@article{8548b3a7bcbf450ea4ce6263cf4e7201,
title = "Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification",
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.",
author = "Sen, {Shurjo K.} and Boelte, {Kimberly C.} and Barb, {Jennifer J.} and Roby Joehanes and Xiaoqing Zhao and Qi Cheng and Lila Adams and Teer, {Jamie K.} and Accame, {David S.} and Soma Chowdhury and Singh, {Larry N.} and Maryam Kavousi and Peyser, {Patricia A.} and Laura Quigley and Priel, {Debra Long} and Karen Lau and Kuhns, {Douglas B.} and Teizo Yoshimura and Johnson, {Andrew D.} and Hwang, {Shih Jen} and Chen, {Marcus Y.} and Arai, {Andrew E.} and Green, {Eric D.} and Mullikin, {James C.} and Kolodgie, {Frank D.} and O'Donnell, {Christopher J.} and Renu Virmani and Munson, {Peter J.} and McVicar, {Daniel W.} and Biesecker, {Leslie G.}",
note = "Funding Information: The authors thank Marjorie Lindhurst, Jennifer Johnston, David Ng, Steve Gonsalves, and the ClinSeq support and nursing staff for their help with the clinical aspects of this study; Yusuf Demirkale for help with statistical analyses; and Danielle Fink, Laura Coffin, and Dara Riva for their help with the neutrophil studies. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government. This research was funded by the NHGRI, NCI, and NHLBI Intramural Research Programs. The National Heart, Lung, and Blood Institute{\textquoteright}s (NHLBI{\textquoteright}s) FHS is supported by NIH Grant NO1-HC-25195. This project has also been funded in part with federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E. L.G.B. is an uncompensated advisor to the Illumina Corporation and receives royalties from the Genentech Corporation. ",
year = "2014",
month = jul,
day = "3",
doi = "10.1016/j.ajhg.2014.06.003",
language = "English",
volume = "95",
pages = "66--76",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "1",
}
