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.

HDL Cholesterol Efflux and Serum Cholesterol Loading Capacity Alterations Associate to Macrophage Cholesterol Accumulation in FH Patients with Achilles Tendon Xanthoma

“…The latter 6 cases had a definite clinical diagnosis of FH according to the DLCN, but no pathogenic variant was identified. They are likely carriers of yet-unidentified genetic mutations associated with the hypercholesterolemic phenotype; this finding is in line with the prevalence reported in published studies of unknown mutations associated with hypercholesterolemia, reported in about 20% of FH subjects [ 49 , 50 ].…”

The Importance of Arterial Stiffness Assessment in Patients with Familial Hypercholesterolemia

“…Such patients often carry a cluster of common polymorphisms affecting several loci associated with markedly raised LDL-C levels, comparable to those observed in patients carrying FH-causative mutations. Even in patients with monogenic FH, a polygenic contribution may subsist, contributing to the variable phenotypic expression [ 11 ]. Both monogenic FH and polygenic hypercholesterolemia are found to be associated with greater risk of cardiovascular disease (CVD) than hypercholesterolemia without a known genetic cause, with monogenic FH associated with the greatest risk [ 12 ].…”

Assessing the genetic burden of familial hypercholesterolemia in a large middle eastern biobank

“…In addition to identifying single rare variants with largeeffect, we investigated the contribution of 12 common variants to LDL-C levels in the Qatari cohort [14,[33][34][35]46]. Based on the 'unlikely' FH individuals SNP LDL-C score distribution, we found 90% LDLR mutation-negative 'definite or probable' FH individuals had SNP scores above the bottom quartile (> 0.66) suggesting that high LDL-C in these individuals is likely to be due to polygenic contribution.…”