Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.
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This work was supported by the following grants: US National Institutes of Health (NIH) grants R21DK084459 and R01DK094184 (A.M.N); R37DK048873 and R01DK056626 to D.E.C.; K24DK078772 to R.T.C.; and R01HL107953 and R01HL106063 to C.F.-H. A.M.N. was supported by a scholar award from the Massachusetts General Hospital (MGH). R.E.G. was supported by an Established Investigator Award from the American Heart Association. C.F.-H. was supported by a Fondation Leducq Transatlantic Network of Excellence in Cardiovascular Research Award. T.H. acknowledges the support of NIH grant R01HL49094 and a Fondation Leducq Transatlantic Network of Excellence in Cardiovascular Research Award. N.S. and J.S.T. were supported by the Intramural Research Program of the US National Institute of Allergy and Infectious Diseases. C.M.R. was supported by the American Heart Association SDG Grant 15SDG23000025. A.W. was supported by a fellowship from the MGH Executive Committee on Research. We thank C. Molony of Merck Research Laboratories for help with genotyping data quality assessment. We thank the Harvard Medical School Neurobiology Department and the Neurobiology Imaging Facility for consultation and instrument availability that supported this work. This facility is supported in part by the Neural Imaging Center as part of a National Institutes on Neurological Disorders and Stroke P30 Core Center grant no. NS072030, and by the Harvard Digestive Diseases Center (P30 DK034854).
A.M.N., A.W. and S.H.N.-S. have issued and pending patents (US Patent nos. 9,045,749 and US 61/865,327) on microRNA-targeting therapeutics for the treatment of cardiometabolic diseases.
Supplementary Figures 1–8 (PDF 3650 kb)
69 miRNAs are associated with abnormal levels of total cholesterol (TC), LDL-C, HDL-C, and TAGs. (XLSX 65 kb)
Gene Ontology analysis of miRNA target genes. (XLSX 37 kb)
List of SNPs associated with total cholesterol, LDL-C, HDL- C and triglycerides in the miR-128-1, miR-148a, miR-130b and miR-301b loci. (XLSX 121 kb)
Selected metabolism genes predicted to be targeted by miR- 128-1, miR-148a, miR-130b and miR-301b. (XLSX 46 kb)
Liver cis miR-QTL data. (XLSX 1002 kb)
Expression changes of predicted miR-128-1 targets in the livers of mice treated with antimiR-128-1 versus control scrambled LNA antimiR over 5 days. (XLSX 91 kb)
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Wagschal, A., Najafi-Shoushtari, S., Wang, L. et al. Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis. Nat Med 21, 1290–1297 (2015). https://doi.org/10.1038/nm.3980
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