Genetic diagnosis of familial hypercholesterolemia is associated with a premature and high coronary heart disease risk

Clin Cardiol. 2018 Mar;41(3):385-391. doi: 10.1002/clc.22881. Epub 2018 Mar 25.


Background: Familial hypercholesterolemia (FH) is a common autosomal dominant disease associated with premature coronary heart disease (CHD). Studies tend to show that patients with FH associated with an identified mutation (mutation+ FH) are at higher risk than patients without an identified mutation (mutation- FH). We compared the clinical and biological profile and the risk of CHD in patients with mutation+ FH and mutation- FH.

Hypothesis: In addition to LDL-C, a pathogenic mutation predicts premature CHD in FH.

Methods: We successively included all patients with suspected FH (LDL-C > 190 mg/dL if age > 18 years; LDL-C > 160 mg/dL if age < 18 years) and compared patients with a pathogenic mutation with those without an identified pathogenic mutation.

Results: We studied 179 patients with mutation+ FH and 147 with mutation- FH. The mean age was 44 (± 18) years. The lipid profile was more atherogenic in those with mutation+ FH, who had higher LDL-C (254 ± 69 mg/dL vs 218 ± 35 mg/dL; P < 0.01) and lower HDL-C (53 ± 14 mg/dL vs 58 ± 17 mg/dL; P < 0.01). Despite the more atherogenic nonlipid cardiovascular profile of patients with mutation- FH, the age of CHD onset was earlier in patients with mutation+ FH (48 vs 56 years; P = 0.026). After multiple adjustment, the presence of a positive mutation was significantly associated with premature CHD (OR: 3.0, 95% CI: 1.38-6.55, P < 0.01).

Conclusions: Patients with mutation+ FH have a more atherogenic lipid profile and a 3-fold higher risk of premature CHD, as well as earlier onset of CHD, than patients with mutation- FH.

Keywords: Dutch Lipid Clinic Network; Familial Hypercholesterolemia; Mutations; Premature Coronary Heart Disease.

MeSH terms

  • Adult
  • Cholesterol, LDL / blood
  • Cholesterol, LDL / genetics*
  • Coronary Disease / diagnosis
  • Coronary Disease / epidemiology
  • Coronary Disease / etiology*
  • DNA / genetics*
  • DNA Mutational Analysis
  • Female
  • Follow-Up Studies
  • France / epidemiology
  • Genetic Testing / methods*
  • Humans
  • Hyperlipoproteinemia Type II / complications
  • Hyperlipoproteinemia Type II / diagnosis*
  • Hyperlipoproteinemia Type II / genetics
  • Incidence
  • Male
  • Middle Aged
  • Mutation*
  • Prospective Studies
  • Risk Assessment / methods*
  • Risk Factors


  • Cholesterol, LDL
  • DNA