Polygenic markers in patients diagnosed of autosomal dominant hypercholesterolemia in Catalonia: Distribution of weighted LDL-c-raising SNP scores and refinement of variant selection

Identifier:  imarina:8996735

Handle: https://hdl.handle.net/20.500.11797/imarina8996735

Authors:  Martín-Campos, JM; Ruiz-Nogales, S; Ibarretxe, D; Ortega, E; Sánchez-Pujol, E; Royuela-Juncadella, M; Vila, A; Guerrero, C; Zamora, A; Ferrer, CSI; Arroyo, JA; Carreras, G; Martínez-Figueroa, S; Roig, R; Plana, N; Blanco-Vaca, F

Abstract:
© 2020 by the authors. Familial hypercholesterolemia (FH) is associatedwithmutations 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 orwGS) 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.