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Integrative functional analysis of super enhancer SNPs for coronary artery disease


Clinical research in coronary artery disease (CAD) primarily focused on genetic variants located in protein-coding regions. Recently, mutations fall within non-coding regions have been suggested to be essential to the pathogenesis of human complex disease. Super enhancer is a densely spaced cluster of transcriptional enhancers located in non-coding regions, which is critical for regulating cell-type specific gene expression. However, the underlying mechanism of the super enhancer single-nucleotide polymorphisms (SNPs) affecting the risk of CAD remains unclear. By integrating genome-wide association study (GWAS) meta-analysis of CAD and cell/tissue-specific histone modification data set, we identified 366 potential CAD-associated super enhancer SNPs in 67 loci, including 94 SNPs that are involved in regulating chromatin interactive and/or affecting the transcription factors binding affinity. Interestingly, we found 7 novel functional loci (CBFA2T3, ZMIZ1, DIP2B, SCNN1D/ACAP3, TMEM105, CAMK2G, and MAPK1) that CAD-associated super enhancer SNPs were clustered into the same or neighboring super enhancers. Pathway analysis showed a significant enrichment in several well-known signaling and regulatory processes, e.g., cAMP signaling pathway and ErbB signaling pathway, which play a key role in CAD metabolism. Our results highlight the potential functional importance of CAD-associated super enhancer SNPs and provide the targets for further insights on the pathogenesis of CAD.

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We thank the DIAGRAM Consortium and GEO project for sharing the data set used in this research. This study was partially supported or benefited by grants from Technological Innovation Project of Foshan City (2017AG100102), and Medical Research Fund of Guangdong Province, China (A2017575).

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Correspondence to Shengyong Yu or Chunping Zeng.

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Gong, J., Qiu, C., Huang, D. et al. Integrative functional analysis of super enhancer SNPs for coronary artery disease. J Hum Genet 63, 627–638 (2018).

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