{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,13]],"date-time":"2026-09-13T20:38:59Z","timestamp":1789331939437,"version":"build-2803163510"},"reference-count":115,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2023,4,28]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is\n                      <jats:italic toggle=\"yes\">UFL1<\/jats:italic>\n                      \u2013four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (\n                      <jats:italic toggle=\"yes\">FHL5<\/jats:italic>\n                      ; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease\/ myocardial infarction GWAS meta-analysis.\n                      <jats:italic toggle=\"yes\">UFL1-FHL5<\/jats:italic>\n                      is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate\n                      <jats:italic toggle=\"yes\">FHL5<\/jats:italic>\n                      as the top candidate causal gene. We unravel the molecular mechanisms of the cross-phenotype genetic associations through in vitro functional analyses and epigenomic profiling experiments in coronary artery smooth muscle cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We prioritized\n                      <jats:italic toggle=\"yes\">FHL5<\/jats:italic>\n                      as the top candidate causal gene at the\n                      <jats:italic toggle=\"yes\">UFL1-FHL5<\/jats:italic>\n                      locus through expression quantitative trait locus colocalization methods.\n                      <jats:italic toggle=\"yes\">FHL5<\/jats:italic>\n                      gene expression was enriched in the smooth muscle cells and pericyte population in human artery tissues with coexpression network analyses supporting a functional role in regulating smooth muscle cell contraction. Unexpectedly, under procalcifying conditions, FHL5 overexpression promoted vascular calcification and dysregulated processes related to extracellular matrix organization and calcium handling. Lastly, by mapping FHL5 binding sites and inferring FHL5 target gene function using artery tissue gene regulatory network analyses, we highlight regulatory interactions between FHL5 and downstream coronary artery disease\/myocardial infarction loci, such as\n                      <jats:italic toggle=\"yes\">FOXL1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">FN1<\/jats:italic>\n                      that have roles in vascular remodeling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of\n                      <jats:italic toggle=\"yes\">UFL1-FHL5.<\/jats:italic>\n                      We show that FHL5 mediates vascular disease risk through transcriptional regulation of downstream vascular remodeling gene programs. These transacting mechanisms may explain a portion of the heritable risk for complex vascular diseases.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.122.321692","type":"journal-article","created":{"date-parts":[[2023,4,5]],"date-time":"2023-04-05T05:00:43Z","timestamp":1680670843000},"page":"1144-1161","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":33,"title":["FHL5 Controls Vascular Disease\u2013Associated Gene Programs in Smooth Muscle Cells"],"prefix":"10.1161","volume":"132","author":[{"given":"Doris","family":"Wong","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I."},{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."},{"name":"Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4900-6959","authenticated-orcid":true,"given":"Ga\u00eblle","family":"Auguste","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5491-4375","authenticated-orcid":true,"given":"Christian L.","family":"Lino Cardenas","sequence":"additional","affiliation":[{"name":"Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (C.L.L.C., R.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam W.","family":"Turner","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixuan","family":"Chen","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yipei","family":"Song","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lijiang","family":"Ma","sequence":"additional","affiliation":[{"name":"Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology (L. Ma, J.L.M.B.), Icahn School of Medicine at Mount Sinai, New York."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3555-0964","authenticated-orcid":true,"given":"R. Noah","family":"Perry","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."},{"name":"Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. Kuppusamy, S.K.S., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."},{"name":"Department of Biomedical Engineering (R.N.P., M.C.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8148-9554","authenticated-orcid":true,"given":"Redouane","family":"Aherrahrou","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."},{"name":"Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland (R.A.)."},{"name":"Institute for Cardiogenetics, Universit\u00e4t zu L\u00fcbeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg\/Kiel\/L\u00fcbeck, Germany, University Heart Centre L\u00fcbeck, L\u00fcbeck, Germany (R.A.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maniselvan","family":"Kuppusamy","sequence":"additional","affiliation":[{"name":"Robert M. Berne Cardiovascular Research Center (D.W., R.N.P., M. 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A.I."},{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7154-6129","authenticated-orcid":true,"given":"Collin J.","family":"Dube","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Immunology, and Cancer Biology (C.J.D.), University of Virginia, Charlottesville. A.I."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammad Daud","family":"Khan","sequence":"additional","affiliation":[{"name":"Center for Public Health Genomics (D.W., G.A., A.W.T., Y.C., Y.S., R.N.P., R.A., C.Y., J.V.M., D.K., M.P., A.M., M.C., C.L.M.), University of Virginia, Charlottesville. 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