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Genetic and functional analysis of Raynaud's syndrome implicates loci in vasculature and immunity.
Tervi, Anniina; Ramste, Markus; Abner, Erik; Cheng, Paul; Lane, Jacqueline M; Maher, Matthew; Valliere, Jesse; Lammi, Vilma; Strausz, Satu; Riikonen, Juha; Nguyen, Trieu; Martyn, Gabriella E; Sheth, Maya U; Xia, Fan; Docampo, Mauro Lago; Gu, Wenduo; Esko, Tõnu; Saxena, Richa; Pirinen, Matti; Palotie, Aarno; Ripatti, Samuli; Sinnott-Armstrong, Nasa; Daly, Mark; Engreitz, Jesse M; Rabinovitch, Marlene; Heckman, Caroline A; Quertermous, Thomas; Jones, Samuel E; Ollila, Hanna M.
Afiliação
  • Tervi A; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland. Electronic address: anniina.tervi@helsinki.fi.
  • Ramste M; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Abner E; Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Cheng P; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Lane JM; Division of Sleep and Circadian Disorders, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Maher M; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Valliere J; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lammi V; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland.
  • Strausz S; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland.
  • Riikonen J; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland.
  • Nguyen T; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Martyn GE; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
  • Sheth MU; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
  • Xia F; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA.
  • Docampo ML; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Stanford Children's Health Betty Irene Moore Children's Heart Center, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
  • Gu W; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Esko T; Institute of Genomics, University of Tartu, Tartu, Estonia.
  • Saxena R; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
  • Pirinen M; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland; Department of Mathematics and Statistics, University of Helsinki, Helsinki, Finland; Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Palotie A; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hos
  • Ripatti S; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Public Health, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
  • Sinnott-Armstrong N; Herbold Computational Biology Program, Public Health Sciences Division, Fred Hutch, Seattle, WA, USA.
  • Daly M; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Analytic and Translational Genetics Unit, Massachusetts General Hos
  • Engreitz JM; Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA; Basic Science and Engineering Initiative, Stanford Children's Health, Betty Irene Moore Children's Heart Center, Stanford, CA, USA; The Novo Nordisk Foundation Center for Genomic Mechanisms of Disease, Broad Institute
  • Rabinovitch M; Stanford Children's Health Betty Irene Moore Children's Heart Center, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
  • Heckman CA; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland.
  • Quertermous T; Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Jones SE; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland.
  • Ollila HM; Institute for Molecular Medicine Finland, FIMM, Helsinki Institute of Life Science - HiLIFE, University of Helsinki, Helsinki, Finland; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Anesthesia, Critical Care, and
Cell Genom ; 4(9): 100630, 2024 Sep 11.
Article em En | MEDLINE | ID: mdl-39142284
ABSTRACT
Raynaud's syndrome is a dysautonomia where exposure to cold causes vasoconstriction and hypoxia, particularly in the extremities. We performed meta-analysis in four cohorts and discovered eight loci (ADRA2A, IRX1, NOS3, ACVR2A, TMEM51, PCDH10-DT, HLA, and RAB6C) where ADRA2A, ACVR2A, NOS3, TMEM51, and IRX1 co-localized with expression quantitative trait loci (eQTLs), particularly in distal arteries. CRISPR gene editing further showed that ADRA2A and NOS3 loci modified gene expression and in situ RNAscope clarified the specificity of ADRA2A in small vessels and IRX1 around small capillaries in the skin. A functional contraction assay in the cold showed lower contraction in ADRA2A-deficient and higher contraction in ADRA2A-overexpressing smooth muscle cells. Overall, our study highlights the power of genome-wide association testing with functional follow-up as a method to understand complex diseases. The results indicate temperature-dependent adrenergic signaling through ADRA2A, effects at the microvasculature by IRX1, endothelial signaling by NOS3, and immune mechanisms by the HLA locus in Raynaud's syndrome.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Raynaud / Locos de Características Quantitativas / Estudo de Associação Genômica Ampla Idioma: En Ano de publicação: 2024 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Doença de Raynaud / Locos de Características Quantitativas / Estudo de Associação Genômica Ampla Idioma: En Ano de publicação: 2024 Tipo de documento: Article