Oligogenic familial hypercholesterolemia, LDL cholesterol, and coronary artery disease

The genetic background of severe familial hypercholesterolemia (FH) has yet to be determined.We tested if genetic variants associated with low-density lipoprotein (LDL)-altering autosomal recessive diseases influenced LDL cholesterol levels and the odds for coronary artery disease in patients with high LDL cholesterol.We recruited 500 individuals with elevated LDL cholesterol levels (≥180 mg/dL or ≥140 mg/dL for subjects <15 years). We sequenced the exons of 3 FH genes (LDLR, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9) and 4 LDL-altering accessory genes (ABCG5, ABCG8, APOE, and LDL receptor adaptor protein 1). In addition, 4 single nucleotide polymorphisms associated with polygenic FH in East Asian subjects were genotyped. Oligogenic FH patients were defined as those who harbored damaging variants of both conventional FH genes and LDL-altering accessory genes.We identified damaging variants of conventional FH genes in 248 participants (50%). We also detected damaging variants in accessory genes in 57 patients (11%) and identified oligogenic FH in 27 of these patients (5%). Polygenic score in the subjects without any FH mutations was significantly higher than those in any other groups. Compared with monogenic FH, oligogenic FH exhibited significantly higher LDL cholesterol (265 mg/dL, 95% confidence interval [CI] 216-312, and 210 mg/dL, 95% CI 189-243; P = .04). Oligogenic FH exhibited higher odds for coronary artery disease when compared with monogenic FH, although it did not reach statistical significance (odds ratio 1.41, 95% CI 0.68-2.21, P = .24).Among patients with elevated LDL cholesterol, those with oligogenic FH had higher LDL cholesterol than monogenic FH.