Diagnosing familial hypercholesterolaemia: the relevance of genetic testing.

Contains fulltext : 50569.pdf (publisher's version ) (Closed access)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

Erythrocyte glutathione concentration and production during hyperinsulinemia, hyperglycemia, and endotoxemia in healthy humans.

In diabetes mellitus and sepsis, low erythrocyte glutathione (GSH) concentrations are found. Whether this is caused by lowered GSH production has not been clarified. To obtain insight in the relationship between erythrocyte GSH concentrations and GSH production, GSH kinetics were measured in healthy male volunteers during 4 different clamps (low-dose or medium-dose insulin [100 or 400 pmol/L] and euglycemia or hyperglycemia [5 or 12 mmol/L]) in a control setting (n = 6; all 4 clamps in the same subject) or after systemic administration of lipopolysaccharide (to mimic sepsis) (4 groups of n = 6; each clamp in a different subject). Hyperinsulinemia decreased erythrocyte GSH concentration (P = .042), but did not affect fractional synthetic rate (FSR) of GSH. Hyperglycemia did not affect erythrocyte GSH concentration, but decreased FSR of GSH (P = .025). Lipopolysaccharide decreased erythrocyte GSH concentration (P <.001), but increased FSR of erythrocyte GSH (P = .035). Depending on the metabolic circumstances, we found either stable GSH concentrations with lower production rates or decreased levels with either no change or an increase in production rate. Based upon these data, it seems inappropriate to infer conclusions about changes in synthesis rate of GSH from changes in its concentration

Familial sudden death is an important risk factor for primary ventricular fibrillation: a case-control study in acute myocardial infarction patients.

Contains fulltext : 49329.pdf (publisher's version ) (Closed access)BACKGROUND: Primary ventricular fibrillation (VF) accounts for the majority of deaths during the acute phase of myocardial infarction. Identification of patients at risk for primary VF remains very poor. METHODS AND RESULTS: We performed a case-control study in patients with a first ST-elevation myocardial infarction (STEMI) to identify independent risk factors for primary VF. A total of 330 primary VF survivors (cases) and 372 controls were included; patients with earlier infarcts or signs of structural heart disease were excluded. Baseline characteristics, including age, gender, drug use, and ECG parameters registered well before the index infarction, as well as medical history, were not different. Infarct size and location, culprit coronary artery, and presence of multivessel disease were similar between groups. Analysis of ECGs performed at hospital admission for the index STEMI revealed that cumulative ST deviation was significantly higher among cases (OR per 10-mm ST deviation 1.59, 95% CI 1.25 to 2.02). Analysis of medical histories among parents and siblings showed that the prevalence of cardiovascular disease was similar between cases and controls (73.1% and 73.0%, respectively); however, familial sudden death occurred significantly more frequently among cases than controls (43.1% and 25.1%, respectively; OR 2.72, 95% CI 1.84 to 4.03). CONCLUSIONS: In a population of STEMI patients, the risk of primary VF is determined by cumulative ST deviation and family history of sudden death

High levels of protein C are determined by PROCR haplotype 3

Contains fulltext : 95956.pdf (publisher's version ) (Closed access)BACKGROUND: Genetic determinants of plasma levels of protein C (PC) are poorly understood. Recently, we identified a locus on chromosome 20 determining high PC levels in a large Dutch pedigree with unexplained thrombophilia. Candidate genes in the LOD-1 support interval included FOXA2, THBD and PROCR. OBJECTIVES: To examine these candidate genes and their influence on plasma levels of PC. PATIENTS/METHODS: Exons, promoter and 3'UTR of the candidate genes were sequenced in 12 family members with normal to high PC levels. Four haplotypes of PROCR, two SNPs in the neighboring gene EDEM2 and critical SNPs encountered during resequencing were genotyped in the family and in a large group of healthy individuals (the Leiden Thrombophilia Study (LETS) controls). Soluble endothelial protein C receptor (sEPCR) and soluble thrombomodulin (sTM) plasma levels were measured in the family. RESULTS: PROCR haplotype 3 (H3) and FOXA2 rs1055080 were associated with PC levels in the family but only PROCR H3 was also associated with plasma levels in the healthy individuals. Carriers of both variants had higher PC levels than carriers of only PROCR H3 in the family but not in healthy individuals, suggesting that a second determinant is present. EDEM2 SNPs were associated with PC levels, but their effect was small. PC and sEPCR levels were associated in both studies. sTM was not associated with variations of THBD or PC levels. CONCLUSIONS: Chromosome 20 harbors genetic determinants of PC and sEPCR levels and the analysis of candidate genes suggests that the PROCR locus is responsible