TY - JOUR
T1 - FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells
AU - Wong, Doris
AU - Auguste, Gaelle
AU - Lino Cardenas, Christian L.
AU - Turner, Adam W.
AU - Chen, Yixuan
AU - Song, Yipei
AU - Ma, Lijiang
AU - Perry, R. Noah
AU - Aherrahrou, Redouane
AU - Kuppusamy, Maniselvan
AU - Yang, Chaojie
AU - Mosquera, Jose Verdezoto
AU - Dube, Collin J.
AU - Khan, Mohammad Daud
AU - Palmore, Meredith
AU - Kalra, Jaspreet
AU - Kavousi, Maryam
AU - Peyser, Patricia A.
AU - Matic, Ljubica
AU - Hedin, Ulf
AU - Manichaikul, Ani
AU - Sonkusare, Swapnil K.
AU - Civelek, Mete
AU - Kovacic, Jason C.
AU - Bjorkegren, Johan L.M.
AU - Malhotra, Rajeev
AU - Miller, Clint L.
N1 - Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.
PY - 2023/4/28
Y1 - 2023/4/28
N2 - 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.
AB - 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.
KW - coronary artery disease
KW - epigenomics
KW - genome-wide association study
KW - myocardial infarction
KW - vascular calcification
UR - http://www.scopus.com/inward/record.url?scp=85157984094&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.122.321692
DO - 10.1161/CIRCRESAHA.122.321692
M3 - Article
C2 - 37017084
AN - SCOPUS:85157984094
SN - 0009-7330
VL - 132
SP - 1144
EP - 1161
JO - Circulation Research
JF - Circulation Research
IS - 9
ER -