Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia.
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ABSTRACT:
SUBMITTER: Hindi NN
PROVIDER: S-EPMC8468752 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Among the 146 patients enrolled in the Korean FH registry, 83 patients who had undergone appropriate LLT escalation and were followed-up for ≥ 6 months were analyzed for pathogenic variants (PVs). The achieved percentage of expected low-density lipoprotein-cholesterol (LDL-C) reduction (primary variable) and achievement rates of LDL-C < 70 mg/dL were assessed. The correlations between the treatment response and the characteristics of PVs, and the weighted 4 SNP-based score were evaluated. The primary variables were significantly lower in the PV-positive patients than in the PV-negative patients (p = 0.007). However, the type of PV did not significantly correlate with the primary variable. The achievement rates of LDL-C < 70 mg/dL was very low, regardless of the PV characteristics. Patients with a higher 4-SNP score showed a lower primary variable (R2 = 0.045, p = 0.048). Among evolocumab users, PV-negative patients or those with only defective PVs revealed higher primary variable, whereas patients with at least one null PV showed lower primary variables. The adjusted response of patients with FH to LLT showed significant associations with PV positivity and 4-SNP score. These results may be helpful in managing FH patients with diverse genetic backgrounds.
| S-EPMC7653043 | biostudies-literature
Project description:Hypercholesterolemia and statins are risk factors for aortic stenosis (AS) and vascular calcification, respectively. Whether heterozygous subjects with familial hypercholesterolemia (HeFH) treated with statins are at risk of AS is unknown. We study the prevalence of AS, aortic valve calcification (AoVC), and aortic sclerosis (ASc) in elderly subjects with HeFH in a prolonged statin treatment. Case-control study, cases were adults ?65 years of age with a genetic diagnosis of HeFH, LDLc >220 mg/dl, and statin treatment ?5 years. Controls were relatives of HeFH patients, with LDLc <190 mg/dl. Participants underwent a cardiac ultrasound for aortic valve analysis. We studied 205 subjects, 112 HeFH and 93 controls, with mean age 71.8(6.5) years and 70.0(7.3) years, respectively. HeHF, with respect to controls, presented greater gradients of aortic transvalvular pressure, 7.4(7.3) mmHg versus 5.0(2.8) mmHg, and maximum aortic velocity, 1.7(0.7) m/s versus 1.5(0.4) m/s, and lower aortic valve opening area, 2.0(0.7) cm2 versus 2.4(0.6) cm2 (all p < 0.05). AoVC and ASc were also more prevalent in HeFH (p < 0.05 between groups). Moderate/severe AS prevalence was higher among HeFH: 7.1% versus 1.1% (age- and sex-adjusted odds ratio (OR) 8.33, p = 0.03). Independent risk factors for aortic valve disease in HeFH were age and LDLc before treatment. The number of years under statin treatment was not associated with any aortic valve measurement. Subjects ?65 years with HeFH in prolonged statin treatment show more aortic valvular disease and higher frequency of AS than controls. Life-long elevated LDLc exposure, rather than time of exposure to statins, explains this higher risk.
| S-EPMC6947617 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) results in very high levels of atherogenic low-density lipoprotein (LDL) cholesterol from the time of birth. Mutations of the genes encoding for the LDL receptor, apolipoprotein B and proprotein convertase subtilisin/kexin type 9, are causes for this autosomal dominant inherited condition. Heterozygous FH is very common, while homozygous FH is rare. Affected individuals can experience premature cardiovascular disease; most homozygous patients experience this before the age of 20 years. Since effective LDL cholesterol lowering therapies are available, morbidity and mortality are decreased. The use of statins is the first choice in therapy; combining other lipid-lowering medications is recommended to lower LDL cholesterol sufficiently. In some cases, lipoprotein apheresis is necessary. In heterozygous FH, these measures are effective to lower LDL cholesterol, but in severe cases and in homozygous FH there remains an unmet need. Emerging therapies, such as the recently approved microsomal triglyceride transfer protein inhibitor and the apolipoprotein B antisense oligonucleotide, might offer further options for these patients with very high cardiovascular risk. Early diagnosis and early treatment are important to reduce cardiovascular events and premature death.
| S-EPMC4315461 | biostudies-literature
Project description:A previous study reported that the myosin regulatory light chain interacting protein (MYLIP) might serve as a novel therapeutic class for treating dyslipidemia. It contributes to variations in the levels of circulating low-density lipoprotein cholesterol (LDL-C), promoting the degradation of LDL-LDLR, thus limiting absorption. The effect of genetic variation in the MYLIP gene in a disease scenario characterized by mutations in the LDLR gene has not been previously evaluated.The aim of this study was to assess the effect of the p.N342S variant on the response to lipid-lowering therapy in Brazilian patients with heterozygous familial hypercholesterolemia (FH).A total of 156 patients with heterozygous FH were followed up for 12 months and received lipid-lowering therapy (different doses of atorvastatin with the addition of ezetimibe in over half the patients of each genotype group). Cholesterol data were assessed, and analysis of the MYLIP rs9370867 (p.N342S) genotypes was carried out by melting curve analysis.Baseline total cholesterol and baseline LDL-C levels were not different between genotypes. After 1 year of treatment, LDL-C responses (expressed as mg/dl and as %) were significantly different among genotypes (AA: -79±68 and -39±27, GA: -60±79 and -27±32, and GG: -30±83 and -15±38; P=0.02 and 0.005, respectively). In addition, FH patients carrying the AA genotype were more likely to achieve LDL-C levels of less than 130?mg/dl after 1 year of treatment (75.0%) compared with patients with the GG and GA genotypes (34.5 and 34.8%, respectively; P=0.001).Our study indicates that MYLIP p.N342S might be a pharmacogenetic marker for lipid-lowering therapy in patients with FH.
| S-EPMC4206345 | biostudies-literature
Project description:Familial hypercholesterolemia (FH), an autosomal dominant disorder of LDL metabolism that is characterized by elevated LDL-cholesterol, is commonly encountered in patients with atherosclerotic coronary heart disease. Combinations of cholesterol-lowering therapies are often used to lower LDL-cholesterol in patients with FH; however, current treatment goals for LDL-cholesterol are rarely achieved in patients with homozygous FH (HoFH) and are difficult to achieve in patients with heterozygous FH (HeFH). Therapies that lower LDL-cholesterol through LDL receptor-mediated mechanisms have thus far been largely ineffective in patients with HoFH, particularly in those with negligible (<2%) LDL receptor activity. Among patients with HeFH who were at very high risk for atherosclerotic cardiovascular disease events, combined therapy consisting of a high dose of high-intensity statin, ezetimibe, and proprotein convertase subtilisin Kexin type 9 inhibitor failed to lower LDL-cholesterol to minimal acceptable goals in more than 50%. This article provides a framework for the use of available and emerging treatments that lower LDL-cholesterol in adult patients with HoFH and HeFH. A framework is provided for the use of angiopoietin-like protein 3 inhibitors in the treatment of HoFH and HeFH.
| S-EPMC8065289 | biostudies-literature
Project description:Familial hypercholesterolemia (FH) is an autosomal dominant condition with a population prevalence of one in 300-500 (heterozygous) that is characterized by high levels of low-density lipoprotein (LDL) cholesterol, tendon xanthomata, and premature atherosclerosis and coronary heart disease (CHD). FH is caused mainly by mutations in the LDLR gene. However, mutations in other genes including APOB and PCSK9, can give rise to a similar phenotype. Homozygous FH with an estimated prevalence of one in a million is associated with severe hypercholesterolemia with accelerated atherosclerotic CHD in childhood and without treatment, death usually occurs before the age of 30 years. Current approaches for the treatment of homozygous FH include statin-based lipid-lowering therapies and LDL apheresis. Mipomersen is a second-generation antisense oligonucleotide (ASO) targeted to human apolipoprotein B (apoB)-100. This review provides an overview of the pathophysiology and current treatment options for familial hypercholesterolemia and describes novel therapeutic strategies focusing on mipomersen, an antisense apoB synthesis inhibitor. Mipomersen is distributed mainly to the liver where it silences apoB mRNA, thereby reducing hepatic apoB-100 and giving rise to reductions in plasma total cholesterol, LDL-cholesterol, and apoB concentrations in a dose-and time-dependent manner. Mipomersen has been shown to decrease apoB, LDL-cholesterol and lipoprotein(a) in patients with heterozygous and homozygous FH on maximally tolerated lipid-lowering therapy. The short-term efficacy and safety of mipomersen has been established, however, injection site reactions are common and concern exists regarding the long-term potential for hepatic steatosis with this ASO. In summary, mipomersen given alone or in combination with standard lipid-lowering medications shows promise as an adjunct therapy in patients with homozygous or refractory heterozygous FH at high risk of atherosclerotic CHD, who are not at target or are intolerant of statins.
| S-EPMC3513909 | biostudies-other
Project description:The extent of hypercholesterolemia varies considerably in patients with familial hypercholesterolemia (FH). We hypothesized that the variability of the FH phenotype might be partly explained by variation in proprotein convertase subtilisin kexin type 9 (PCSK9) activity. Individuals between 18 and 53 years of age who had been tested for a pathogenic LDLR or APOB mutation were eligible. Mutation carriers with a LDL-C level below the 75(th) percentile (called "FH low") were selected, as well as those with LDL-C above the 90(th) percentile (called "FH high"). Relatives who tested negative for the mutation were the "controls." PCSK9 plasma levels were assessed in 267 individuals who did not receive cholesterol-lowering treatment at the time of the study. Mean PCSK9 plasma levels (95% CI) were lower in the FH-low group compared with the FH-high group [152 (137-167) ng/ml vs. 186 (165-207) ng/ml, P = 0.010] and the control group [177 (164-190) ng/ml, P = 0.013]. Mean PCSK9 levels did not statistically differ between the FH-high and control groups (P = 0.50). Plasma PCSK9 levels are positively associated with LDL-C levels in FH patients and might contribute to the phenotypic severity in this disorder. Therefore, the results of pharmaceutical inhibition of PCSK9 in FH patients are eagerly awaited.
| S-EPMC3329397 | biostudies-literature
Project description:BackgroundData on treatment results of lipid-lowering therapy (LLT) in familial hypercholesterolemia (FH) are limited, particularly in Asian patients.HypothesisWe sought to evaluate the target achievement rate and associated variables in Korean patients with FH after maximal statin-based LLT.MethodsWe enrolled 146 patients with heterozygous FH, and 90 patients were finally analyzed. Patients were initially prescribed rosuvastatin 10 mg or atorvastatin 20 mg, and the regimen was adjusted to achieve the low-density lipoprotein cholesterol (LDL-C) target of 100 mg/dL. The primary evaluation point was the achievement rate of the LDL-C targets at 12 months: LDL-C < 100 mg/dL and ≥50% LDL-C reduction. The associations between clinical variables and target achievement were also analyzed.ResultsAt 12 months, 58% of patients were receiving high-intensity regimens, whereas 46% were receiving combination therapy. The mean pre- and post-treatment LDL-C levels were 229 and 118 mg/dL, respectively. Twenty-eight percent of patients achieved LDL-C < 100 mg/dL, and 47% achieved ≥50% LDL-C reduction. Pretreatment LDL-C and high-intensity regimens indicated a negative tendency toward the attainment of LDL-C < 100 mg/dL. Conversely, pretreatment LDL-C and diabetes mellitus were positively associated with a higher rate of ≥50% LDL-C reduction.ConclusionsThe target achievement of LDL-C < 100 mg/dL was low, and 50% LDL-C reduction was moderately achieved in Korean patients with FH receiving maximal statin-based LLT. Pretreatment LDL-C levels and diabetes mellitus were associated with target achievement. Our results provide rare and informative data on FH treatment in Asian patients.
| S-EPMC6490571 | biostudies-literature
Project description:Background With the availability of new lipid-lowering therapy options, there is a need to compare the expected clinical benefit of different treatment strategies in different patient populations and over various time frames. We aimed to develop a time-dependent model from published randomized controlled trials summarizing the relationship between low-density lipoprotein cholesterol lowering and cardiovascular risk reduction and to apply the model to investigate the effect of treatment scenarios over time. Methods and Results A cardiovascular treatment benefit model was specified with parameters as time since treatment initiation, magnitude of low-density lipoprotein cholesterol reduction, and additional patient characteristics. The model was estimated from randomized controlled trial data from 22 trials for statins and nonstatins. In 15 trials, the new time-dependent model had better predictions than cholesterol treatment trialists' estimations for a composite of coronary heart disease death, nonfatal myocardial infarction, and ischemic stroke. In explored scenarios, absolute risk reduction ≥2% with intensive treatment with high-intensity statin, ezetimibe, and high-dose proprotein convertase subtilisin/kexin type 9 inhibitor compared with high- or moderate-intensity statin alone were achieved in higher-risk populations with 2 to 5 years of treatment, and lower-risk populations with 9 to 11 years of treatment. Conclusions The time-dependent model accurately predicted treatment benefit seen from randomized controlled trials with a given lipid-lowering therapy by incorporating patient profile, timing, duration, and treatment type. The model can facilitate decision making and scenario analyses with a given lipid-lowering therapy strategy in various patient populations and time frames by providing an improved assessment of treatment benefit over time.
| S-EPMC7792260 | biostudies-literature
Project description:Gene polymorphisms associated so far with plasma lipid concentrations explain only a fraction of their heritability, which can reach up to 60%. Recent studies suggest that epigenetic modifications (DNA methylation) could contribute to explain part of this missing heritability. We therefore assessed whether the DNA methylation of key lipoprotein metabolism genes is associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglyceride levels in patients with familial hypercholesterolemia (FH). Untreated FH patients (61 men and 37 women) were recruited for the measurement of blood DNA methylation levels at the ABCG1, LIPC, PLTP and SCARB1 gene loci using bisulfite pyrosequencing. ABCG1, LIPC and PLTP DNA methylation was significantly associated with HDL-C, LDL-C and triglyceride levels in a sex-specific manner (all P<0.05). FH subjects with previous history of coronary artery disease (CAD) had higher LIPC DNA methylation levels compared with FH subjects without CAD (P = 0.02). Sex-specific multivariable linear regression models showed that new and previously reported epipolymorphisms (ABCG1-CpGC3, LIPC-CpGA2, mean PLTP-CpGC, LPL-CpGA3, CETP-CpGA2, and CETP-CpGB2) significantly contribute to variations in plasma lipid levels (all P<0.001 in men and P<0.02 in women), independently of traditional predictors such as age, waist circumference, blood pressure, fasting plasma lipids and glucose levels. These results suggest that epigenetic perturbations of key lipoprotein metabolism genes are associated with plasma lipid levels, contribute to the interindividual variability and might partially explain the missing heritability of plasma lipid levels, at least in FH.
| S-EPMC4063831 | biostudies-literature