{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTREML4, a member of the TREM receptor family, has emerged as an important biomarker and potential contributor to coronary artery disease. Integrated transcriptomic, genomic, and proteomic studies have demonstrated that TREML4 is upregulated in individuals with coronary artery calcification, where its expression is closely linked to the severity of lesions. Notably, eQTL variants (e.g., rs2803496) are associated with heightened TREML4 expression, conferring increased relative risk of calcification, while immunohistochemical analyses have localized the protein to macrophages adjacent to the necrotic cores and microcalcification areas within advanced plaques."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFunctional studies reveal that TREML4 plays a key role in modulating inflammatory responses in macrophages. In human M1 macrophages, which represent the proinflammatory phenotype, TREML4 upregulation is associated with significant dysregulation of pathways involved in leukocyte activation, apoptosis, and extracellular matrix degradation—mechanisms that may contribute to increased plaque vulnerability. Further, experiments in murine models and oxLDL-treated macrophages have confirmed that TREML4 influences genes related to inflammation and lipid regulation, with its absence corresponding to reduced plaque burden and simpler lesion morphology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional investigations into TREML4’s role across different stages of atherosclerosis have shown that its mRNA expression in blood leukocytes is modulated by specific minor alleles, such as the rs2803495 G and rs2803496 C variants. However, this modulation appears to be distinct across disease phases; TREML4 expression is elevated in patients with significant coronary lesions yet does not associate with the early atherosclerotic plaque formation or with post–myocardial infarction remodeling. These findings underscore TREML4’s potential both as a biomarker of lesion extent and as a mediator of inflammatory progression in coronary artery disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shurjo K Sen, Kimberly C Boelte, Jennifer J Barb, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Integrative DNA, RNA, and protein evidence connects TREML4 to coronary artery calcification."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2014.06.003"}], "href": "https://doi.org/10.1016/j.ajhg.2014.06.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24975946"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24975946"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Victor Hugo Rezende Duarte, Carolinne Thaisa de Oliveira Fernandes Miranda, Marina Sampaio Cruz, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TREML4 mRNA Expression and Polymorphisms in Blood Leukocytes are Associated with Atherosclerotic Lesion Extension in Coronary Artery Disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-019-43745-y"}], "href": "https://doi.org/10.1038/s41598-019-43745-y"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31076644"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31076644"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Marieli Gonzalez-Cotto, Liang Guo, Megan Karwan, et al. "}, {"type": "b", "children": [{"type": "a", "children": [{"type": "t", "text": "i"}], "href": "i"}, {"type": "t", "text": "TREML4"}, {"type": "a", "children": [{"type": "t", "text": "/i"}], "href": "/i"}, {"type": "t", "text": " Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Front Immunol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.3389/fimmu.2020.00397"}], "href": "https://doi.org/10.3389/fimmu.2020.00397"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32292401"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32292401"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Victor Hugo Rezende Duarte, Marina Sampaio Cruz, Adriana Bertolami, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TREML4 polymorphisms increase the mRNA in blood leukocytes in the progression of atherosclerosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Rep (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41598-022-22040-3"}], "href": "https://doi.org/10.1038/s41598-022-22040-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "36329152"}], "href": "https://pubmed.ncbi.nlm.nih.gov/36329152"}]}]}]}