RESUMEN
BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for atherosclerotic cardiovascular disease (ASCVD). Few data are available on the distribution of Lp(a) levels among subjects at different cardiovascular risk and in subjects with monogenic and polygenic dyslipidemias (familial hypercholesterolemia, FH and familial hypobetalipoproteinemia type 1, FHBL1). The aim of this study was to investigate the distribution of Lp(a) plasma levels in subjects with high and low LDL-C levels (FH and FHBL1) and in the general population. METHODS AND RESULTS: The study cohorts included 356 hypercholesterolemic patients, 212 carrying a FH causative mutation, 144 with clinical FH (mutation negative - FHneg), 52 FHBL1 and 797 free-living subjects. Lp(a) levels were significantly higher in FH subjects (both FH and FHneg) (median 12.46 mg/dl and 14.0 mg/dl, respectively) compared with FHBL1 and free-living subjects (7.68 mg/dl and 7.18 mg/dl, respectively). More, Lp(a) levels were similar in FH subjects carrying LDLR defective and null mutations and FHneg. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels (median 10.68 mg/dl and 9.20 mg/dl, respectively) compared with low and moderate CV risk (median 5.72 mg/dl and 7.80 mg/dl, respectively) (p < 0.0008). CONCLUSIONS: FH subjects exhibit higher Lp(a) levels than FHBL1 and general population. Lp(a) slightly contribute to hypercholesterolemia in FH patients. Subjects at high and very high CV risk exhibited significant higher Lp(a) levels compared with low and moderate CV risk. Combined evaluation of Lp(a) levels in FH subjects with other traditional risk factors could identify very high-risk individuals who may benefit from early aggressive treatments to avoid premature CV events.
RESUMEN
BACKGROUND: Primary Hypobetalipoproteinemias (HBL) are a group of dominant and recessive monogenic genetic disorders caused by mutations in APOB, PCSK9, ANGPTL3, MTTP, Sar1b genes and characterized by plasma levels of total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5th percentile of the distribution in a given population. Mutations in the candidate genes account only for a small proportion of subjects with HBL suggesting a role for a polygenic contribution to the low cholesterol phenotype. OBJECTIVE: To explore the complex genetic architecture of HBL we compared two polygenic risk scores in order to assess the role of the polygenic burden and the differences in the clinical phenotype between monogenic and polygenic HBL; we studied a cohort of 170 subjects with primary HBL referred over a 25-year period to 2 Italian reference centers have been studied. METHODS: The genetic analyses have been based on: Sanger sequencing, in-house NGS customized panel and two scores, PRS1 and PRS2 for the polygenic burden. RESULTS: Sixty 60 (35%) and 63 (37%) subjects had a monogenic and polygenic HBL respectively. LDL-C plasma levels were significantly lower in monogenic HBL (30.87 ± 3.12 mg/dl) compared with the non-monogenic HBL (42.80 ± 2.18 mg/dl) (p<0.002) with no differences in the percentage of fatty liver. CONCLUSION: Only PRS1 is effective in detecting polygenic HBL while PRS2 does not improve the polygenic diagnosis.
Asunto(s)
Hipobetalipoproteinemias , Trastornos del Metabolismo de los Lípidos , Proteína 3 Similar a la Angiopoyetina/genética , Apolipoproteínas B/genética , LDL-Colesterol/sangre , Humanos , Hipobetalipoproteinemias/genética , Trastornos del Metabolismo de los Lípidos/genética , Proteínas de Unión al GTP Monoméricas/genética , Herencia Multifactorial , Mutación , Proproteína Convertasa 9/genética , Factores de RiesgoRESUMEN
BACKGROUND AND AIMS: Familial hypercholesterolemia (FH) is the most relevant genetic cause of early cardiovascular disease (CVD). FH is suspected when low density lipoprotein cholesterol (LDL-C) levels exceed the 95th percentile of the population distribution. Different diagnostic scoring systems have been developed, as the Dutch Lipid Clinic Network (DLCN) score, used worldwide. The aim of the study is to describe the characteristics of FH patients of a large cohort of more than eight hundred genotyped subjects enrolled in an Italian Lipid Clinic, and evaluate the DLCN score performance applied retrospectively to the case study. METHODS: 836 hypercholesterolemic patients with LDL-C > 4.88 mmol/L were genotyped for FH causative gene variants in the LDLR, PCSK and APOB genes. Relatives of mutated patients were also analyzed by cascade screening. RESULTS: Gene variant carriers were younger, presented higher LDL-C and DLCN score and lower HDL-C levels in comparison with hypercholesterolemic (HC) non-carriers and presented a five-fold higher prevalence of previous CV events. Carotid US data available in 490 subjects showed that variant carriers had an odds ratio of 3.66 (1.43-10.24) for atherosclerotic plaques in comparison with non-carriers. Scoring system were evaluated by ROC analysis in 203 subjects without missing DLCN items and with available pre-therapy LDL-C levels, and LDL-C levels (A.U.C. = 0.737) resulted to be more performing than the DLCN score (A.U.C. = 0.662), even including carotid US data (A.U.C. = 0.641) in a modified DLCN score version. CONCLUSIONS: the DLCN score failed to demonstrate a clear superiority in predicting FH gene variants in comparison with the measure of LDL-C levels in a retrospective case study.
Asunto(s)
Hiperlipoproteinemia Tipo II , LDL-Colesterol/genética , Estudios de Cohortes , Heterocigoto , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiología , Hiperlipoproteinemia Tipo II/genética , Estudios RetrospectivosRESUMEN
BACKGROUND AND AIMS: Novel genetic determinants associated with coronary artery disease (CAD) have been discovered by genome wide association studies. Variants encompassing the CELSR2- PSRC1-SORT1 gene cluster have been associated with CAD. This study is aimed to investigate the rs629301 polymorphism association with the extent of CAD evaluated by coronary angiography (CAG), and to evaluate its associations with an extensive panel of lipid and lipoprotein measurements in a large Italian cohort of 2429 patients. METHODS AND RESULTS: The patients were collected by four Intensive Care Units located in Palermo and Verona (Italy). Clinical Records were filed, blood samples were collected, lipids and apolipoproteins (apo) were measured in separate laboratories. CAD was defined by the presence of stenotic arteries (>50% lumen diameter) by CAG. The presence of CAD was associated with the rs629301 genotype. Patients with CAD were 78% and 73% (p = 0.007) of the T/T vs. T/G + G/G genotype carriers respectively. T/T genotype was also correlated with the number of stenotic arteries, with a 1.29 (1.04-1.61) risk to have a three-arteries disease. T/T genotype correlated with higher levels of LDL-, non-HDL cholesterol, apoB, apoE and apoCIII, and lower HDL-cholesterol. Logistic Regression confirmed that rs629301was associated with CAD independently from the common risk factors, with a risk similar to that conferred by ten years of age [odds ratios were 1.43 (1.04-1.96) and 1.39 (1.22-1.58) respectively]. CONCLUSIONS: rs629301 risk allele was independently associated with the extension and severity of CAD and positively with apoE and apoB containing lipoproteins.
Asunto(s)
Cadherinas/genética , Angiografía Coronaria , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/genética , Polimorfismo de Nucleótido Simple , Factores de Edad , Anciano , Biomarcadores/sangre , Estenosis Coronaria/sangre , Estenosis Coronaria/epidemiología , Femenino , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Italia/epidemiología , Lípidos/sangre , Masculino , Persona de Mediana Edad , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
BACKGROUND AND AIMS: Proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to low density lipoprotein receptor (LDLR) through the LDLR epidermal growth factor-like repeat A (EGF-A) domain and induces receptor internalization and degradation. PCSK9 has emerged as a novel therapeutic target for hypercholesterolemia. Clinical studies with PCSK9 inhibiting antibodies have demonstrated strong LDL-c lowering effects, but other therapeutic approaches using small molecule inhibitors for targeting PCSK9 functions may offer supplementary therapeutic options. The aim of our study was to evaluate the effect of synthetic EGF-A analogs on mutated (D374Y) PCSK9-D374Y mediated LDLR degradation in vitro. METHODS: Huh7 human hepatoma cells were transiently transfected to overexpress the gain-of-function D374Y PCSK9 mutation, which has been associated with severe hypercholesterolemia in humans. RESULTS: Transient transfection of cells with PCSK9-D374Y expression vector very effectively enhanced degradation of mature LDLR in Huh7. Treatment with both EGF-A and EGF-A truncated peptides inhibited this effect and showed increased LDLR protein in Huh7 cells transfected with PCSK9-D374Y in a clear concentration dependent manner. Huh7 transfected cells treated with increasing concentration of EGF-A analogs also showed an increase internalization of labeled Dil-LDL. CONCLUSIONS: The result of our study shows that EGF-A analogs are able to effectively hamper the enhanced degradation of LDLR in liver cells expressing PCSK9-D374Y.