遺伝的多様性は,PPARγの機能と抗糖尿病薬への反応を,生体内で決定する
Raymond E Soccio1, Eric R Chen1, Satyajit R Rajapurkar1
1Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell
|July 4, 2015
まとめ
PPARγ結合部位の遺伝的変異は,疾患のリスクと薬物反応に影響する. これらの単一ヌクレオチドポリモルフィズム (SNP) は遺伝子発現と代謝特性に影響を与え,パーソナライズされた医療の道を開く.
科学分野:
- ゲノミクスゲノミクスとは
- 分子生物学は分子生物学である.
- 薬理学 薬理学とは
背景:
- 疾患リスクに関連した単一ヌクレオチドポリモルフィズム (SNP) は,非コーディングDNAで頻繁に発見されます.
- ペロキシソーム増殖器活性化受容体ガンマ (PPARγ) は,抗糖尿病薬の標的となる核受容体であり,脂肪組織機能に役割を果たします.
研究 の 目的:
- PPARγ結合部位におけるSNPの役割と,遺伝子調節と薬物反応に対するSNPの機能的影響を調査する.
- PPARγの占有率における遺伝的変動と,代謝疾患に対する個々の感受性,および薬剤の有効性との関連を調査する.
主な方法:
- マウスの脂肪組織におけるPPARγ結合部位におけるSNP濃縮の分析.
- PPARγ結合モチーフと近隣の遺伝子発現に対するSNPの影響の評価.
- チアゾリジンダイオン (TZD) 薬に対するマウス株特有の転写応答の評価.
- PPARγ結合に影響するヒト脂肪組織SNPと,その代謝特性との関連を調べた.
主要な成果:
- SNPsはマウスの株選択性PPARγ結合部位で有意に濃縮されています.
- 多くのSNPは,PPARγまたはその協力因子の結合モチーフを変化させ,株選択的遺伝子調節につながります.
- 遺伝的に決定されたPPARγ結合は,株特異的なTZD薬物効果を説明する.
- 人間では,PPARγの部位にあるモチーフ変異性SNPは,差異結合を引き起こし,発現量的な特征の位置 (eQTLs) を説明し,代謝症候群のパラメータと関連しています.
結論:
- PPARγゲノム占有における自然な遺伝的多様性は,個々の疾患リスクと薬物反応の重要な決定因子です.
- PPARγ結合変異を理解することは,代謝障害におけるパーソナライズド医薬品のための分子基盤を提供します.
- PPARγ結合に影響するSNPは,代謝特性と代謝不全の遺伝的構造の洞察を提供します.
関連する概念動画
01:29Pharmacogenomics: Identification of New Drug Targets
84
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...
84
01:29Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
112
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...
112
01:27Pharmacogenetics of Drug Metabolism: Overview
117
Genetic polymorphism in drug metabolism is crucial to the inter-individual variability observed in drug responses. Drug metabolism primarily involves the chemical modification of drugs and other xenobiotics to enhance their elimination by increasing their polarity. Two main classes of enzymes mediate this biotransformation process: Phase I enzymes, primarily cytochrome P450s, catalyze oxidation and reduction reactions, while other enzymes, such as esterases, mediate hydrolysis, and Phase II...
117
01:11Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
69
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...
69
01:27Principles of Pharmacogenetics: Types of Genetic Variants
98
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...
98
01:58Cell Specific Gene Expression
17.0K
Multicellular organisms contain a variety of structurally and functionally distinct cell types, but the DNA in all the cells originated from the same parent cells. The differences in the cells can be attributed to the differential gene expression. Liver cells, whose functions include detoxification of blood, production of bile to metabolize fats, and synthesis of proteins essential for metabolism, must express a specific set of genes to perform their functions. Gene expression also varies with...
17.0K