biostudies-literatureChignon ACanadian Institutes of Health ResearchNIH HHS102241https://www.ebi.ac.uk/biostudies/studies/S-EPMC7970363biostudies-literatureUnknown24(3)Genome-wide association studies for calcific aortic valve stenosis (CAVS) previously reported strong signal for noncoding variants at 1p21.2. Previous study using Mendelian randomization suggested that the locus controls the expression of <i>PALMD</i> encoding Palmdelphin (PALMD). However, the molecular regulation at the locus and the impact of PALMD on the biology of the aortic valve is presently unknown. 3D genetic mapping and CRISPR activation identified rs6702619 as being located in a distant-acting enhancer, which controls the expression of <i>PALMD</i>. DNA-binding assay showed that the risk variant modified the DNA shape, which prevented the recruitment of NFATC2 and lowered the expression of <i>PALMD</i>. In co-expression network analysis, a module encompassing <i>PALMD</i> was enriScienceEnhancer-associated aortic valve stenosis risk locus 1p21.2 alters NFATC2 binding site and promotes fibrogenesis.PMC7970363S10 OD026929Gosselin DRufiange ARosa MMathieu PTheriault SBon-Baret VLi ZDevillers RBoulanger MCGaudreault NChignon AArgaud DMkannez GBosse YfalseEnhancer-associated aortic valve stenosis risk locus 1p21.2 alters NFATC2 binding site and promotes fibrogenesis.Genome-wide association studies for calcific aortic valve stenosis (CAVS) previously reported strong signal for noncoding variants at 1p21.2. Previous study using Mendelian randomization suggested that the locus controls the expression of <i>PALMD</i> encoding Palmdelphin (PALMD). However, the molecular regulation at the locus and the impact of PALMD on the biology of the aortic valve is presently unknown. 3D genetic mapping and CRISPR activation identified rs6702619 as being located in a distant-acting enhancer, which controls the expression of <i>PALMD</i>. DNA-binding assay showed that the risk variant modified the DNA shape, which prevented the recruitment of NFATC2 and lowered the expression of <i>PALMD</i>. In co-expression network analysis, a module encompassing <i>PALMD</i> was enr2021-01-01T00:00:00Z2021 Mar2026-05-01T16:44:23.313Z2022-02-09T17:56:56.772ZS-EPMC79703633374872210.1016/j.isci.2021.102241