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.
Circ Res. 2023 Apr 28;132(9):1144-1161. doi: 10.1161/CIRCRESAHA.122.321692. Epub 2023 Apr 5.
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.
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.
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.
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.
全基因组关联研究已经确定了数百个与常见血管疾病相关的基因座，如冠心病、心肌梗死和高血压。然而，许多 GWAS 基因座的机制见解缺乏，限制了它们向临床的转化。在这些功能未知的基因座中，有一个位于染色体 6q16.1 上的四个半 LIM（LIN-11、Isl-1、MEC-3）结构域 5（），在最近的冠心病/心肌梗死 GWAS 荟萃分析中达到了全基因组显著水平。还与几种血管疾病相关，与 GWAS 基因座观察到的广泛表型多效性一致。
我们应用一种多模式方法，利用统计精细映射、表观基因组分析和人类冠状动脉组织的体外分析，暗示作为候选因果基因的首要候选基因。我们通过体外功能分析和冠状动脉平滑肌细胞的表观基因组分析实验，揭示了跨表型遗传关联的分子机制。
我们通过表达数量性状基因座共定位方法将基因优先确定为该基因座的首要候选因果基因。在人类动脉组织中，基因表达在平滑肌细胞和周细胞群体中富集，共表达网络分析支持其在调节平滑肌细胞收缩中的功能作用。出乎意料的是，在促钙化条件下，FHL5 的过表达促进了血管钙化，并失调了与细胞外基质组织和钙处理相关的过程。最后，通过绘制 FHL5 结合位点，并使用动脉组织基因调控网络分析推断 FHL5 靶基因的功能，我们突出了 FHL5 与下游冠心病/心肌梗死基因座（如和）之间的调控相互作用，这些基因座在血管重塑中发挥作用。
综上所述，这些研究为提供了机制见解，了解了的多效遗传关联。我们表明，FHL5 通过对下游血管重塑基因程序的转录调控来介导血管疾病风险。这些反式作用机制可能解释了复杂血管疾病部分可遗传风险的原因。
