Cardiometabolic risk loci share downstream cis- and trans-gene regulation across tissues and diseases.

Autor:	Franzén O; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden., Ermel R; Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406 Tartu, Estonia., Cohain A; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Akers NK; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Di Narzo A; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Talukdar HA; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden., Foroughi-Asl H; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden., Giambartolomei C; Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Fullard JF; Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Sukhavasi K; Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia., Köks S; Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia., Gan LM; Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden., Giannarelli C; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Cardiovascular Research Center Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Kovacic JC; Cardiovascular Research Center Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Betsholtz C; AstraZeneca-Karolinska Integrated CardioMetabolic Centre (ICMC), Karolinska Institutet, Novum, Blickagången 6, 141 57 Huddinge, Sweden. Department of Immunology, Genetics and Pathology Dag Hammarskjölds Väg 20, 751 85 Uppsala, Sweden., Losic B; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Michoel T; Division of Genetics and Genomics, The Roslin Institute, University of Edinburgh, Old College, South Bridge, Edinburgh EH8 9YL, UK., Hao K; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Roussos P; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Division of Psychiatric Genomics, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Department of Psychiatry, J. J. Peters VA Medical Center, Mental Illness Research Education and Clinical Center (MIRECC), 130 West Kingsbridge Road, Bronx, NY 10468, USA., Skogsberg J; Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden., Ruusalepp A; Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Department of Cardiac Surgery, Tartu University Hospital, 1a Ludwig Puusepa Street, 50406 Tartu, Estonia., Schadt EE; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA., Björkegren JL; Department of Genetics and Genomic Sciences, The Icahn Institute for Genomics and Multiscale Biology Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York , NY 10029, USA. Clinical Gene Networks AB, Jungfrugatan 10, 114 44 Stockholm, Sweden. Department of Pathophysiology, Institute of Biomedicine and Translation Medicine, University of Tartu, Biomeedikum, Ravila 19, 50411, Tartu, Estonia. Division of Vascular Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Scheeles Väg 2, 171 77 Stockholm, Sweden. johan.bjorkegren@mssm.edu.
Jazyk:	angličtina
Zdroj:	Science (New York, N.Y.) [Science] 2016 Aug 19; Vol. 353 (6301), pp. 827-30.
DOI:	10.1126/science.aad6970
Abstrakt:	Genome-wide association studies (GWAS) have identified hundreds of cardiometabolic disease (CMD) risk loci. However, they contribute little to genetic variance, and most downstream gene-regulatory mechanisms are unknown. We genotyped and RNA-sequenced vascular and metabolic tissues from 600 coronary artery disease patients in the Stockholm-Tartu Atherosclerosis Reverse Networks Engineering Task study (STARNET). Gene expression traits associated with CMD risk single-nucleotide polymorphism (SNPs) identified by GWAS were more extensively found in STARNET than in tissue- and disease-unspecific gene-tissue expression studies, indicating sharing of downstream cis-/trans-gene regulation across tissues and CMDs. In contrast, the regulatory effects of other GWAS risk SNPs were tissue-specific; abdominal fat emerged as an important gene-regulatory site for blood lipids, such as for the low-density lipoprotein cholesterol and coronary artery disease risk gene PCSK9 STARNET provides insights into gene-regulatory mechanisms for CMD risk loci, facilitating their translation into opportunities for diagnosis, therapy, and prevention. (Copyright © 2016, American Association for the Advancement of Science.)
Databáze:	MEDLINE
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