Editors' ChoiceCARDIOVASCULAR GENETICS

All Systems Point to TREML4

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Science Translational Medicine  23 Jul 2014:
Vol. 6, Issue 246, pp. 246ec129
DOI: 10.1126/scitranslmed.3009814

The completion of the Human Genome Project in 2001 heralded a great hope that a new understanding of disease would begin the march to a healthier future. That march has been slow, although the pace of discovery is accelerating. One reason for this acceleration is the availability of publicly available data sets, spanning multiple biologic systems, from many thousands of individuals. Sen et al. tap into these data to identify genetic causes of coronary artery calcification (CAC), a major contributor to coronary artery disease.

The authors began with the hypothesis that genetic determinants of CAC would manifest in the gene expression profile (transcriptome) of subjects with severe CAC, but not in unaffected controls. Eight case-control pairs from the ClinSeq cohort revealed 302 differentially expressed genes. Validation in a group of 40 matched pairs narrowed this to 18 genes. Microarray data from the Framingham Heart Study identified only one of the 18 genes as differentially expressed: TREML4. Although the difference in expression did not meet statistically significant thresholds, suspicion for biological relevance was high, which prompted the ensuing experiments.

TREML4 exome sequencing identified seven heterozygous variants, one of which was significantly different in the two clinical groups. Moreover, there was a dose-response relationship between TREML4 expression and the number of minor alleles present, suggesting causality. Additional supporting genetic data came in the form of genotypes from 758 ClinSeq subjects and a genome-wide association study analysis from the 1000 Genomes database. The authors then discovered the biological role of TREML4 as a protein-coding gene, primarily in neutrophils and monocytes. Confirming this, the TREML4 protein was found to be in macrophages associated with atherotic and calcified endovascular lesions in human subjects with sudden cardiac death. Although the function of TREML4 in disease is still unknown, Sen and colleagues highlight its importance in CAC. This study exemplifies how combining large and comprehensive genomic data can quicken the pace of the post–Human Genome Project march.

S. K. Sen et al., Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification. Am. J. Hum. Genet. 95, 66–76 (2014). [PubMed]

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