Monogenetic disorders of the cholesterol metabolism and premature cardiovascular disease.

Cholesterol is of vital importance for normal function of organisms. However, a high serum level is associated with an increased risk of cardiovascular disease. In this review an overview is presented of the different known monogenetic disorders of the cholesterol metabolism which lead to unfavourable lipid profiles form childhood onwards and premature cardiovascular disease. Since these monogenetic disorders have a large variety in clinical presentation, ranging from scarcely any to extreme premature cardiovascular disease, the frequency is underestimated and often the correct diagnosis is not made. This results into a missed opportunity for optimal treatment as well as for appropriate counselling of family members. Therefore, greater awareness among physicians is needed.

Variation in the von Willebrand factor gene is associated with von Willebrand factor levels and with the risk for cardiovascular disease.

High levels of von Willebrand factor (VWF) are associated with an increased risk for cardiovascular disease (CVD). Although VWF levels are strongly heritable and genetic susceptibility is an important risk factor for CVD, information on the contribution of common VWF gene variants to VWF levels and CVD risk is limited. In a case-control study of 421 young patients with a first event of acute coronary heart disease (CHD) or ischemic stroke (IS), and 409 healthy control participants (men aged ≤ 45 years, women aged ≤ 55 years), 27 haplotype-tagging single-nucleotide polymorphisms (ht-SNPs), covering the total common VWF gene variation, were selected and genotyped. The associations between these SNPs, VWF antigen (VWF:Ag) levels, VWF collagen-binding (VWF:CB) activity, and CVD risk was investigated. Two new associations were identified. For ht-SNP rs4764478 (intron 45), the increase in VWF:Ag levels and VWF:CB activity per minor allele was 0.082 (± 0.026) IU/mL (P = .001) and 0.096 (± 0.030) IU/mL (P = .002), respectively. ht-SNP rs216293 (intron 17) was associated with CVD risk (odds ratio, 1.44; 95% confidence interval [CI], 1.12-1.86 per minor allele). We confirmed the association between rs1063857 and CVD risk. Our data show that common variants in the VWF gene are associated with VWF levels and with the risk for CVD.

High von Willebrand factor levels increase the risk of stroke: the Rotterdam study.

BACKGROUND AND PURPOSE: Many studies have investigated the role of plasma von Willebrand factor level in coronary heart disease, but few have investigated its role in stroke. The aim of this study was to determine if von Willebrand factor levels are associated with the risk of stroke. METHODS: The study was part of the Rotterdam Study, a large population-based cohort study among subjects aged ≥55 years. We included 6 250 participants who were free from stroke at baseline (1997 to 2001) and for whom blood samples were available. Follow-up for incident stroke was complete up to January 1, 2005. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally with models adjusted for other potential confounders including ABO blood group. A subgroup analysis was performed in participants without atrial fibrillation. Effect modification by sex was tested on a multiplicative and on an additive scale. RESULTS: During an average follow-up time of 5.0 years, 290 first-ever strokes occurred, of which 197 were classified as ischemic. The risk of stroke increased with increasing von Willebrand factor levels (age- and sex-adjusted hazard ratios per SD increase in von Willebrand factor level: 1.12 [95% CI, 1.01 to 1.25] for stroke, 1.13 [95% CI, 0.99 to 1.29] for ischemic stroke). Adjustments for additional confounders slightly attenuated the association. The association was also present in subjects without atrial fibrillation and did not differ between sexes. CONCLUSIONS: High von Willebrand factor levels are associated with stroke risk in the general population.