Abstract
Familial hypercholesterolemia (FH) is associated with mutations in the low-density lipoprotein (LDL) receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) genes. A pathological variant has not been identified in 30–70% of clinically diagnosed FH patients, and a burden of LDL cholesterol (LDL-c)-raising alleles has been hypothesized as a potential cause of hypercholesterolemia in these patients. Our aim was to study the distribution of weighted LDL-c-raising single-nucleotide polymorphism (SNP) scores (weighted gene scores or wGS) in a population recruited in a clinical setting in Catalonia. The study included 670 consecutive patients with a clinical diagnosis of FH and a prior genetic study involving 250 mutation-positive (FH/M+) and 420 mutation-negative (FH/M−) patients. Three wGSs based on LDL-c-raising variants were calculated to evaluate their distribution among FH patients and compared with 503 European samples from the 1000 Genomes Project. The FH/M− patients had significantly higher wGSs than the FH/M+ and control populations, with sensitivities ranging from 42% to 47%. A wGS based only on the SNPs significantly associated with FH (wGS8) showed a higher area under the receiver operating characteristic curve, and higher diagnostic specificity and sensitivity, with 46.4% of the subjects in the top quartile. wGS8 would allow for the assignment of a genetic cause to 66.4% of the patients if those with polygenic FH are added to the 37.3% of patients with monogenic FH. Our data indicate that a score based on 8 SNPs and the75th percentile cutoff point may identify patients with polygenic FH in Catalonia, although with limited diagnostic sensitivity and specificity.
Highlights
Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by elevated plasma low-density lipoprotein (LDL) cholesterol (LDL-c) >4.9 mmol/L and high risk of premature cardiovascular disease (CVD) [1]
Since only two of 44 (11 single-nucleotide polymorphism (SNP) × 4) comparisons (4.5%) were significant, it was estimated that the heterogeneity of the European population for the analyzed variants allowed the use of the 503 European samples as controls in our study
(p = 3.1 × 10−5 ) were the components of the Dutch Lipid Clinic Network (DLCN) score that mainly contributed to the difference; both were higher in the FH/M+ patients
Summary
Familial hypercholesterolemia (FH) is an autosomal codominant disease characterized by elevated plasma low-density lipoprotein (LDL) cholesterol (LDL-c) >4.9 mmol/L and high risk of premature cardiovascular disease (CVD) [1]. As quantitative traits, are influenced by common multiple susceptibility variants in several genes involved in lipoprotein metabolism [11] Such genes are mainly identified in genome-wide association studies (GWASs) [12]. We selected a sample of clinically diagnosed FH patients in Catalonia who participated in a previous genetic study about the classical candidate genes (LDLR, APOB, and PCSK9), and we calculated different weighted LDL-c-raising gene scores [16,17]. (1) devise a small-scale genetic risk score that could be used to identify polygenic FH; (2) if not all the variants are informative, refine the number of SNPs in the score; (3) calculate a putative cutoff point for diagnosing polygenic hypercholesterolemia for our population
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