Twelve Variants Polygenic Score for Low-Density Lipoprotein Cholesterol Distribution in a Large Cohort of Patients With Clinically Diagnosed Familial Hypercholesterolemia With or Without Causative Mutations

Abstract

Background A significant proportion of individuals clinically diagnosed with familial hypercholesterolemia (FH), but without any disease-causing mutation, are likely to have polygenic hypercholesterolemia. We evaluated the distribution of a polygenic risk score, consisting of 12 low-density lipoprotein cholesterol (LDL-C)-raising variants (polygenic LDL-C risk score), in subjects with a clinical diagnosis of FH. Methods and Results Within the Lipid Transport Disorders Italian Genetic Network (LIPIGEN) study, 875 patients who were FH-mutation positive (women, 54.75%; mean age, 42.47±15.00 years) and 644 patients who were FH-mutation negative (women, 54.21%; mean age, 49.73±13.54 years) were evaluated. Patients who were FH-mutation negative had lower mean levels of pretreatment LDL-C than patients who were FH-mutation positive (217.14±55.49 versus 270.52±68.59 mg/dL, P<0.0001). The mean value (±SD) of the polygenic LDL-C risk score was 1.00 (±0.18) in patients who were FH-mutation negative and 0.94 (±0.20) in patients who were FH-mutation positive (P<0.0001). In the receiver operating characteristic analysis, the area under the curve for recognizing subjects characterized by polygenic hypercholesterolemia was 0.59 (95% CI, 0.56-0.62), with sensitivity and specificity being 78% and 36%, respectively, at 0.905 as a cutoff value. Higher mean polygenic LDL-C risk score levels were observed among patients who were FH-mutation negative having pretreatment LDL-C levels in the range of 150 to 350 mg/dL (150-249 mg/dL: 1.01 versus 0.91, P<0.0001; 250-349 mg/dL: 1.02 versus 0.95, P=0.0001). A positive correlation between polygenic LDL-C risk score and pretreatment LDL-C levels was observed among patients with FH independently of the presence of causative mutations. Conclusions This analysis confirms the role of polymorphisms in modulating LDL-C levels, even in patients with genetically confirmed FH. More data are needed to support the use of the polygenic score in routine clinical practice.

Keywords: familial hypercholesterolemia; molecular diagnosis; polygenic risk score.

Figure 1. Distribution (A) and mean (SD) values (B) of the LDLc‐score in FH/M− and FH/M+ patients with FH.

FH indicates familial hypercholesterolemia; FH/M+, patients with mutation‐positive FH; FH/M−, patients with mutation‐negative FH; and LDLc‐score, polygenic low‐density lipoprotein cholesterol risk score.

Figure 2. Mean values of LDLc‐score by LDL‐C classes in patients with FH/M− and FH/M+ FH.

FH indicates familial hypercholesterolemia; FH/M+, patients with mutation‐positive FH; FH/M−, patients with mutation‐negative FH; LDL‐C, low‐density lipoprotein cholesterol; and LDLc‐score, polygenic LDL‐C risk score. *** means Pvalue for differences among gentic classes lower than 0.001 (P value<0.001).

Figure 3. Correlation between LDL‐C levels and LDLc‐score in mutation‐negative (A) and mutation‐positive (B) FH patients.

FH indicates familial hypercholesterolemia; LDL‐C, low‐density lipoprotein cholesterol; and LDLc‐score, polygenic LDL‐C risk score.