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Clinical phenotype in relation to the distance-to-index-patient in familial hypercholesterolemia

Joost Besseling1, Roeland Huijgen1, Seth S Martin2

  • 1Department of Vascular Medicine, Academic Medical Centre, Amsterdam, The Netherlands.

Atherosclerosis
|January 9, 2016
PubMed

Insights

Familial hypercholesterolemia (FH) phenotype severity, including LDL-C levels and cardiovascular disease risk, does not decrease with increasing family distance from the index patient. This finding supports the effectiveness of genetic cascade testing for FH management.

Area of Science:

  • Cardiovascular Genetics
  • Monogenic Disorders
  • Genetic Epidemiology

Background:

  • Familial hypercholesterolemia (FH) is a genetic disorder characterized by high levels of low-density lipoprotein cholesterol (LDL-C).
  • Cascade screening is a common method for identifying FH patients and their relatives.
  • The relationship between genetic distance from an index patient and FH phenotype severity is not well understood.

Purpose of the Study:

  • To evaluate if the severity of the familial hypercholesterolemia (FH) phenotype decreases in patients more distantly related to the index case.
  • To assess the association between distance-to-index and both LDL-C levels and cardiovascular disease (CVD) risk.

Main Methods:

  • A cohort of heterozygous FH patients identified through genetic cascade screening in the Netherlands (1994-2014) was analyzed.
  • Distance-to-index was determined based on family relationships.
  • Multivariable linear and Cox regression models were used to assess associations between distance-to-index, LDL-C levels, and CVD risk.

Main Results:

  • LDL-C levels did not significantly differ across family members at increasing distances from the index patient (1st, 2nd, 3rd, and 4th+ degree relatives).
  • The adjusted hazard ratio for CVD with increasing distance-to-index was 0.92 (95% CI: 0.82-1.03), indicating no significant increase in risk with greater distance.
  • This study included 13,374 FH patients.

Conclusions:

  • The severity of the FH phenotype, including LDL-C levels and CVD risk, does not diminish with increasing family distance from the index patient.
  • These findings support the continued use and effectiveness of genetic cascade testing for identifying and managing FH.
  • This is the first study to investigate the association between distance-to-index and phenotype severity in a monogenic disorder.
Abstract

Keywords:
Distance-to-indexFamilial hypercholesterolemiaGenotype–phenotype relationLow-density lipoprotein cholesterol

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