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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

6 Citations (Scopus)


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 UFL1-four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (FHL5; chr6q16.1), which reached genome-wide significance in a recent coronary artery disease/ myocardial infarction GWAS meta-analysis. UFL1-FHL5 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 FHL5 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 FHL5 as the top candidate causal gene at the UFL1-FHL5 locus through expression quantitative trait locus colocalization methods. FHL5 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 FOXL1 and FN1 that have roles in vascular remodeling. Conclusions: Taken together, these studies provide mechanistic insights into the pleiotropic genetic associations of UFL1-FHL5. 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.

Original languageEnglish
Pages (from-to)1144-1161
Number of pages18
JournalCirculation Research
Issue number9
Publication statusPublished - 28 Apr 2023

Bibliographical note

Funding Information:
This work was supported by grants from: the National Institutes of Health (R01HL148239, R01HL164577, and R00HL125912 to C.L. Miller; F31HL156463 to D. Wong; R01HL142809 to R. Malhotra; K01HL164687 to C.L. Lino Cardenas; R01HL125863 to J.L.M. Björkegren; R01HL130423 to J.C. Kovacic) and the Fondation Leducq ("PlaqOmics" 18CVD02 to J.LM. Björkegren and C.L. Miller).

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.


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