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Genetic regulators of TMAO levels are largely unknown. In the present study, we used 288 mice from a genetically heterogeneous mouse population [Diversity Outbred (DO)] to determine hepatic microRNA associations with TMAO in the context of an atherogenic diet. We also validated findings in two additional animal models of atherosclerosis: liver-specific insulin receptor knockout mice fed a chow diet (LIRKO) and African green monkeys fed high-fat\/high-cholesterol diet. Small RNA-sequencing analysis in DO mice, LIRKO mice, and African green monkeys identified only one hepatic microRNA (miR-146a-5p) that is aberrantly expressed across all three models. Moreover, miR-146a-5p levels are associated with circulating TMAO after atherogenic diet in each of these models. We also performed high-resolution genetic mapping and identified a novel quantitative trait locus on Chromosome 12 for TMAO levels. This interval includes two genes, Numb and Dlst, which are inversely correlated with both miR-146a and TMAO and are predicted targets of miR-146a. Both of these genes have been validated as direct targets of miR-146a, though in other cellular contexts. This is the first report to our knowledge of a link between miR-146 and TMAO. Our findings suggest that miR-146-5p, as well as one or more genes at the Chromosome 12 QTL (possibly Numb or Dlst), is strongly linked to TMAO levels and likely involved in the control of atherosclerosis.<\/jats:p>","DOI":"10.1152\/physiolgenomics.00079.2018","type":"journal-article","created":{"date-parts":[[2019,1,11]],"date-time":"2019-01-11T17:49:35Z","timestamp":1547228975000},"page":"59-71","source":"Crossref","is-referenced-by-count":27,"title":["microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO"],"prefix":"10.1152","volume":"51","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1792-7999","authenticated-orcid":false,"given":"Alisha R.","family":"Coffey","sequence":"first","affiliation":[{"name":"Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, North Carolina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matt","family":"Kanke","sequence":"additional","affiliation":[{"name":"Department of 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