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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: The noninvasive and accurate evaluation of vessel characteristics in mouse models has become an intensive focus of vascular medicine. This study aimed to apply ultrasound biomicroscopy to evaluate aortic atherosclerotic progression in a low-density lipoprotein receptor (LDL-R) knockout mouse model of atherosclerosis. Ten male LDL-R(-/-)C57BL/6 mice aged 16 and 24 weeks and 8 male wild-type C57BL/6 mice aged 16 and 24 weeks were used as experimental and control groups, respectively. Ultrasound biomicroscopy was applied to detect the morphologic characteristics of the aortic root, ascending aorta, aortic arch, and carotid artery and to measure the aortic root intima-media thickness and carotid artery bifurcation. Ultrasound biomicroscopy showed a significant increase in the aortic root intima-media thickness from 0.10 ± 0.03 mm in 16-week-old mice to 0.16 ± 0.04 mm in 24-week-old mice (P < .01). The ultrasound biomicroscopically measured intima-media thickness was highly correlated with the histologic measurement (r = 0.81). Ultrasound biomicroscopy could be used for a noninvasive, accurate, and dynamic analysis of aortic atherosclerosis in LDL-R knockout mice. © 2015 by the American Institute of Ultrasound in Medicine.
    Journal of ultrasound in medicine: official journal of the American Institute of Ultrasound in Medicine 01/2015; 34(1):111-6. DOI:10.7863/ultra.34.1.111 · 1.53 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Atherosclerosis is considered the main cause of cardiovascular diseases. This is a multifactorial disease, characterized by inflammatory processes and the continuous internalization of lipid molecules into the blood vessel. Candidate gene studies have provided knowledge on the pathophysiology of this disease and have allowed postulating some polymorphisms as responsible for the genetic susceptibility in several populations. In particular, these polymorphisms that modulate certain molecular pathways such as oxidative stress, lipid metabolism and thrombogenesis are associated to the development of cardiovascular diseases. Several studies have been used to identify new variants associated with the disease enabling the discovery of new disease pathways. Although the discovery of novel genes associated with cardiovascular disease through approaches such as global scan of the genome has contributed to understanding the development of this disease, knowledge is still limited and inconclusive. The aim of this review is to identify genes and polymorphic variants associated with cardiovascular disease, according to the different approaches of genetic association analysis.
    Revista Colombiana de Cardiologia 11/2014; DOI:10.1016/j.rccar.2014.09.003
  • [Show abstract] [Hide abstract]
    ABSTRACT: Evaluation of: Raal F, Scott R, Somaratne R et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 126(20), 2408-2417 (2012). Familial hypercholesterolemia (FH) is a genetic disorder mainly caused by mutations in the LDL receptor gene. The heterozygous FH (heFH) condition is inherited in an autosomal dominant pattern and is characterized by very high levels of LDL cholesterol (LDL-C) and cardiovascular risk. Although statins reduce LDL-C levels and risk in heFH, many of these patients do not reach the current treatment goal for LDL-C below 100 mg/dl (2.5 mmol/l). Moreover, statins increase the plasma levels of PCSK9, a liver-secreted protein that binds to the LDL receptor, which prevent its recycling to the cell surface and ultimately lead to its degradation in lysosomes. Monoclonal antibodies (mAbs) against PCSK9 to reduce LDL-C levels are under clinical development by several pharmaceutical companies and have shown convincing results with regards to efficacy and safety in Phase I and II studies. Recently, the RUTHERFORD study in heFH patients who were not at goal despite maximally tolerated lipid-lowering therapy has shown that the AMG-145((R)) mAb (Amgen, CA, USA) significantly reduces LDL-C levels by 55% and allows 89% of patients to reach an LDL-C <100 mg/dl. These findings, along with similar data with the REGN727((R)) mAb (Regeneron Pharmaceuticals, NY, USA) highlight the beneficial effects of anti-PCSK9 mAbs in patients with heFH.
    Clinical Lipidology 10/2013; 8(5):513-517. DOI:10.2217/clp.13.49 · 0.86 Impact Factor

Ronald L Zimmern