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

Hipercolesterolèmia familiar; Aterosclerosi; Puntuació de risc genètic Familial hypercholesterolemia; Atherosclerosis; Genetic risk scores Hipercolesterolemia familiar; Aterosclerosis; Puntuaciones de riesgo genético 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 This research was funded by the Instituto de Salud Carlos III (ISCIII), and Fondo Europeo de DesarrolloRegional (FEDER) “Una manera de hacer Europa”, grants PI14/01648 (to F.B.-V. and J.M.M.-C.) and PI18/00164(to F.B.-V.), as well as by Fundacióla Maratóde TV3 grant 20152431 (to F.B.-V.), Centro de Investigación Biomédicaen Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), and Centro de Investigación Biomédicaen Red de Fisiopatología de la Obesidad y Nutrición (CIBEROBN). CIBERDEM and CIBEROBN are ISCIII projects