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PLoS Genet. 2018 Nov 16;14(11):e1007755. doi: 10.1371/journal.pgen.1007755. eCollection 2018 Nov.

Functional regulatory mechanism of smooth muscle cell-restricted LMOD1 coronary artery disease locus.

Author information

1
Department of Surgery, Division of Vascular Surgery, Stanford University School of Medicine, Stanford, California, United States of America.
2
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, California, United States of America.
3
Department of Genetics, Stanford University School of Medicine, Stanford, California, United States of America.
4
Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, California, United States of America.
5
Department of Biology, Stanford University School of Medicine, Stanford, California, United States of America.
6
Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America.
7
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
8
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, United States of America.
9
Clinical Gene Networks AB, Stockholm, Sweden.
10
Department of Cardiac Surgery, Tartu University Hospital, Tartu, Estonia.
11
Department of Medical Biochemistry and Biophysics, Vascular Biology Unit, Karolinska Institutet, Stockholm, Sweden.
12
Department of Physiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Tartu, Estonia.
13
Center for Public Health Genomics, Department of Public Health Sciences, Department of Biochemistry and Molecular Genetics, and Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America.

Abstract

Recent genome-wide association studies (GWAS) have identified multiple new loci which appear to alter coronary artery disease (CAD) risk via arterial wall-specific mechanisms. One of the annotated genes encodes LMOD1 (Leiomodin 1), a member of the actin filament nucleator family that is highly enriched in smooth muscle-containing tissues such as the artery wall. However, it is still unknown whether LMOD1 is the causal gene at this locus and also how the associated variants alter LMOD1 expression/function and CAD risk. Using epigenomic profiling we recently identified a non-coding regulatory variant, rs34091558, which is in tight linkage disequilibrium (LD) with the lead CAD GWAS variant, rs2820315. Herein we demonstrate through expression quantitative trait loci (eQTL) and statistical fine-mapping in GTEx, STARNET, and human coronary artery smooth muscle cell (HCASMC) datasets, rs34091558 is the top regulatory variant for LMOD1 in vascular tissues. Position weight matrix (PWM) analyses identify the protective allele rs34091558-TA to form a conserved Forkhead box O3 (FOXO3) binding motif, which is disrupted by the risk allele rs34091558-A. FOXO3 chromatin immunoprecipitation and reporter assays show reduced FOXO3 binding and LMOD1 transcriptional activity by the risk allele, consistent with effects of FOXO3 downregulation on LMOD1. LMOD1 knockdown results in increased proliferation and migration and decreased cell contraction in HCASMC, and immunostaining in atherosclerotic lesions in the SMC lineage tracing reporter mouse support a key role for LMOD1 in maintaining the differentiated SMC phenotype. These results provide compelling functional evidence that genetic variation is associated with dysregulated LMOD1 expression/function in SMCs, together contributing to the heritable risk for CAD.

PMID:
30444878
DOI:
10.1371/journal.pgen.1007755
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Conflict of interest statement

JLMB is a founder, consultant and major shareholder of Clinical Gene Networks AB (CGN) together with AR. OF is a part-time employee of CGN. JLMB, AR and EES are members of the board of directors. CGN has an invested interest in the STARNET biobank and data set. However, CGN has expressed no claims or sought any patents related to the results presented in this manuscript.

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