Greater preclinical atherosclerosis in treated monogenic familial hypercholesterolemia vs. polygenic hypercholesterolemia

Atherosclerosis. 2017 Aug;263:405-411. doi: 10.1016/j.atherosclerosis.2017.05.015. Epub 2017 May 13.


Background and aims: Familial hypercholesterolemia (FH) is a common inherited disorder of low density lipoprotein-cholesterol (LDL-C) metabolism. It is associated with higher risk of premature coronary heart disease. Around 60% of patients with a clinical diagnosis of FH do not have a detectable mutation in the genes causing FH and are most likely to have a polygenic cause for their raised LDL-C. We assessed the degree of preclinical atherosclerosis in treated patients with monogenic FH versus polygenic hypercholesterolemia.

Methods: FH mutation testing and genotypes of six LDL-C-associated single nucleotide polymorphisms (SNPs) were determined using routine methods. Those with a detected mutation (monogenic) and mutation-negative patients with LDL-C SNP score in the top two quartiles (polygenic) were recruited. Carotid intima media thickness (IMT) was measured by B-mode ultrasound and the coronary artery calcium (CAC) score was performed in three lipid clinics in the UK and the Netherlands.

Results: 86 patients (56 monogenic FH, 30 polygenic) with carotid IMT measurement, and 166 patients (124 monogenic, 42 polygenic) with CAC score measurement were examined. After adjustment for age and gender, the mean of all the carotid IMT measurements and CAC scores were significantly greater in the monogenic than the polygenic patients [carotid IMT mean (95% CI): 0.74 mm (0.7-0.79) vs. 0.66 mm (0.61-0.72), p = 0.038 and CAC score mean (95%): 24.5 (14.4-41.8) vs. 2.65 (0.94-7.44), p = 0.0004].

Conclusions: In patients with a diagnosis of FH, those with a monogenic cause have a higher severity of carotid and coronary preclinical atherosclerosis than those with a polygenic aetiology.

Keywords: Carotid intima media thickness; Coronary artery calcification; Familial hypercholesterolemia; Polygenic hypercholesterolemia; Preclinical atherosclerosis.

Publication types

  • Comparative Study
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Asymptomatic Diseases
  • Biomarkers / blood
  • Carotid Artery Diseases / blood
  • Carotid Artery Diseases / diagnostic imaging
  • Carotid Artery Diseases / etiology*
  • Carotid Intima-Media Thickness
  • Cholesterol, LDL / blood
  • Computed Tomography Angiography
  • Coronary Angiography / methods
  • Coronary Artery Disease / blood
  • Coronary Artery Disease / diagnostic imaging
  • Coronary Artery Disease / etiology*
  • DNA Mutational Analysis
  • England
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Hyperlipoproteinemia Type II / blood
  • Hyperlipoproteinemia Type II / complications
  • Hyperlipoproteinemia Type II / drug therapy
  • Hyperlipoproteinemia Type II / genetics*
  • Male
  • Middle Aged
  • Multifactorial Inheritance*
  • Mutation*
  • Netherlands
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Severity of Illness Index


  • Biomarkers
  • Cholesterol, LDL