Key result
The CAD risk allele rs34091558-A disrupts FOXO3 binding, leading to downregulated LMOD1 expression, increased proliferation, and decreased contraction in smooth muscle cells.
Why the study?
It was unknown whether LMOD1 is the causal gene at its CAD-associated locus and how associated variants alter LMOD1 expression, function, and CAD risk.
The CAD-associated risk variant rs34091558-A downregulates LMOD1 expression by disrupting FOXO3 binding, promoting a dedifferentiated, proliferative smooth muscle cell phenotype that contributes to CAD risk.
LMOD1 variant disrupts FOXO3 binding and SMC phenotype; extends GWAS loci to functional arterial mechanisms but leaves open clinical relevance.
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.
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Nanda et al. (2018) studied Coronary artery disease. rs34091558 risk allele vs. rs34091558-TA protective allele was evaluated on LMOD1 expression and smooth muscle cell phenotype. The CAD risk allele rs34091558-A disrupts FOXO3 binding, leading to downregulated LMOD1 expression, increased proliferation, and decreased contraction in smooth muscle cells.
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