Redouane Aherrahrou1, Liang Guo2, V Peter Nagraj3, Aaron Aguhob1,4, Jameson Hinkle1, Lisa Chen1,4, Joon Yuhl Soh1, Dillon Lue1,4, Gabriel F Alencar5, Arjan Boltjes6, Sander W van der Laan6, Emily Farber1, Daniela Fuller2, Rita Anane-Wae1,4, Ngozi Akingbesote1, Ani W Manichaikul1, Lijiang Ma7,8, Minna U Kaikkonen9, Johan L M Björkegren7,8,10, Suna Önengüt-Gümüşcü1, Gerard Pasterkamp6, Clint L Miller1, Gary K Owens5, Aloke Finn2, Mohamad Navab11, Alan M Fogelman11, Judith A Berliner11, Mete Civelek1,4. 1. Center for Public Health Genomics (R.A., A.A., J.H., L.C., J.Y.S., D.L., E.F., R.A.-W., N.A., A.W.M., S.O.-G., C.L.M., M.C.), University of Virginia, Charlottesville. 2. CVPath Institute, Inc, Gaithersburg, MD (L.G., D.F., A.F.). 3. School of Medicine Research Computing (V.P.N.), University of Virginia, Charlottesville. 4. Biomedical Engineering (A.A., L.C., D.L., R.A.-W., M.C.), University of Virginia, Charlottesville. 5. Molecular Physiology, Biological Physics, Medicine, Division of Cardiology, Robert M. Berne Cardiovascular Research Center (G.F.A., G.K.O.), University of Virginia, Charlottesville. 6. Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, University of Utrecht (A.B., S.W.v.d.L., G.P.). 7. Genetics and Genomic Sciences (L.M., J.L.M.B.), Icahn School of Medicine at Mount Sinai, NY. 8. Icahn Institute of Genomics and Multiscale Biology (L.M., J.L.M.B.), Icahn School of Medicine at Mount Sinai, NY. 9. A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland (M.U.K.). 10. Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet (J.L.M.B.). 11. Medicine, David Geffen School of Medicine, University of California, Los Angeles (M.N., A.M.F., J.A.B.).
Abstract
RATIONALE: Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent genome-wide association studies revealed 163 loci associated with CAD. However, the precise molecular mechanisms by which the majority of these loci increase CAD risk are not known. Vascular smooth muscle cells (VSMCs) are critical in the development of CAD. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. OBJECTIVE: To identify genetic variants associated with atherosclerosis-relevant phenotypes in VSMCs. METHODS AND RESULTS: We quantified 12 atherosclerosis-relevant phenotypes related to calcification, proliferation, and migration in VSMCs isolated from 151 multiethnic heart transplant donors. After genotyping and imputation, we performed association mapping using 6.3 million genetic variants. We demonstrated significant variations in calcification, proliferation, and migration. These phenotypes were not correlated with each other. We performed genome-wide association studies for 12 atherosclerosis-relevant phenotypes and identified 4 genome-wide significant loci associated with at least one VSMC phenotype. We overlapped the previously identified CAD loci with our data set and found nominally significant associations at 79 loci. One of them was the chromosome 1q41 locus, which harbors MIA3. The G allele of the lead risk single nucleotide polymorphism (SNP) rs67180937 was associated with lower VSMC MIA3 expression and lower proliferation. Lentivirus-mediated silencing of MIA3 (melanoma inhibitory activity protein 3) in VSMCs resulted in lower proliferation, consistent with human genetics findings. Furthermore, we observed a significant reduction of MIA3 protein in VSMCs in thin fibrous caps of late-stage atherosclerotic plaques compared to early fibroatheroma with thick and protective fibrous caps in mice and humans. CONCLUSIONS: Our data demonstrate that genetic variants have significant influences on VSMC function relevant to the development of atherosclerosis. Furthermore, high MIA3 expression may promote atheroprotective VSMC phenotypic transitions, including increased proliferation, which is essential in the formation or maintenance of a protective fibrous cap.
RATIONALE: Coronary artery disease (CAD) is a major cause of morbidity and mortality worldwide. Recent genome-wide association studies revealed 163 loci associated with CAD. However, the precise molecular mechanisms by which the majority of these loci increase CAD risk are not known. Vascular smooth muscle cells (VSMCs) are critical in the development of CAD. They can play either beneficial or detrimental roles in lesion pathogenesis, depending on the nature of their phenotypic changes. OBJECTIVE: To identify genetic variants associated with atherosclerosis-relevant phenotypes in VSMCs. METHODS AND RESULTS: We quantified 12 atherosclerosis-relevant phenotypes related to calcification, proliferation, and migration in VSMCs isolated from 151 multiethnic heart transplant donors. After genotyping and imputation, we performed association mapping using 6.3 million genetic variants. We demonstrated significant variations in calcification, proliferation, and migration. These phenotypes were not correlated with each other. We performed genome-wide association studies for 12 atherosclerosis-relevant phenotypes and identified 4 genome-wide significant loci associated with at least one VSMC phenotype. We overlapped the previously identified CAD loci with our data set and found nominally significant associations at 79 loci. One of them was the chromosome 1q41 locus, which harbors MIA3. The G allele of the lead risk single nucleotide polymorphism (SNP) rs67180937 was associated with lower VSMC MIA3 expression and lower proliferation. Lentivirus-mediated silencing of MIA3 (melanoma inhibitory activity protein 3) in VSMCs resulted in lower proliferation, consistent with human genetics findings. Furthermore, we observed a significant reduction of MIA3 protein in VSMCs in thin fibrous caps of late-stage atherosclerotic plaques compared to early fibroatheroma with thick and protective fibrous caps in mice and humans. CONCLUSIONS: Our data demonstrate that genetic variants have significant influences on VSMC function relevant to the development of atherosclerosis. Furthermore, high MIA3 expression may promote atheroprotective VSMC phenotypic transitions, including increased proliferation, which is essential in the formation or maintenance of a protective fibrous cap.
Entities:
Keywords:
cell proliferation; coronary artery disease; genome-wide association study; human genetics
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