Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease

Area of Science:

• Genetics
• Cardiovascular Medicine
• Biochemistry

Background:

• Familial hypercholesterolemia (FH) is a genetic disorder characterized by high LDL cholesterol levels.
• The genetic underpinnings of severe FH are not fully understood, prompting investigation into various genetic factors.
• Autosomal recessive diseases affecting LDL cholesterol offer insights into FH pathogenesis.

Purpose of the Study:

• To investigate whether genetic variants associated with LDL-altering autosomal recessive diseases impact LDL cholesterol levels.
• To determine the influence of these variants on coronary artery disease risk in individuals with elevated LDL cholesterol.
• To explore the genetic basis of severe FH by examining conventional FH genes and accessory genes.

Main Methods:

• Sequencing of 3 conventional FH genes (LDLR, APOB, PCSK9) and 4 accessory genes (ABCG5, ABCG8, APOE, LRP1) in 500 individuals with elevated LDL cholesterol.
• Genotyping of 4 single nucleotide polymorphisms associated with polygenic FH in East Asian populations.
• Definition of oligogenic FH as the presence of damaging variants in both conventional FH and accessory genes.

Main Results:

• Damaging variants in conventional FH genes were found in 50% of participants.
• Accessory gene variants were detected in 11% of patients, with oligogenic FH identified in 5%.
• Oligogenic FH patients showed significantly higher LDL cholesterol levels (265 mg/dL) compared to monogenic FH (210 mg/dL) (P=.04).

Conclusions:

• Oligogenic FH is associated with higher LDL cholesterol levels than monogenic FH in patients with elevated LDL cholesterol.
• While not statistically significant, oligogenic FH showed a trend towards increased coronary artery disease odds compared to monogenic FH.
• These findings highlight the importance of considering multiple genetic factors in the etiology of severe FH.