Biomedicines (Sep 2020)

Polygenic Markers in Patients Diagnosed of Autosomal Dominant Hypercholesterolemia in Catalonia: Distribution of Weighted LDL-c-Raising SNP Scores and Refinement of Variant Selection

  • Jesús M. Martín-Campos,
  • Sheila Ruiz-Nogales,
  • Daiana Ibarretxe,
  • Emilio Ortega,
  • Elisabet Sánchez-Pujol,
  • Meritxell Royuela-Juncadella,
  • Àlex Vila,
  • Carolina Guerrero,
  • Alberto Zamora,
  • Cristina Soler i Ferrer,
  • Juan Antonio Arroyo,
  • Gemma Carreras,
  • Susana Martínez-Figueroa,
  • Rosa Roig,
  • Núria Plana,
  • Francisco Blanco-Vaca,
  • Xarxa d’Unitats de Lípids i Arteriosclerosi (XULA)

DOI
https://doi.org/10.3390/biomedicines8090353
Journal volume & issue
Vol. 8, no. 9
p. 353

Abstract

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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.

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