CETP遺伝子ポリモルフィズムを持つコレステロールエステル転送タンパク質阻害剤のメカニズムに基づく作用と非標的作用の分離
Reecha Sofat1, Aroon D Hingorani, Liam Smeeth
1Centre for Clinical Pharmacology, Department of Medicine, University College London, London, United Kingdom.
Circulation
|December 23, 2009
まとめ
コレステリルエステル転送タンパク質 (CETP) 阻害剤はHDLコレステロールに影響するが,トルセトラピブは高血圧を引き起こした. 遺伝子解析により,トルセトラピビブが発見された.
科学分野:
- ファルマコゲノミクスは,
- 心血管医学 心血管医学
- 脂質代謝 脂質代謝とは
背景:
- コレステロールエステル転送タンパク質 (CETP) 阻害剤は,HDLコレステロールを増加させます.
- CETP阻害剤であるトルセトラピブは,予期せぬ高血圧と心血管疾患を引き起こしました.
- トルセトラピブの高血圧効果 (CETP阻害対非標的作用) の原因は議論された.
研究 の 目的:
- CETP遺伝子の単核酸多形態 (SNPs) が,CETP阻害剤のメカニズムに基づく効果と非標的効果を区別できるかどうかを判断する.
- 薬物効果と遺伝子効果を分析することによって,CETPを治療目標として検証する.
主な方法:
- CETP SNPとtorcetrapibが脂質,血圧,電解質に及ぼす効果を比較する.
- 遺伝子研究 (67,687人) とランダム化試験 (17,911人) のデータを活用した.
- CETP活動に関連して分析された脂質分数,血圧,電解質の変化.
主要な成果:
- CETP SNPとtorcetrapibの両方がCETPの活性を低下させ,HDLコレステロールを含む8つの脂質特性を一貫して影響しました.
- トルセトラピブ (60 mg) は,シストリック血圧 (4.47 mm Hg) とダイアストリック血圧 (2.08 mm Hg) を著しく上昇させた.
- CETP SNPは血圧にゼロの効果 (シストリック:0.16 mm Hg,ダイアストリック: -0.04 mm Hg) を有しており,torcetrapibの影響と著しく異なる.
結論:
- CETP SNPとtorcetrapibの間の血圧効果の不一致は,torcetrapibの高血圧がCETP阻害によるものではないことを示唆しています.
- トルセトラピブの高血圧作用は,他のCETP阻害剤と共有される可能性は低い.
- 遺伝子研究は,薬物開発の貴重なツールであり,ヒトにおける薬物標的の検証のためのランダム化証拠を提供します.
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