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Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures.
Örd, Tiit; Lönnberg, Tapio; Nurminen, Valtteri; Ravindran, Aarthi; Niskanen, Henri; Kiema, Miika; Õunap, Kadri; Maria, Maleeha; Moreau, Pierre R; Mishra, Pashupati P; Palani, Senthil; Virta, Jenni; Liljenbäck, Heidi; Aavik, Einari; Roivainen, Anne; Ylä-Herttuala, Seppo; Laakkonen, Johanna P; Lehtimäki, Terho; Kaikkonen, Minna U.
Afiliación
  • Örd T; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland. Electronic address: tiit.ord@uef.fi.
  • Lönnberg T; Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland; InFLAMES Research Flagship Center, University of Turku.
  • Nurminen V; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Ravindran A; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Niskanen H; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Kiema M; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Õunap K; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Maria M; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Moreau PR; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Mishra PP; Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland.
  • Palani S; Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520 Turku, Finland.
  • Virta J; Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520 Turku, Finland.
  • Liljenbäck H; Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520 Turku, Finland; Turku Center for Disease Modeling, University of Turku, 20520 Turku, Finland.
  • Aavik E; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Roivainen A; Turku PET Centre, University of Turku, Kiinamyllynkatu 4-8, 20520 Turku, Finland; Turku Center for Disease Modeling, University of Turku, 20520 Turku, Finland; Turku PET Centre, Turku University Hospital, 20520 Turku, Finland.
  • Ylä-Herttuala S; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Laakkonen JP; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland.
  • Lehtimäki T; Department of Clinical Chemistry, Fimlab Laboratories and Finnish Cardiovascular Research Center Tampere, Faculty of Medicine and Health Technology, Tampere University, 33100 Tampere, Finland.
  • Kaikkonen MU; A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland. Electronic address: minna.kaikkonen@uef.fi.
Am J Hum Genet ; 110(5): 722-740, 2023 05 04.
Article en En | MEDLINE | ID: mdl-37060905
Coronary artery disease (CAD) is a pandemic disease where up to half of the risk is explained by genetic factors. Advanced insights into the genetic basis of CAD require deeper understanding of the contributions of different cell types, molecular pathways, and genes to disease heritability. Here, we investigate the biological diversity of atherosclerosis-associated cell states and interrogate their contribution to the genetic risk of CAD by using single-cell and bulk RNA sequencing (RNA-seq) of mouse and human lesions. We identified 12 disease-associated cell states that we characterized further by gene set functional profiling, ligand-receptor prediction, and transcription factor inference. Importantly, Vcam1+ smooth muscle cell state genes contributed most to SNP-based heritability of CAD. In line with this, genetic variants near smooth muscle cell state genes and regulatory elements explained the largest fraction of CAD-risk variance between individuals. Using this information for variant prioritization, we derived a hybrid polygenic risk score (PRS) that demonstrated improved performance over a classical PRS. Our results provide insights into the biological mechanisms associated with CAD risk, which could make a promising contribution to precision medicine and tailored therapeutic interventions in the future.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de la Arteria Coronaria / Aterosclerosis Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Enfermedad de la Arteria Coronaria / Aterosclerosis Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Am J Hum Genet Año: 2023 Tipo del documento: Article