FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.

Mohammad Daud Khan, Clint L Miller, Rajeev Malhotra, Johan L M Björkegren, Jason C Kovacic, Mete Civelek, Swapnil K Sonkusare, Ani Manichaikul, Ulf Hedin, Ljubica Matic, Patricia A Peyser, Maryam Kavousi, Jaspreet Kalra, Meredith Palmore, Doris Wong, Collin J Dube, Jose Verdezoto Mosquera, Chaojie Yang, Maniselvan Kuppusamy, Redouane Aherrahrou, R Noah Perry, Lijiang Ma, Yipei Song, Yixuan Chen, Adam W Turner, Christian L Lino Cardenas, Gaëlle Auguste

Journal: Circulation research 2023;132(9):1144-1161

PMID: 37017084

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Abstract

BACKGROUND

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 -four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis. is also associated with several vascular diseases, consistent with the widespread pleiotropy observed for GWAS loci.

METHODS

We apply a multimodal approach leveraging statistical fine-mapping, epigenomic profiling, and ex vivo analysis of human coronary artery tissues to implicate 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.

RESULTS

We prioritized as the top candidate causal gene at the locus through expression quantitative trait locus colocalization methods. 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 and that have roles in vascular remodeling.

CONCLUSIONS

Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of 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.

Address: Department of Biochemistry and Molecular Genetics (D.W., C.Y., J.V.M., A.M., C.L.M.), University of Virginia, Charlottesville. A.I.; 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.; 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.; Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston (C.L.L.C., R.M.).; 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.; Department of Biomedical Engineering (R.N.P., M.C.), University of Virginia, Charlottesville. A.I.; Virtanen Institute for Molecular Sciences, University of Eastern Finland, Finland (R.A.).; Institute for Cardiogenetics, Universität zu Lübeck, DZHK (German Centre for Cardiovascular Research), Partner Site Hamburg/Kiel/Lübeck, Germany, University Heart Centre Lübeck, Lübeck, Germany (R.A.).; Department of Microbiology, Immunology, and Cancer Biology (C.J.D.), University of Virginia, Charlottesville. A.I.; Department of Molecular Physiology and Biological Physics (J.K., S.K.S.), University of Virginia, Charlottesville. A.I.; Department of Epidemiology, Erasmus University Medical Center, the Netherlands (M. Kavousi).; Department of Epidemiology, University of Michigan, Ann Arbor (P.A.P.).; Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden (L. Matic, U.H.).; Department of Public Health Sciences (A.M.), University of Virginia, Charlottesville. A.I.; Cardiovascular Research Institute (J.C.K.), Icahn School of Medicine at Mount Sinai, New York.; Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia (J.C.K.).; St. Vincent's Clinical School, University of New South Wales, Sydney, Australia (J.C.K.).; Integrated Cardio Metabolic Centre, Department of Medicine, Karolinska Institutet, Huddinge, Sweden (J.L.M.B.).

DOI: 10.1161/CIRCRESAHA.122.321692