High risk/high priority: familial hypercholesterolemia--a paradigm for molecular medicine

Familial hypercholesterolemia provides an excellent model for demonstrating how disease prevention can be facilitated by molecular characterization of a genetic disease. To achieve the most efficient yield in terms of patient identification and coronary heart disease prevention, family information should be obtained in the primary care setting. In the majority of cases, measurement of cholesterol levels in a patient's relatives is sufficient to determine presence or absence of familial hypercholesterolemia, and DNA testing may be used in those cases in which cholesterol level is not diagnostic. DNA testing has enabled a more refined assessment of the absolute cardiovascular risks associated with familial hypercholesterolemia, which is currently estimated to have a 50% mortality rate by age 60. Recent investigations using DNA testing have suggested that familial hypercholesterolemia is implicated in one of 12 cases of cardiovascular disease in individuals aged <65 years. Only the most potent lipid-modifying therapies should be used in those found to be affected by this disorder. In this regard, it is noteworthy that the new statin rosuvastatin (Crestor; AstraZeneca) was recently shown to produce significantly greater low-density lipoprotein (LDL) cholesterol reductions and high-density lipoprotein (HDL) cholesterol increases than atorvastatin in a large study in patients with familial hypercholesterolemia, while bringing more of these patients to LDL cholesterol goals. Familial hypercholesterolemia should serve as a paradigm of molecular medicine: we understand the genetic defect, we have the tools to identify the individuals who are at high risk of disease because they have the defect, and we have therapies that can prevent clinical disease. It nevertheless requires effort on the part of clinicians to ensure that optimal risk assessment is performed and optimal treatment provided.