Familial hypercholesterolemia and coronary heart disease: A HuGE association review

University of Cambridge, Cambridge, England, United Kingdom
American Journal of Epidemiology (Impact Factor: 4.98). 10/2004; 160(5):421-9. DOI: 10.1093/aje/kwh237
Source: PubMed

ABSTRACT Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein cholesterol. The FH clinical phenotype has been shown to be associated with increased coronary heart disease and premature death. Mutations in the low density lipoprotein receptor gene (LDLR) can result in the FH phenotype, and there is evidence that receptor-negative mutations result in a more severe phenotype than do receptor-defective mutations. Mutations in the apolipoprotein B-100 gene (APOB) can result in a phenotype that is clinically indistinguishable from familial hypercholesterolemia, and mutations in this gene have also been shown to be associated with coronary heart disease. Preliminary research indicates that the FH phenotype is influenced by other genetic and environmental factors; however, it is not clear if these are synergistic interactions or simply additive effects.

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    ABSTRACT: OBJECTIVES: To systematically evaluate the cost-effectiveness of screening and treatment of familial hypercholesterolaemia (FH). METHODS: An extensive search strategy using MeSH terms was used to search Medline, Embase, EBM review (includes databases such as the Centre for Reviews and Dissemination database), the NHS Economic-Evaluation Database, the HTA database, the Cochrane Library and the Database of Abstracts of Reviews of Effects. Completed studies that evaluated cost-effectiveness of treatment and screening of FH were included. Two reviewers independently assessed the quality of the studies. The studies were assessed using the Consensus on Health-Economic Criteria and a published checklist for evaluating model-based economic evaluations (EE). RESULTS: Nine studies were identified. Three studies that focused on lipid-lowering treatment among patients with known FH suggested this strategy is highly cost-effective. Six studies reported on the cost-effectiveness of FH screening, and subsequent treatment of those identified with the condition. Compared with no screening, the incremental cost-effectiveness ratio of screening ranged from €3177-€29,554 per life year gained. The results of modelled EE were sensitive to the underlying prevalence of FH among the population being screened, the validity of the screening test and the price and efficacy of lipid-lowering therapy. CONCLUSION: Overall, cascade screening for new cases of FH appears to be cost-effective. However, there were uncertainties in the modelling methods, especially with regard to the underlying prevalence of FH, validity of the screening tests, and use of different approaches to assess the outcomes of treatment. Further health EE based on high quality and country-specific data are required.
    International journal of cardiology 03/2013; 167(6). DOI:10.1016/j.ijcard.2013.01.280
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    ABSTRACT: Epidemiological studies indicate that high midlife plasma cholesterol levels increases the risk of Alzheimer's disease. Moreover, middle-aged familial hypercholesterolemia (FH) subjects show a particularly high incidence of mild cognitive impairments (MCI). These evidence points to hypercholesterolemia as one of the modifiable risk factors focused on prevention/treatment of cognitive deterioration. The present study draws a comparison between pharmacological (lipid-lowering drug probucol) and non-pharmacological (voluntary running wheel, RW) approaches for the management of hypercholesterolemia and cognitive impairments associated with the low-density lipoprotein receptor-deficient (LDLr-/) mice, a well-established rodent model of FH. We also investigated whether exposure to environmental enrichment (EE), a feasible option to increase physical activity in young mice cohort, from birth to adolescence (PN45) yields long-term behavioral changes in adult LDLr-/- mice (PN90). We observed that both probucol and RW significantly decreased total and non-HDL plasma cholesterol levels in LDLr-/- mice. Notably, only physical exercise mitigated the spatial memory deficits of LDLr-/- mice. In addition, we showed that exposure to EE from birth until the adolescence did not mitigate the spatial memory deficits of adult LDLr-/- mice in the object location task, although it induced persistent anxyolitic-like effects in the open field arena. Collectively, our results emphasize the advantages physical exercise, in comparison to lipid-lowering drugs, for the management of cognitive deficits associated with FH.
    Neuroscience Letters 03/2013; 541. DOI:10.1016/j.neulet.2013.02.043
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    ABSTRACT: Familial hypercholesterolemia (FH), Niemann-Pick disease type C (NPC) and Tangier disease (TD) are genetic inherited disorders with impaired processing of cholesterol, caused by mutations in genes that regulate cellular uptake, intracellular movement and transport of cholesterol. Various studies have shown a crucial regulatory role of the SREBP-pathway for cellular cholesterol homeostasis in these diseases. Since cholesterol is an essential structural component of cells, we assessed the impact of a severe FH causing LDLR mutation (FH p.W556R) on the SREBP pathway in primary FH fibroblasts. Primary FH fibroblasts derived from patients with the LDL receptor mutation p.W556R were used for gene expression experiments. Gene expression studies revealed increased expressions of SREBP regulated genes HMGCR, LDLR, SREBP-2, SREBP-1, SR-BI, INSIG-1, but interestingly not SCAP. In contrast expression of ABCA1, was strongly decreased in homozygous, but not in heterozygous p.W556R fibroblasts. Gene expression experiments with LDL receptor lacking primary FH fibroblasts, revealed that SR-BI and ABCA1 are important regulators for cholesterol acquisition in FH cells, consistent with findings in cells from NPC and TD patients.
    Gene 03/2012; 499(1):218-22. DOI:10.1016/j.gene.2012.02.031

Ronald L Zimmern