Scholarlink

<p>Genome-wide association studies have identified over 300 genomic loci associated with coronary artery disease (CAD) risk, but identifying functional variants remains challenging due to linkage disequilibrium. Here we show a comprehensive functional characterization of CAD-associated variants in primary vascular smooth muscle cells (SMCs). We performed lentivirus-based massively parallel reporter assays (lentiMPRAs) on 25,892 CAD-associated variants, testing their allele-specific enhancer activity in quiescent and proliferative SMCs. We identified 122 candidate variants with enhancer activity and allelic imbalance, including 23 variants showing condition-biased and 41 showing sex-biased effects. Integrating lentiMPRA with CUT&amp;RUN epigenome profiling and expression quantitative trait loci data, we prioritized 49 functionally relevant variants. CRISPRi experiments on eight variants confirmed their regulatory effects on nine variant–gene pairs: <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs35976034">rs35976034</a> (MAP1S), <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs4888409">rs4888409</a> (CFDP1), <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs73193808">rs73193808</a> (MAP3K7CL), <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs67631072">rs67631072</a> (INPP5B/FHL3), <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs1651285">rs1651285</a> (SNHG18), <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs17293632">rs17293632</a> (SMAD3), <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs2238792">rs2238792</a> (ARVCF) and <a href="https://www.ncbi.nlm.nih.gov/snp/?term=rs4627080">rs4627080</a> (NRIP3). Our results fine-map the causal variants that confer CAD risk through their effects on vascular SMCs.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Coronary artery disease-associated variants regulate vascular smooth muscle cell gene expression

  • 期刊论文

  • 发表日期：

    2025年10月7日

查看全文
  • Nicolas Barbera,
  • Lily Lei,
  • Alexia Wallace,
  • Faruk Erin,
  • R. Noah Perry,
  • Hester M. den Ruijter,
  • Mete Civelek

摘要

Genome-wide association studies have identified over 300 genomic loci associated with coronary artery disease (CAD) risk, but identifying functional variants remains challenging due to linkage disequilibrium. Here we show a comprehensive functional characterization of CAD-associated variants in primary vascular smooth muscle cells (SMCs). We performed lentivirus-based massively parallel reporter assays (lentiMPRAs) on 25,892 CAD-associated variants, testing their allele-specific enhancer activity in quiescent and proliferative SMCs. We identified 122 candidate variants with enhancer activity and allelic imbalance, including 23 variants showing condition-biased and 41 showing sex-biased effects. Integrating lentiMPRA with CUT&RUN epigenome profiling and expression quantitative trait loci data, we prioritized 49 functionally relevant variants. CRISPRi experiments on eight variants confirmed their regulatory effects on nine variant–gene pairs: rs35976034 (MAP1S), rs4888409 (CFDP1), rs73193808 (MAP3K7CL), rs67631072 (INPP5B/FHL3), rs1651285 (SNHG18), rs17293632 (SMAD3), rs2238792 (ARVCF) and rs4627080 (NRIP3). Our results fine-map the causal variants that confer CAD risk through their effects on vascular SMCs.