{"doi":"10.1101/2023.02.08.527795","title":"Coronary Artery Disease risk variant dampens the expression of CALCRL by reducing HSF binding to shear stress responsive enhancer in endothelial cells","abstract":"ABSTRACT Coronary artery disease (CAD) is one of the major causes of mortality worldwide. Recent genome-wide association studies have started to unravel the genetic architecture of the disease. Such efforts have identified Calcitonin receptor-like (CALCRL), an important mediator of the endothelial fluid shear stress response, associated with CAD risk variants. In this study we functionally characterized the non-coding regulatory elements carrying CAD risks SNPs and studied their role in the regulation of CALCRL expression in endothelial cells. We demonstrate that rs880890-harboring regulatory element exhibits high enhancer activity and significant allelic bias with A allele showing 40% more activity than G allele. We also observed that the A allele of rs880890 is favored over the G allele under shear stress. CRISPR deletion of rs880890-enhancer resulted in downregulation of CALCRL expression. EMSA further showed that heat shock factors are binding to the enhancer with a preference for A allele over the G allele. In line with this, HSF1 knockdown resulted in a significant decrease in CALCRL expression. CALCRL knockdown as well as variant perturbation experiments confirmed the role of CALCRL in the regulation of eNOS, apelin, angiopoietin, prostaglandins and endothelin-1 signaling pathways while demonstrating a significant decrease in cell proliferation and tube formation. Overall, our results demonstrate the existence of an endothelial-specific heat shock factor regulated transcriptional enhancer carrying a CAD risk SNP rs880890 that regulates CALCRL expression. Better understanding of CALCRL gene regulation and the role of SNPs in modulation of CALCRL expression could provide important steps towards understanding genetic regulation of shear stress signaling responses.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":395814,"datarank":0.17915831169049173,"base_score":1.0986122886681096,"endowment":1.0986122886681096,"self_citation_contribution":0.16479184330021646,"citation_network_contribution":0.01436646839027528,"self_endowment_contribution":0.16479184330021646,"citer_contribution":0.01436646839027528,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":2,"citers_with_citation_signal":1,"citers_with_endowment":1,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9536,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":673866,"name":"Jin Li","orcid":"0000-0002-7957-1476","position":1,"is_corresponding":false},{"id":573869,"name":"Petri Pölönen","orcid":"0000-0001-6128-9985","position":2,"is_corresponding":false},{"id":56925,"name":"Tiit Örd","orcid":"0000-0002-3098-1749","position":3,"is_corresponding":false},{"id":348228,"name":"Kadri Õunap","orcid":"0000-0001-7397-3231","position":4,"is_corresponding":false},{"id":682182,"name":"Aarthi Ravindran","orcid":"0000-0002-5783-1409","position":5,"is_corresponding":false},{"id":1171327,"name":"Kiira Mäklin","orcid":null,"position":6,"is_corresponding":false},{"id":56926,"name":"Anu Toropainen","orcid":"0000-0001-9292-5147","position":7,"is_corresponding":false},{"id":236708,"name":"Lindsey K. Stolze","orcid":"0000-0003-2269-769X","position":8,"is_corresponding":false},{"id":1170971,"name":"Stephen J. White","orcid":"0000-0003-0090-6358","position":9,"is_corresponding":false},{"id":236709,"name":"Casey E. Romanoski","orcid":"0000-0002-0149-225X","position":10,"is_corresponding":false},{"id":990845,"name":"Merja Heinäniemi","orcid":"0000-0001-6190-3439","position":11,"is_corresponding":false},{"id":348231,"name":"Yun Fang","orcid":"0000-0003-4597-3095","position":12,"is_corresponding":false},{"id":5694,"name":"Minna Kaikkonen-Määttä","orcid":"0000-0001-6294-0979","position":13,"is_corresponding":false},{"id":348229,"name":"Ilakya Selvarajan","orcid":"0000-0003-3357-9576","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:19:22.857556Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}