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Optimal goala mg/dL


Low 10-year risk Moderate 10-year risk High 10-year risk

160 130 100

4.1 3.4 2.6

Table 5 LDLc treatment goals according to categories of risk

Notes: aif these optimal goals are not reached, the minimum reductions in LDLc to be achieved are: 40, 50, and 60%, respectively. Abbreviation: LDLc, low-density lipoprotein cholesterol.

Several intervention studies have clearly demonstrated that a healthy diet reduce cardiovascular risk factors indepen- dently of classic risk factors (Table 2). Moreover, this kind of diet can increase the LDLc-lowering power of drugs.19 The beneficial effect is probably mediated by a variety of mechanisms including improved carbohydrate metabolism, lower blood pressure, greater antioxidant protection, and regulating inflammatory and thrombogenic processes.


In this manuscript, we have reviewed the recently genetic and molecular mechanisms described as target for hypercholes- terolemia and updated FH diagnosis and treatment.

FH has been studied widely since its first description in 1938.2 Despite this knowledge, new mutations and genes implicated in cholesterol pathway, as PCSK9 or Idol,88,91 have been recently associated with hypercholesterolemia. In fact, over 17% ofADH is caused by unknown mechanisms, because of that an exhaustive research in this way has to be done.9

Moreover, an accurate FH clinical diagnosis combined with genetic testing allows physicians to discriminate FH from other dyslipemias.104 The treatment goal in FH for decreasing CHD risk is LDLc levels but not denying the benefits obtained with lifestyle changes that reduce the environmental risk factors.


This work has been partially funded by grants FIS PS09/00665, PI06/1238, and PSE 010000-2008-5.


The authors report no conflicts of interest in this work.


  • 1.

    Goldstein JL, Hobbs HH, Brown MS. Familial hypercholesterolemia. In: Scriver CR, AB, Sly WS, Valle D, editors. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw-Hill; 2001. p. 2863–2913.

  • 2.

    Müller C. Xanthomata, hypercholesterolemia, angina pectoris. Acta Med Scand. 1938(89):75–84.

The Application of Clinical Genetics 2010:3

Familial hypercholesterolemia: genetic diagnosis

    • 3.

      Langer T, Strober W, Levy RI. The metabolism of low density lipo- protein in familial type II hyperlipoproteinemia. J Clin Invest. 1972; 51:1528–1536.

    • 4.

      Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzymeA reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci U S A. 1973;70:2084–2088.

    • 5.

      Brown MS, Goldstein JL. Familial hypercholesterolemia: defective binding of lipoproteins to cultured fibroblasts associated with impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activ- ity. Proc Natl Acad Sci U S A. 1974;71:788–792.

    • 6.

      Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34–47.

    • 7.

      Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111: 1795–1803.

    • 8.

      Damgaard D, Jensen JM, Larse ML, et al. NO genetic linkage or molecular evidence for involvement of the PCSK9, ARH or CYP7A1 genes in the familial hypercholesterolemia phenotype in a sample of Danish families without pathogenic mutations in the LDL receptor and APOB genes. Atherosclerosis. 2004;177:415–422.

    • 9.

      Graham CA, McIlhatton BP, Kirk CW, et al. Genetic screening protocol for familial hypercholesterolemia which includes splicing defects gives an improved mutation detection rate. Atherosclerosis. 2005;182:331–340.

  • 10.

    Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34: 154–156.

  • 11.

    Leitersdorf E, Tobin EJ, Davignon J, Hobbs HH. Common low-density lipoprotein receptor mutations in the French Canadian population. J Clin Invest. 1990;85:1014–1023.

  • 12.

    Lehrman MA, Russell DW, Goldstein JL, Brown MS. Alu-Alu recombination deletes splice acceptor sites and produces secreted low den- sity lipoprotein receptor in a subject with familial hypercholesterolemia. J Biol Chem. 1987;262:3354–3361.

  • 13.

    Landsberger D, Meiner V, Reshef A, et al. A nonsense mutation in the LDL receptor gene leads to familial hypercholesterolemia in the Druze sect. Am J Hum Genet. 1992;50:427–433.

  • 14.

    Koivisto UM, Turtola H, Aalto-Setala K, et al. The familial hypercho- lesterolemia (FH)-North Karelia mutation of the low density lipoprotein receptor gene deletes seven nucleotides of exon 6 and is a common cause of FH in Finland. J Clin Invest. 1992;90:219–228.

  • 15.

    Kotze MJ, Langenhoven E, Warnich L, du Plessis L, Retief AE. The molecular basis and diagnosis of familial hypercholesterolaemia in South African Afrikaners. Ann Hum Genet. 1991;55:115–121.

  • 16.

    Meiner V, Landsberger D, Berkman N, et al. A common Lithuanian mutation causing familial hypercholesterolemia in Ashkenazi Jews. Am J Hum Genet. 1991;49:443–449.

  • 17.

    Scientific Steering Committee on behalf of the Simon Broome Register Group. Mortality in treated heterozygous familial hypercho- lesterolaemia: implications for clinical management. Atherosclerosis. 1999;142:105–112.

  • 18.

    Scientific Steering Committee on behalf of the Simon Broome Register Group. Risk of fatal coronary heart disease in familial hypercholestero- laemia. BMJ. 1991;303(6807):893–896.

  • 19.

    Civeira F. Guidelines for the diagnosis and management of heterozy- gous familial hypercholesterolemia. Atherosclerosis. 2004;173: 55–68.

  • 20.

    Koivisto UM, Hamalainen L, Taskinen MR, Kettunen K, Kontula K. Prevalence of familial hypercholesterolemia among young north Karelian patients with coronary heart disease: a study based on diagnosis by polymerase chain reaction. J Lipid Res. 1993;34:269–277.

  • 21.

    Baron H, Fung S, Aydin A, Bahring S, Luft FC, Schuster H. Oligonucleotide ligation assay (OLA) for the diagnosis of familial hypercholesterolemia. Nat Biotechnol. 1996;14:1279–1282.

  • 22.

    Schuster H. High risk/high priority: familial hypercholesterolemia – a paradigm for molecular medicine. Atheroscler Suppl. 2002;2:27–30.

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