Improved Genetic Characterization of Hypercholesterolemia in Latvian Patients with Familial Hypercholesterolemia: A Combined Monogenic and Polygenic Approach Using Whole-Genome Sequencing

Abstract

Despite the implementation of next-generation sequencing-based genetic testing on patients with clinical familial hypercholesterolemia (FH), most cases lack complete genetic characterization. We aim to investigate the utility of the polygenic risk score (PRS) in specifying the genetic background of patients from the Latvian Registry of FH (LRFH). We analyzed the whole-genome sequencing (WGS) data of the clinically diagnosed FH patients (n = 339) and controls selected from the Latvian reference population (n = 515). Variant pathogenicity in FH patients was classified according to the ACMG/AMP guidelines. The low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (LPA) PRS were calculated based on the WGS data. We identified unique causative variants in 80 (23.6%) of the tested individuals (39 variants in FH genes and 4 variants in phenocopy genes, with 6 variants being novel). The LDL-C PRS was highly discriminative compared to the LPA PRS. Nevertheless, both PRS were able to explain the genetic cause of hypercholesterolemia in 26.3% of the remaining non-monogenic patients. The combined genetic analysis of monogenic and polygenic hypercholesterolemia resulted in 43.7% genetically explained hypercholesterolemia cases. Even though the application of PRS alone does not exclude monogenic testing in clinical FH patients, it is a valuable tool for diagnosis specification.

Keywords: familial hypercholesterolemia; lipoprotein (a); low-density lipoprotein cholesterol; monogenic hypercholesterolemia; polygenic risk score; severe hypercholesterolemia; whole-genome sequencing.

Figure 1

Distribution of LDL-C and LPA PRS values in FH (green) and non-FH (pink) patients vs. control group (purple). The box plots show the median, interquartile range, and minimum to maximum value of (A) LDL-C PRS values and (C) LPA PRS values in controls and hypercholesterolemia groups. Significant p-values are shown above the box plots. The density plots show the (B) LDL-C PRS and (D) LPA-C PRS distribution between controls and hypercholesterolemia groups. The dashed lines represent each group’s mean PRS value. LDL-C—low-density lipoprotein cholesterol; LPA—gene encoding lipoprotein (a); FH—familial hypercholesterolemia; Non-FH—FH patients without FH P/LP variants; PRS—polygenic risk score. *—statistically significant at p < 0.05.

Figure 2

The number of hypercholesterolemia patients with (black bars) and without (gray bars) proven FH P/LP variants in (A) LDL-C PRS quartiles and (B) LPA PRS quartiles. The proportion of FH and non-FH groups is shown above bars as a percentage. Q1—<P₂₅; Q2—P₂₅–<P₅₀; Q3—P₅₀–<P₇₅; Q4—≥P₇₅; LDL-C—low-density lipoprotein cholesterol; LPA—gene encoding lipoprotein (a); FH—familial hypercholesterolemia; Non-FH—patients without P/LP variants; PRS—polygenic risk score. *—statistically significant at p < 0.05. Chi-square test p-values for LDL-C and LPA PRS are shown in the top-left corner.