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Related Concept Videos

Principles of Pharmacogenetics: Types of Genetic Variants01:27

Principles of Pharmacogenetics: Types of Genetic Variants

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The human genome is over 99.9% identical between individuals, yet genetic differences exist at millions of bases. The human genome contains approximately 3 million variant positions per individual, many of which are heterozygous, contributing to genetic diversity and individual traits. Genetic variations include single-nucleotide polymorphisms (SNPs), insertions, deletions, and copy number variations (CNVs).SNPs, the most common variation, involve single-base changes in DNA. These can be...
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Pharmacogenomics: Identification of New Drug Targets01:29

Pharmacogenomics: Identification of New Drug Targets

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Advances in genomics have profoundly influenced drug discovery by increasing both the speed and accuracy of pharmaceutical development. Pharmacogenomics, which examines how genetic variation influences drug response, facilitates the identification of novel therapeutic targets and enables patient stratification for personalized treatment. These strategies contribute to improved drug efficacy, minimized adverse effects, and more efficient clinical trial design.Mapping genetic differences...
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Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters01:16

Pharmacogenetics of Drug Transporters: P-Glycoprotein and Solute Carrier Transporters

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The pharmacogenetics of drug transporters is increasingly recognized as a critical factor influencing interindividual variability in drug absorption, distribution, and elimination. These membrane-bound proteins regulate drugs' movement across cellular barriers by actively pumping them out (efflux) or facilitating their uptake (influx). Among the major transporter families, ATP-binding cassette (ABC) and solute carrier (SLC) transporters play particularly prominent roles. Genetic polymorphisms...
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Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu01:29

Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu

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Genetic variations significantly influence drug response through pharmacokinetics, receptor interactions, and biologic milieu modifications. Pharmacokinetic alterations impact drug metabolism and clearance, affecting efficacy and toxicity. Variants in drug-metabolizing enzymes, such as CYP2C9 and CYP2C19, alter drug activation and elimination. For example, CYP2C9 loss-of-function variants require lower warfarin doses to prevent excessive bleeding, while CYP2C19 variants reduce clopidogrel...
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Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase01:11

Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase

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Genetic polymorphisms in drug targets have emerged as critical determinants of interindividual variability in drug response and toxicity. Pharmacogenomic investigations increasingly focus on identifying these variations to personalize and optimize therapeutic interventions. A drug target may be a receptor, enzyme, or signaling protein involved in pharmacologic responses or disease-related pathways. While early pharmacogenetic studies focused primarily on drug metabolism, current research...
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Single Nucleotide Polymorphisms-SNPs01:05

Single Nucleotide Polymorphisms-SNPs

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A single nucleotide polymorphism or SNP is a single nucleotide variation at a specific genomic position in a large population. It is the most prevalent type of sequence variation found in the human genome. Point mutations that occur in more than 1% of the population qualify as SNPs. These are present once every 1000 nucleotides on an average in the human genome. Replacement of a purine with another purine (A/G) or a pyrimidine with another pyrimidine (C/T) is known as a transition. In contrast,...
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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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The UCL low-density lipoprotein receptor gene variant database: pathogenicity update.

Sarah Leigh1, Marta Futema1, Ros Whittall1

  • 1Centre for Cardiovascular Genetics, Institute of Cardiovascular Sciences, University College London, London, UK.

Journal of Medical Genetics
|November 9, 2016
PubMed
Summary

This study updates the University College London low-density lipoprotein receptor (LDLR) variant database, classifying genetic variations. The updated database aids in predicting the pathogenicity of LDLR variants, crucial for diagnosing familial hypercholesterolaemia.

Keywords:
Familial HypercholesterolemiaLDLRdatabasein silico pathogenicity predictionslocus specific variant

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Area of Science:

  • Genetics
  • Molecular Biology
  • Cardiovascular Disease Research

Background:

  • Familial hypercholesterolaemia is primarily caused by mutations in the low-density lipoprotein receptor (LDLR) gene.
  • Classifying the pathogenicity of novel LDLR variants, particularly missense and synonymous types, presents diagnostic challenges.
  • The Association of Clinical Genetic Scientists provides guidelines for variant classification, categorizing them from unlikely pathogenic to clearly pathogenic.

Purpose of the Study:

  • To update the University College London (UCL) LDLR variant database with the latest curated variants.
  • To classify novel LDLR variants according to established clinical genetic guidelines.
  • To improve the prediction of variant pathogenicity for familial hypercholesterolaemia diagnosis.

Main Methods:

  • Utilized PubMed searches and alerts to identify and incorporate novel LDLR variants into the database.
  • Employed standard in silico tools for predicting the potential pathogenicity of identified variants.
  • Classified variants as class 4/5 when predictions were concordant across tools and class 3 when discordant.

Main Results:

  • The updated UCL LDLR variant database contains 2925 curated variants (1707 independent events).
  • Nonsense, frameshifting, and rearrangement variants were predominantly classified as pathogenic (class 4/5).
  • Out of 795 missense variants, 605 were classified as pathogenic (class 4), 75 as variants of unknown significance (class 3), and 115 as non-pathogenic (classes 1-2).

Conclusions:

  • The updated LDLR variant database provides a crucial resource for genetic variant interpretation.
  • Identified variants of unknown significance (VUS) require further family and in vitro studies for definitive pathogenicity assessment.
  • This update aids in the clinical genetic diagnosis of familial hypercholesterolaemia by refining variant classification.