Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

Hindi, Nagham Nafiz; Alenbawi, Jamil; Nemer, Georges

doi:10.3390/jpm11090877

Cited by 15 publications

(8 citation statements)

References 95 publications

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“…The most common side effects of PCSK9 inhibitors are injection-site reactions and Influenza-like symptoms (Gürgöze et al, 2019). Pharmacogenomic studies carried out in individuals with familial hypercholesterolemia have reported that the efficacy of PSCK9 inhibitors such as evolocumab and alirocumab are affected by polymorphisms in apo B, low density lipoprotein receptor (LDL-R) and LDL-R adapter protein 1 genes (Hindi et al, 2021). Remarkably, a recent metanalysis provided evidence that the efficacy of PCSK9 inhibitors could be similar for different ethnicities (Sawant and Wang, 2023).…”

Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

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High density lipoprotein as a therapeutic target: Focus on its functionality

ROSSO,

DAVICO,

CHIAPPE

et al. 2023

BIOCELL

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Cardiovascular diseases (CVDs) are the leading cause of death globally. CVDs are a group of disorders of the heart and blood vessels and include coronary heart disease, cerebrovascular disease and rheumatic heart disease among other conditions. There are multiple independent risk factors for CVD, including hypertension, age, smoking, insulin resistance, elevated low-density lipoprotein cholesterol (LDL-C) levels, and triglyceride levels. LDL-C levels have traditionally been the target for therapies aimed at reducing CVD risk. High density lipoprotein (HDL) constitutes the only lipoprotein fraction with atheroprotective functions. Early HDL-targeted therapies have focused on increasing HDL-C levels. However, clinical trials have shown that raising HDL-C with niacin failed to achieve CVD reduction. A possible explanation for these findings is that these drugs could interfere with lipid metabolism and cause alterations in HDL structure and composition, leading to loss of functionality. As a result, targeting HDL-C levels would be insufficient to achieve CVD risk reduction, making HDL functionality a more desirable focus for HDL-directed therapies. There are several drugs which show the potential to improve HDL functionality. These drugs include molecules already approved for human use, such as statins and niacin, and particularly, compounds currently undergoing development such as apolipoprotein A-I mimetics and reconstituted HDL preparations. These therapies show promising potential to improve HDL functionality specifically. Future therapeutic strategies should incorporate HDL functionality as a main target of interest.

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Section: Pcsk9 Inhibitorsmentioning

confidence: 99%

“…The effect of these genes would depend on the specific statin considered (Zineh, 2007). Similarly, polymorphisms in genes involved in lipid metabolism such as ABCA 1, LDL-R and HMGCR can influence the efficacy of statins (Hindi et al, 2021). Moreover, there is evidence of interracial differences in the response to statins (Lee et al, 2005).…”

Section: Statinsmentioning

confidence: 99%

High density lipoprotein as a therapeutic target: Focus on its functionality

ROSSO,

DAVICO,

CHIAPPE

et al. 2023

BIOCELL

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“…It has been observed that the NPC1L1 transporter primarily absorbs dietary cholesterol, with plant sterols and stanols being absorbed to a lesser extent (3,4) . The e ux transporters, ABCG5 and ABCG8, have been identi ed as the main proteins responsible for the active transport of plant sterols back to the intestinal lumen (4,5) . The sterols are assimilated into chylomicrons that are rich in cholesterol and carried to the liver.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Association Study and Meta-Analysis of Phytosterols Identifies a Novel Locus for Serum Levels of Campesterol

Alenbawi,

Al-Sarraj,

Umlai

et al. 2024

Preprint

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Sitosterolemia is a rare inherited disorder caused by mutations in the ABCG5/ABCG8 genes. These genes encode proteins involved in the transport of plant sterols. Mutations in these genes lead to decreased excretion of phytosterols, which can accumulate in the body and lead to a variety of health problems, including premature coronary artery disease. We conducted the first genome-wide association study (GWAS) in the Middle East/North Africa (MENA) population to identify genetic determinants of plant sterol levels in Qatari people. GWAS was performed on serum levels of β-sitosterol and campesterol using the Metabolon platform from Qatar Biobank and genome sequence data provided by Qatar Genome Program. A trans-ancestry meta-analysis of data from our Qatari cohort with summary statistics from a previously published large cohort (9,758 subjects) of European ancestry was conducted. Using conditional analysis, we identified two independent single nucleotide polymorphisms (SNPs) associated with β-sitosterol (rs145164937 and rs4299376), and two others with campesterol (rs7598542 and rs75901165) in the Qatari population in addition to previously reported variants. All of them map to the ABCG5/8 locus except rs75901165 which is located within the Intraflagellar Transport 43 (IFT43) gene. The meta-analysis replicated most of the reported variants, and our study provided significant support for the association of variants in SCARB1 and ABO with sitosterolemia. We also evaluated the performance of a polygenic risk score for this trait from a European GWAS in QBB. These findings may have future implications on the personalized treatment of hyperlipidemia in general while showing the importance of building population-specific multi-omics databases.

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“…Furthermore, recently blood-lipid drugs are antisense or monoclonal antibodies for genes implicated in lipid regulation, such as APOC3 and ANGPTL3. However, it is necessary to consider polygenic risk scores to identify the best pharmacological treatment [6,7] alongside nutrient-gene interactions.…”

Section: Introductionmentioning

confidence: 99%

Lipid‐Related Genetic Variants for Personalized Dietary Interventions: A Systematic Review

Rivera-Iñiguez

González-Becerra

Ramos-López

et al. 2023

Molecular Nutrition Food Res

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Dyslipidemias are known risk factors for chronic diseases. Precision nutrition interventions are designed according to characteristics, such as diet, phenotype, and genotype. This systematic review aims to define a panel of genetic variants associated with lipid abnormalities that could be later used in nutrigenetic intervention studies. A systematic review is conducted following the PRISMA-P. Studies published from January 2010 to December 2020 in English language and humans are included from PubMed and ScienceDirect databases. Articles that demonstrate a strong association between polymorphisms (single nucleotide variation) of genes involved in lipid metabolism and increased risk for dyslipidemia are included. A total of 3031 articles are screened, but only 51 articles fulfill the inclusion criteria. The genes included are FABP2, MTTP related to CM synthesis and secretion; LPL, LIPC involved in triglyceride hydrolysis; CETP, APOA1, LCAT, ABCA1, and APOA5 related to lipoprotein metabolism, and APOE, LDLR, SCARB1, APOC3 involved in lipid clearance. In this systematic review, genetic variants related to chylomicron synthesis, triglyceride hydrolysis, lipoprotein metabolism, and lipid clearance demonstrate a strong association with lipid abnormalities, which can be used to design precision nutrition interventions that may help to prevent and treat dyslipidemia effectively.

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Pharmacogenomics Variability of Lipid-Lowering Therapies in Familial Hypercholesterolemia

Cited by 15 publications

References 95 publications

High density lipoprotein as a therapeutic target: Focus on its functionality

High density lipoprotein as a therapeutic target: Focus on its functionality

Genome-Wide Association Study and Meta-Analysis of Phytosterols Identifies a Novel Locus for Serum Levels of Campesterol

Lipid‐Related Genetic Variants for Personalized Dietary Interventions: A Systematic Review

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