Clinical and Molecular Genetic Risk Factors for Severe Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is an autosomal dominant disorder associated with a markedly elevated, yet heterogeneous, risk of atherosclerotic cardiovascular disease (ASCVD). To improve identification of highest-risk individuals, the International Atherosclerosis Society (IAS) introduced the concept of "severe FH." This study investigated clinical and molecular genetic risk factors associated with severe FH in Korean patients.

Patients enrolled in the Korean FH Registry were analyzed. Severe FH was defined according to IAS criteria, including the presence of ASCVD, subclinical atherosclerosis detected by imaging, or markedly elevated low-density lipoprotein cholesterol levels together with cardiovascular risk factors. FH-associated genes were analyzed using whole-exome sequencing or targeted exome sequencing. Clinical and genetic characteristics were compared between patients with severe and non-severe FH.

Among 296 patients, 172 (58%) had severe FH. Compared with patients with non-severe FH, those with severe FH were older, more frequently male, and had higher prevalence of smoking, hypertension, and diabetes mellitus. Triglyceride levels, lipoprotein(a), and high-sensitivity C-reactive protein concentrations were also significantly higher in the severe FH group. Although the frequency of pathogenic or likely pathogenic variants was numerically higher in severe FH patients (38.3% vs. 30.7%), this difference did not reach statistical significance, likely due to limited statistical power (p=0.170).

Korean patients with severe FH exhibited distinct clinical characteristics, including older age, male predominance, and a greater burden of cardiometabolic risk factors. However, the presence and type of pathogenic or likely pathogenic variants in FH-associated genes did not differ significantly between severe and non-severe FH groups.