RESUMEN
INTRODUCTION AND OBJECTIVES: Our objective was to approximate the prevalence of mutations in candidate genes for familial hypercholesterolemia (FH) in a middle-aged Spanish population and to establish the predictive value of criteria for clinical suspicion in the detection of causative mutations. METHODS: Unrelated individuals aged ≥ 18 years from the Aragon Workers' Health Study (AWHS) with high low-density lipoprotein cholesterol (LDL-C) and clinical suspicion of FH (participants with LDL-C concentrations above the 95th percentile, participants with premature cardiovascular disease and/or participants with high LDL-C [130 mg/dL] under statin therapy), assuming that any participant with FH exhibits at leats 1 trait, were selected and the LDLR, APOB, PCSK9, APOE, STAP1 and LDLRAP1 genes were sequenced by next generation sequencing technology. RESULTS: Of 5400 individuals from the AWHS, 4514 had complete data on lipid levels and lipid-lowering drugs, 255 participants (5.65%) met the criteria for suspicion of FH, 24 of them (9.41%) were diagnosed with hyperlipoproteinemia(a), and 16 (6.27% of those sequenced) were found to carry causative mutations in candidate genes: 12 participants carried 11 different pathogenic LDLR alleles and 4 participants carried 1 pathogenic mutation in PCSK9. LDL-C concentrations> 220 mg/dL and LDL-C> 130 mg/dL despite statin therapy showed the strongest association with the presence of mutations (P=.011). CONCLUSIONS: Our results show that the prevalence of FH in Spain is 1:282 and suggest that the combination of high untreated LDL-C and high levels of LDL-C despite statin therapy are the best predictors of a positive FH genetic test.
Asunto(s)
Hipercolesterolemia , Hiperlipoproteinemia Tipo II , Humanos , Hipercolesterolemia/diagnóstico , Hipercolesterolemia/epidemiología , Hipercolesterolemia/genética , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Persona de Mediana Edad , Mutación , Proproteína Convertasa 9/genética , España/epidemiologíaRESUMEN
BACKGROUND AND AIMS: Marked hypercholesterolemia, defined as low density lipoprotein cholesterol (LDL-C) levelsâ¯≥â¯190â¯mg/dL, may be due to LDLR, APOB, and PCSK9 variants. In a recent analysis, only 1.7% of cases had such variants. Our goal was to identify other potential genetic causes of hypercholesterolemia. METHODS: In a total of 51,253 subjects with lipid testing, 3.8% had elevated total cholesterol >300â¯mg/dL and/or LDL-C≥190â¯mg/dL. Of these, 246 were further studied, and 69 without kidney, liver, or thyroid disease and who met Dutch Lipid Clinic Network criteria of ≥6 points had DNA sequencing done at the LDLR, APOB, PCSK9, APOE, LDLRAP1, STAP1, ABCG5, ABCG8, CYP27A1, LIPA, LIPC, LIPG, LPL, and SCARB1 gene loci and also had 10 SNP analysis for a weighted high LDL-C genetic risk score. RESULTS: In the 69 subjects with genetic analyses, the following variants were observed in 37 subjects (53.6%): LDLR (nâ¯=â¯20, 2 novel), ABCG5/8 (nâ¯=â¯7, 2 novel), APOB (nâ¯=â¯3, 1 novel), CYP27A1 (nâ¯=â¯3, 1 novel), LIPA (nâ¯=â¯2, 1 novel), APOE (nâ¯=â¯2), LIPC (nâ¯=â¯1, novel), LIPG (nâ¯=â¯1, novel), and SCARB1 (nâ¯=â¯1); 14 subjects (20.3%) had a high polygenic score, with 4 (5.8%) having no variants. CONCLUSIONS: Our data indicate that in addition to variants in LDLR, APOB, PCSK9, APOE, LDLRAP1, and STAP1, variants in ABCG5/8, CYP27A1, LIPA, LIPC, and LIPG may be associated with hypercholesterolemia and such information should be used to optimize therapy.