiovascular disease, the association between the functional ER22/23EK polymorphism and cardiovascular risk was not significant overall, although it varied significantly by gender.

Adult↗
PubMed2006

Diagnosing familial hypercholesterolaemia: the relevance of genetic testing.

AIMS: We assembled a cohort of patients with familial hypercholesterolaemia (FH) for both basic and clinical research. We used a set of established diagnostic criteria to define FH. Some put forward that a definite diagnosis of FH is made when a mutation in the LDL-receptor (LDLR) gene is identified. We therefore set out to determine in these patients whether patients with a DNA diagnosis would differ significantly from those diagnosed clinically. METHODS AND RESULTS: We randomly selected 4000 hypercholesterolaemic patients from the Dutch Lipid Clinic network database. Phenotypical data were acquired by reviewing medical records. After review of medical records, 2400 patients could be defined as having FH. An LDLR mutation was identified in 52.3% of these patients. Patients with and without an LDLR mutation demonstrated different clinical and laboratory characteristics. Low-density lipoprotein cholesterol was higher in patients with an LDLR mutation, whereas triglycerides were higher in patients without an LDLR mutation. The phenotypic differences between the groups remained even after stratification for the presence or absence of tendon xanthomas. CONCLUSION: Despite the use of stringent clinical criteria to define FH patients, two cohorts could be identified within our study population, namely those patients with and those without an LDLR mutation. Our findings suggest that among those without an LDLR mutation, patients with other causes of dyslipidaemia may be present. These observations underline the relevance of genetic testing in FH for clinical practice, for screening purposes, and for research involving these patients.

Adult↗
PubMed2006

The effects of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 gene on glucose/insulin metabolism interact with prenatal exposure to famine.

OBJECTIVE: An adverse fetal environment may permanently modify the effects of specific genes on glucose tolerance, insulin secretion, and insulin sensitivity. In the present study, we assessed a possible interaction of the peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism with prenatal exposure to famine on glucose and insulin metabolism. RESEARCH DESIGN AND METHODS: We measured plasma glucose and insulin concentrations after an oral glucose tolerance test and determined the PPAR-gamma2 genotype among 675 term singletons born around the time of the 1944-1945 Dutch famine. RESULTS: A significant interaction effect between exposure to famine during midgestation and the PPAR-gamma2 Pro12Ala polymorphism was found on the prevalence of impaired glucose tolerance and type 2 diabetes. The Ala allele of the PPAR-gamma2 gene was associated with a higher prevalence of impaired glucose tolerance and type 2 diabetes but only in participants who had been prenatally exposed to famine during midgestation. Similar interactions were found for area under the curve for insulin and insulin increment ratio, which were lower for Ala carriers exposed to famine during midgestation. CONCLUSIONS: The effects of the PPAR-gamma2 Pro12Ala polymorphism on glucose and insulin metabolism may be modified by prenatal exposure to famine during midgestation. This is possibly due to a combined deficit in insulin secretion, as conferred by pancreatic beta-cell maldevelopment and carrier type of the Ala allele in the PPAR-gamma2 gene.

Aged↗
PubMed2005

Genetic determinants of cardiovascular disease risk in familial hypercholesterolemia.

OBJECTIVE: To investigate the contribution of polymorphisms in multiple candidate genes to cardiovascular disease (CVD) risk in a large cohort of patients with heterozygous familial hypercholesterolemia (FH). METHODS AND RESULTS: We genotyped 1940 FH patients for 65 polymorphisms in 36 candidate genes. During 91.451 person-years, 643 (33.1%) patients had at least 1 cardiovascular event. Multifactorial Cox survival analysis revealed that the G20210A polymorphism in the prothrombin gene was strongly associated with a significantly increased CVD risk (GA versus GG; P<0.001). CONCLUSIONS: In a large cohort of FH patients, we found that the G20210A polymorphism in the prothrombin gene is strongly associated with CVD risk. Our results constitute a step forward in the unraveling of the hereditary propensity toward CVD in FH and might lead to better risk stratification and hence to more tailored therapy for CVD prevention.

Adult↗
PubMed2005

Complete deficiency of the low-density lipoprotein receptor is associated with increased apolipoprotein B-100 production.

OBJECTIVE: We addressed the role of the low-density lipoprotein (LDL) receptor in determining clearance rates and production rate (PR) of apolipoprotein B (apoB) in humans. METHODS AND RESULTS: Kinetic studies using endogenous labeling of apoB with deuterated leucine were performed in 7 genetically defined patients with homozygous familial hypercholesterolemia (FH) and compared with 4 controls. The fractional catabolic rates (FCR) and PRs for apoB were determined by multicompartmental modeling. The FCRs of very-low-density lipoprotein 1 (VLDL1), VLDL2, intermediate-density lipoprotein (IDL), and LDL apoB were lower in FH than in controls, with the LDL apoB FCR being significantly lower (0.148+/-0.049 versus 0.499+/-0.099 pools x d(-1); P=0.008). Whereas receptor-defective FH patients had a total apoB PR similar to controls, receptor-null FH patients had a significantly greater total apoB PR than controls (35.97+/-10.51 versus 21.32+/-4.21 mg x kg(-1) x d(-1), respectively; P=0.02). CONCLUSIONS: This first study of apoB metabolism in homozygous FH using endogenous labeling with stable isotopes demonstrates that the LDL receptor contributes significantly to the clearance of LDL from plasma but plays a lesser role in the clearance of larger apoB-containing lipoproteins. Furthermore, these data also indicate that absence of a LDL receptor in humans substantially influences the apoB PR in vivo.

Adolescent↗
PubMed2005

Update of the molecular basis of familial hypercholesterolemia in The Netherlands.

Autosomal-dominant hypercholesterolemia (ADH) has been identified as a major risk factor for coronary vascular disease (CVD) and is associated with mutations in the low-density lipoprotein receptor (LDLR) and the apolipoprotein B (APOB) gene. Since 1991 DNA samples from clinically diagnosed ADH patients have been routinely analyzed for the presence of LDLR and APOB gene mutations. As of 2001, 1,641 index patients (164 index patients per year) had been identified, while from 2001 onward a more sensitive, high-throughput system was used, resulting in the identification of 1,177 new index patients (average=294 index patients per year). Of these 1,177 index cases, 131 different causative genetic variants in the LDLR gene and six different causative mutations in the APOB gene were new for the Dutch population. Of these 131 mutations, 83 LDLR and four APOB gene mutations had not been reported before. The inclusion of all 2,818 index cases into the national screening program for familial hypercholesterolemia (FH) resulted in the identification of 7,079 relatives who carried a mutation that causes ADH. Screening of the LDLR and APOB genes in clinically diagnosed FH patients resulted in approximately 77% of the patients being identified as carriers of a causative mutation. The population of patients with ADH was divided into three genetically distinct groups: carriers of an LDLR mutation (FH), carriers of an APOB mutation (FDB), and non-LDLR/non-APOB patients (FH3). No differences were found with regard to untreated cholesterol levels, response to therapy, and onset of CVD. However, all groups were at an increased risk for CVD. Therefore, to ultimately identify all individuals with ADH, the identification of new genes and mutations in the genes that cause ADH is of crucial importance for the ongoing national program to identify patients with ADH by genetic cascade screening.

Adult↗
PubMed2005

Genetic determinants of plasma HDL-cholesterol levels in familial hypercholesterolemia.

The objective of this study was to determine the extent to which common genetic variants can explain the variation of high-density lipoprotein cholesterol (HDL-C) plasma levels in familial hypercholesterolemia (FH). FH is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease (CVD). Although low HDL-C levels have been shown to affect the severity of the clinical phenotype, little is known about the factors that determine HDL-C levels in these patients. A cohort of 1002 heterozygous FH patients was genotyped for polymorphisms in the genes encoding for ATP-binding cassette transporter A1, apolipoprotein (apo) AIV, apoCIII, apoE, cholesteryl transfer ester protein, hepatic lipase, lipoprotein lipase, and two paraoxonases. Multiple linear regression showed that, together, these polymorphisms explain only 3.9% of the variation of HDL-C plasma levels. When significant two-way interactions between the polymorphisms were also taken into account, the explained variation rose to 12.5%. In a regression model that also incorporated sex, smoking, alcohol use, body mass index, and concomitant beta-blocker use as covariates, the explained variation of HDL-C plasma levels even increased to 32.5%. This study provides direct evidence that multiple, modestly penetrant, but highly prevalent, polymorphisms can explain a substantial part of the variation of HDL-C plasma levels in a representative large cohort of heterozygous FH patients.

ATP Binding Cassette Transporter 1↗
PubMed2005

Management of hereditary dyslipidaemia; the paradigm of autosomal dominant hypercholesterolaemia.

Inherited, or autosomal dominant, hypercholesterolaemia, with an average global prevalence of one in 500 individuals, is one of the most frequent inherited metabolic disorders. The disorder is associated with a high risk for premature cardiovascular disease (CVD) and death as a consequence of accelerated atherosclerosis. Although the molecular genetic basis is largely elucidated and effective medical treatment, in the form of inhibitors of intracellular cholesterol synthesis, is available, the disorder is severely underdiagnosed and undertreated. On the other hand, with the well-understood aetiology, the accurate diagnosis, the availability of sensitive predictive makers and efficacious therapy, this disorder can serve as a model for disease management: from early presymptomatic diagnosis, accurate prognosis, optimal treatment and large-scale screening to population-based prevention of CVD.

Dyslipidemias↗
PubMed2004

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.

Adolescent↗
PubMed2004

Advanced method for the identification of patients with inherited hypercholesterolemia.

Familial hypercholesterolemia (FH) has a prevalence of 1 in 500 in Western society and predisposes for premature cardiovascular disease. Lipid-lowering treatment of affected individuals is widely advocated. Maximum health benefit can be obtained in FH if treatment is started as early as possible, as the World Health Organization has recently recommended. In 1994 we initiated an active case-finding program for individuals with FH, based on family investigation and DNA-testing. In an initial pilot study we established that active family screening supported by DNA diagnostics resulted in the identification of substantial numbers of FH heterozygotes and determined that diagnosis by DNA analysis was superior to conventional cholesterol measurement. Since its initiation, the program has led to the identification of more than 6000 individuals with FH, of whom the greatest part was not adequately treated at the time of identification. Our findings indicate not only that this case-finding approach is effective in identifying FH patients who otherwise would not have been identified but also that the vast majority of these patients seek treatment and are successfully started on cholesterol-lowering therapy to reduce their risk of premature cardiovascular disease. Here we describe an effective model to identify and bring under treatment large numbers of individuals affected by FH.

Cardiovascular Diseases↗
PubMed2004

Cost-effectiveness analysis of the genetic screening program for familial hypercholesterolemia in The Netherlands.

Familial hypercholesterolemia (FH) is associated with pronounced atherosclerosis leading to premature cardiovascular disease and untimely death. Despite the availability of effective preventative drug treatments, many affected individuals remain undiagnosed and untreated until they become symptomatic with cardiovascular disease. To assess the cost-effectiveness of systematic genetic screening of family members of persons diagnosed with FH, an analysis was conducted using data from a nationwide screening program for the identification of individuals with FH, instituted in The Netherlands in 1994, and from other sources. There was DNA testing of families with a known genetic defect to identify new cases of FH in the presymptomatic stage of the disease. After identification, most newly identified patients were started on cholesterol-lowering statin treatment. On average, new cases diagnosed by the screening program gained 3.3 years of life each. Twenty-six myocardial infarctions would be avoided for every 100 persons treated with statins between the ages of 18 and 60 years. The average total lifetime incremental costs, over all age ranges and both sexes, including costs for screening and testing, lifetime drug treatment, and treatment of cardiovascular events, was US dollars 7500 per new case identified. Cost per life-year gained was US dollars 8700. Therefore, systematic genetic screening of family members of persons diagnosed with FH is cost-effective in The Netherlands and should be considered for other settings.

Adolescent↗
PubMed2004

Low-density lipoprotein receptor--its structure, function, and mutations.

Uptake of cholesterol, mediated by the low-density lipoprotein (LDL)-receptor, plays a crucial role in lipoprotein metabolism. The LDL-receptor is responsible for the binding and subsequent cellular uptake of apolipoprotein B- and E-containing lipoproteins. To accomplish this, the receptor has to be transported from the site of synthesis, the membranes of the rough endoplasmatic reticulum (ER), through the Golgi apparatus, to its position on the surface of the cellular membrane. The translation of LDL-receptor messenger RNA into the polypeptide chain for the receptor protein takes place on the surface-bound ribosomes of the rough ER. Immature O-linked carbohydrate chains are attached to this integral precursor membrane protein. The molecular weight of the receptor at this stage is 120.000 d. The precursor-protein is transported from the rough ER to the Golgi apparatus, where the O-linked sugar chains are elongated until their final size is reached. The molecular weight has then increased to 160.000 d. The mature LDL-receptor is subsequently guided to the "coated pits" on the cell surface. These specialized areas of the cell membrane are rich in clathrin and interact with the LDL-receptor protein. Only here can the LDL-receptor bind LDL-particles. Within 3 to 5 minutes of its formation, the LDL-particle-receptor complex is internalized through endocytosis and is further metabolized through the receptor-mediated endocytosis pathway. Mutations in the gene coding for the LDL-receptor can interfere to a varying extent with all the different stages of the posttranslational processing, binding, uptake, and subsequent dissociation of the LDL-particle-LDL-receptor complex, but invariably the mutations lead to familial hypercholesterolemia. Thus, mutations in the LDL-receptor gene give rise to a substantially varying clinical expression of familial hypercholesterolemia.

Genotype↗
PubMed2004

Familial defective apolipoprotein B versus familial hypercholesterolemia: an assessment of risk.

Patients with familial hypercholesterolemia (FH) or familial defective apolipoprotein B (FDB) have severely increased low-density lipoprotein (LDL)-cholesterol levels and increased risk for premature coronary artery disease (CAD). Previous data on FDB patients were collected in patients referred to lipid clinics and were therefore subject to referral bias. We assessed the clinical phenotype of FDB in a population free from selection on CAD to compare the atherosclerotic burden with that of heterozygous FH. The study population was actively recruited in a large-scale screening program for inherited hypercholesterolemia in which FH and FDB heterozygotes were diagnosed by standard molecular techniques. Patients with FH and FDB had significantly higher plasma total cholesterol and LDL-cholesterol levels compared with their unaffected relatives. As with previous findings in FH, in FDB 19% of the carriers and 17% of the noncarriers of apoB mutations would have been misdiagnosed by cholesterol measurement alone, taking the age- and sex-specific 95th percentile as the diagnostic criterion. In FH patients the CAD risk was 8.5 relative to unaffected family members, whereas FDB patients had a 2.7-fold higher risk of CAD than unaffected relatives. FDB patients, free from clinical selection bias, do show lower total and LDL-cholesterol levels and lower CAD risk compared with FH heterozygotes. However, FDB patients are still exposed to a substantially higher CAD risk compared with unaffected relatives.

Apolipoproteins B↗
PubMed2003

Family history and cardiovascular risk in familial hypercholesterolemia: data in more than 1000 children.

BACKGROUND: Elevated LDL cholesterol (LDL-C) levels in childhood predict cardiovascular disease (CVD) later in life. Familial hypercholesterolemia (FH) represents the paradigm of this relation. METHODS AND RESULTS: The objectives of this study were to (1) establish the LDL-C level that provides the most accurate diagnosis of FH in children from families with known FH and (2) assess whether lipoprotein variation in these children is associated with premature CVD in relatives. Foremost, however, it was our objective to identify children with FH who are at high risk and in need of early intervention. A total of 1034 consecutive children from FH kindreds were investigated. First, LDL-C levels >3.50 mmol/L had a 0.98 post-test probability (95% CI, 0.96 to 0.99) of predicting the presence of an LDL receptor mutation. Second, children with FH in the highest LDL-C tertile (>6.23 mmol/L) had a 1.7-times higher incidence (95% CI, 1.24 to 2.36) of having a parent with FH suffering from premature CVD (P=0.001). In addition, such a parent was found 1.8 times more often (95% CI, 1.20 to 2.59) among children with FH who had HDL-C <1.00 mmol/L (P=0.004). Last, children with FH whose lipoprotein(a) was >300 mg/L had a 1.45-times higher incidence (95% CI, 0.99 to 2.13) of having a parent with FH suffering from premature CVD (P=0.05). CONCLUSIONS: In FH families, LDL-C levels allow accurate diagnosis of FH in childhood. Moreover, increased LDL-C and lipoprotein(a) and decreased HDL-C levels in children identify FH kindreds with the highest CVD risk.

Adolescent↗
PubMed2003

The apolipoprotein epsilon4 allele confers additional risk in children with familial hypercholesterolemia.

Children with familial hypercholesterolemia (FH) exhibit substantial variance of LDL cholesterol. In previous studies, family members of children with FH were included, which may have influenced results. To avoid such bias, we studied phenotype in 450 unrelated children with FH and in 154 affected sib-pairs. In known families with classical FH, diagnosis was based on plasma LDL cholesterol above the age- and gender-specific 95th percentile. Girls had 0.47 +/- 0.15 mmol/L higher LDL cholesterol, compared with boys (p = 0.002). Also in girls, HDL cholesterol increased by 0.07 +/- 0.03 mmol/L per 5 y (pfor trend = 0.005); this age effect was not observed in boys. The distribution of apolipoprotein (apo) E genotypes was not significantly different between probands, their paired affected siblings, or a Dutch control population. Carriers with or without one epsilon4 allele had similar LDL and HDL cholesterol levels. Within the affected sib-pairs, the epsilon4 allele explained 72.4% of the variance of HDL cholesterol levels (-0.15 mmol/L, 95% confidence interval -0.24 to -0.05, p = 0.003). The effect of apoE4 on HDL cholesterol differed with an analysis based on probands or on affected sib-pairs. The affected sib-pair model used adjustment for shared environment, type of LDL receptor gene mutation, and a proportion of additional genetic factors and may, therefore, be more accurate in estimating effects of risk factors on complex traits. We conclude that the epsilon4 allele was associated with lower HDL cholesterol levels in an affected sib-pair analysis, which strongly suggests that apoE4 influences HDL cholesterol levels in FH children. Moreover, the strong association suggests that apoE4 carries an additional disadvantage for FH children.

Adolescent↗