冠動脈疾患に関連する変異が血管の滑らかな筋肉細胞に及ぼす影響

Charles U Solomon¹, David G McVey¹, Catherine Andreadi¹

¹Department of Cardiovascular Sciences, University of Leicester, and National Institute for Health Research Leicester Biomedical Research Centre, UK (C.U.S., D.G.M., C.A., P.G., L.T., P.J.S., S.K., J.C.C., T.R.W., C.P.N., J.N.S., S.Y.).

Circulation

|June 23, 2022

まとめ

冠動脈疾患 (CAD) に関する遺伝的変異は,血管の滑らかな筋肉細胞 (VSMC) の遺伝子発現に影響を与えます. この研究は,VSMCにおける薬効性遺伝子を,CADの潜在的な治療標的として特定しています.

科学分野:

遺伝学
心血管生物学
ファルマゲノミクス

背景:

全ゲノム関連研究 (GWAS) では,冠動脈疾患 (CAD) に関連した多数の遺伝位置が特定されています.
ほとんどのCADに関連したロシウムの基礎にある生物学的メカニズムは,治療的な翻訳を阻害する,ほとんど未知のままです.
CADへの遺伝的傾向は,部分的に血管の滑らかな筋肉細胞 (VSMC) によって媒介される可能性があります.

研究の目的:

VSMC内の遺伝子発現と機能を調節するCAD関連遺伝子変異の役割を調査する.
遺伝子関連データをVSMC特異的な発現量的な特徴ロシ (eQTL) と統合することによって,CADの候補因果遺伝子を特定する.
診断された候補遺伝子の潜在的治療開発に対する薬効性を評価する.

主な方法:

ゲノタイプ化,RNAシーケンシング,および細胞行動アッセイは,多数のVSMC (n>1499) で実施された.
発現量的な特質ロカス (eQTL) とスプライシング量的な特質ロカス (sQTL) の分析は,CAD変異と遺伝子発現の変化を関連付けるために行われました.
原因変異の識別と要約データに基づくメンデルのランダム化を含むコロカライゼーション分析は,候補因果遺伝子を特定するために使用されました.
治療の可能性とVSMCの行動に対する累積的な遺伝的影響を評価するために,薬効性評価と多遺伝子リスクスコア分析が使用されました.

主要な成果:

既知のCAD関連変異の約60%は,VSMCで有意なeQTLまたはsQTL効果を示した.
コロカリゼーション分析では,eQTL信号がCAD関連信号と重なり合っている84の候補因果遺伝子を特定しました.
このうち38の候補遺伝子は薬効性があり,13は薬と遺伝子の相互作用の証拠を示した.
VSMCの増殖,移動,またはアポトーシスと関連付けられ,多遺伝子スコアはVSMCの行動変化の最大5. 94%を説明しました.

結論:

VSMCにおける遺伝子発現と行動に,CADの遺伝的位置の相当な割合が影響する.
特定された薬効性候補因果遺伝子は,CADの介入のための有望な治療標的を表しています.
この研究は遺伝学的な発見と潜在的臨床応用における CAD治療のギャップを埋めています

キーワード:

冠動脈疾患遺伝学筋肉滑らか血管トランスクリプトーム

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