Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification

Shurjo K. Sen, Kimberly C. Boelte, Jennifer J. Barb, Roby Joehanes, Xiaoqing Zhao, Qi Cheng, Lila Adams, Jamie K. Teer, David S. Accame, Soma Chowdhury, Larry N. Singh, Maryam Kavousi, Patricia A. Peyser, Laura Quigley, Debra Long Priel, Karen Lau, Douglas B. Kuhns, Teizo Yoshimura, Andrew D. Johnson, Shih Jen HwangMarcus Y. Chen, Andrew E. Arai, Eric D. Green, James C. Mullikin, Frank D. Kolodgie, Christopher J. O'Donnell, Renu Virmani, Peter J. Munson, Daniel W. McVicar, Leslie G. Biesecker

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Coronary artery calcification (CAC) is a heritable and definitive morphologic marker of atherosclerosis that strongly predicts risk for future cardiovascular events. To search for genes involved in CAC, we used an integrative transcriptomic, genomic, and protein expression strategy by using next-generation DNA sequencing in the discovery phase with follow-up studies using traditional molecular biology and histopathology techniques. RNA sequencing of peripheral blood from a discovery set of CAC cases and controls was used to identify dysregulated genes, which were validated by ClinSeq and Framingham Heart Study data. Only a single gene, TREML4, was upregulated in CAC cases in both studies. Further examination showed that rs2803496 was a TREML4 cis-eQTL and that the minor allele at this locus conferred up to a 6.5-fold increased relative risk of CAC. We characterized human TREML4 and demonstrated by immunohistochemical techniques that it is localized in macrophages surrounding the necrotic core of coronary plaques complicated by calcification (but not in arteries with less advanced disease). Finally, we determined by von Kossa staining that TREML4 colocalizes with areas of microcalcification within coronary plaques. Overall, we present integrative RNA, DNA, and protein evidence implicating TREML4 in coronary artery calcification. Our findings connect multimodal genomics data with a commonly used clinical marker of cardiovascular disease.

Original languageEnglish
Pages (from-to)66-76
Number of pages11
JournalAmerican Journal of Human Genetics
Volume95
Issue number1
DOIs
Publication statusPublished - Jul 3 2014

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Sen, S. K., Boelte, K. C., Barb, J. J., Joehanes, R., Zhao, X., Cheng, Q., Adams, L., Teer, J. K., Accame, D. S., Chowdhury, S., Singh, L. N., Kavousi, M., Peyser, P. A., Quigley, L., Priel, D. L., Lau, K., Kuhns, D. B., Yoshimura, T., Johnson, A. D., ... Biesecker, L. G. (2014). Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. American Journal of Human Genetics, 95(1), 66-76. https://doi.org/10.1016/j.ajhg.2014.06.003