Genetically Confirmed Familial Hypercholesterolemia in Patients With Acute Coronary Syndrome

J Am Coll Cardiol. 2017 Oct 3;70(14):1732-1740. doi: 10.1016/j.jacc.2017.08.009.

Abstract

Background: Genetic screening programs in unselected individuals with increased levels of low-density lipoprotein cholesterol (LDL-C) have shown modest results in identifying individuals with familial hypercholesterolemia (FH).

Objectives: This study assessed the prevalence of genetically confirmed FH in patients with acute coronary syndrome (ACS) and compared the diagnostic performance of FH clinical criteria versus FH genetic testing.

Methods: Genetic study of 7 genes (LDLR, APOB, PCSK9, APOE, STAP1, LDLRAP1, and LIPA) associated with FH and 12 common alleles associated with polygenic hypercholesterolemia was performed in 103 patients with ACS, age ≤65 years, and LDL-C levels ≥160 mg/dl. Dutch Lipid Clinic (DLC) and Simon Broome (SB) FH clinical criteria were also applied.

Results: The prevalence of genetically confirmed FH was 8.7% (95% confidence interval [CI]: 4.3% to 16.4%; n = 9); 29% (95% CI: 18.5% to 42.1%; n = 18) of patients without FH variants had a score highly suggestive of polygenic hypercholesterolemia. The prevalence of probable to definite FH according to DLC criteria was 27.2% (95% CI: 19.1% to 37.0%; n = 28), whereas SB criteria identified 27.2% of patients (95% CI: 19.1% to 37.0%; n = 28) with possible to definite FH. DLC and SB algorithms failed to diagnose 4 (44%) and 3 (33%) patients with genetically confirmed FH, respectively. Cascade genetic testing in first-degree relatives identified 6 additional individuals with FH.

Conclusions: The prevalence of genetically confirmed FH in patients with ACS age ≤65 years and with LDL-C levels ≥160 mg/dl is high (approximately 9%). FH clinical algorithms do not accurately classify patients with FH. Genetic testing should be advocated in young patients with ACS and high LDL-C levels to allow prompt identification of patients with FH and relatives at risk.

Keywords: Dutch Lipid Clinic; Simon Broome criteria; cholesterol; genetics; low-density lipoprotein cholesterol.

MeSH terms

  • Acute Coronary Syndrome* / diagnosis
  • Acute Coronary Syndrome* / epidemiology
  • Acute Coronary Syndrome* / prevention & control
  • Adaptor Proteins, Signal Transducing / genetics
  • Apolipoprotein B-100 / genetics
  • Apolipoproteins E / genetics
  • Cholesterol, LDL / blood*
  • Comorbidity
  • Female
  • Genetic Testing / methods
  • Humans
  • Hyperlipoproteinemia Type II* / diagnosis
  • Hyperlipoproteinemia Type II* / drug therapy
  • Hyperlipoproteinemia Type II* / epidemiology
  • Hyperlipoproteinemia Type II* / genetics
  • Hypolipidemic Agents / therapeutic use*
  • Male
  • Middle Aged
  • Multifactorial Inheritance / genetics*
  • Patient Selection
  • Prevalence
  • Prognosis
  • Proprotein Convertase 9 / genetics
  • Receptors, LDL / genetics
  • Reproducibility of Results
  • Risk Assessment / methods
  • Risk Factors
  • Spain / epidemiology
  • Sterol Esterase / genetics

Substances

  • APOB protein, human
  • Adaptor Proteins, Signal Transducing
  • ApoE protein, human
  • Apolipoprotein B-100
  • Apolipoproteins E
  • Cholesterol, LDL
  • Hypolipidemic Agents
  • LDLR protein, human
  • LDLRAP1 protein, human
  • Receptors, LDL
  • STAP1 protein, human
  • LIPA protein, human
  • Sterol Esterase
  • PCSK9 protein, human
  • Proprotein Convertase 9