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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.

SUBMITTER: Sen SK

PROVIDER: S-EPMC4085627 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Sen Shurjo K SK Boelte Kimberly C KC Barb Jennifer J JJ Joehanes Roby R Zhao XiaoQing X Cheng Qi Q Adams Lila L Teer Jamie K JK Accame David S DS Chowdhury Soma S Singh Larry N LN Kavousi Maryam M Peyser Patricia A PA Quigley Laura L Priel Debra Long DL Lau Karen K Kuhns Douglas B DB Yoshimura Teizo T Johnson Andrew D AD Hwang Shih-Jen SJ Chen Marcus Y MY Arai Andrew E AE Green Eric D ED Mullikin James C JC Kolodgie Frank D FD O'Donnell Christopher J CJ Virmani Renu R Munson Peter J PJ McVicar Daniel W DW Biesecker Leslie G LG

American journal of human genetics 20140626 1

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 c ...[more]

PMID: 24975946

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Project description:BACKGROUND:Vascular calcification is seen in most patients on dialysis and is strongly associated with cardiovascular mortality. Vascular calcification is promoted by phosphate, which generally reaches higher levels in hemodialysis than in peritoneal dialysis. However, whether vascular calcification develops less in peritoneal dialysis than in hemodialysis is currently unknown. Therefore, we compared coronary artery calcification (CAC), its progression, and calcification biomarkers between patients on hemodialysis and peritoneal dialysis. METHODS:We measured CAC in 134 patients who had been treated exclusively with hemodialysis (n = 94) or peritoneal dialysis (n = 40) and were transplantation candidates. In 57 of them (34 on hemodialysis and 23 on peritoneal dialysis), we also measured CAC progression annually up to 3 years and the inactive species of desphospho-uncarboxylated matrix Gla protein (dp-ucMGP), fetuin-A, osteoprotegerin. We compared CAC cross-sectionally with Tobit regression. CAC progression was compared in 2 ways: with linear mixed models as the difference in square root transformed volume score per year (?CAC SQRV) and with Tobit mixed models. We adjusted for potential confounders. RESULTS:In the cross-sectional cohort, CAC volume scores were 92 mm3 in hemodialysis and 492 mm3 in peritoneal dialysis (adjusted difference 436 mm3; 95% CI -47 to 919; p = 0.08). In the longitudinal cohort, peritoneal dialysis was associated with significantly more CAC progression defined as ?CAC SQRV (adjusted difference 1.20; 95% CI 0.09 to 2.31; p = 0.03), but not with Tobit mixed models (adjusted difference in CAC score increase per year 106 mm3; 95% CI -140 to 352; p = 0.40). Peritoneal dialysis was associated with higher osteoprotegerin (adjusted p = 0.02) but not with dp-ucMGP or fetuin-A. CONCLUSIONS:Peritoneal dialysis is not associated with less CAC or CAC progression than hemodialysis, and perhaps with even more progression. This indicates that vascular calcification does not develop less in peritoneal dialysis than in hemodialysis.

Dataset Information

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

Publications

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

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