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Uncovering genetic mechanisms of hypertension through multi-omic analysis of the kidney.
Eales, James M; Jiang, Xiao; Xu, Xiaoguang; Saluja, Sushant; Akbarov, Artur; Cano-Gamez, Eddie; McNulty, Michelle T; Finan, Christopher; Guo, Hui; Wystrychowski, Wojciech; Szulinska, Monika; Thomas, Huw B; Pramanik, Sanjeev; Chopade, Sandesh; Prestes, Priscilla R; Wise, Ingrid; Evangelou, Evangelos; Salehi, Mahan; Shakanti, Yusif; Ekholm, Mikael; Denniff, Matthew; Nazgiewicz, Alicja; Eichinger, Felix; Godfrey, Bradley; Antczak, Andrzej; Glyda, Maciej; Król, Robert; Eyre, Stephen; Brown, Jason; Berzuini, Carlo; Bowes, John; Caulfield, Mark; Zukowska-Szczechowska, Ewa; Zywiec, Joanna; Bogdanski, Pawel; Kretzler, Matthias; Woolf, Adrian S; Talavera, David; Keavney, Bernard; Maffia, Pasquale; Guzik, Tomasz J; O'Keefe, Raymond T; Trynka, Gosia; Samani, Nilesh J; Hingorani, Aroon; Sampson, Matthew G; Morris, Andrew P; Charchar, Fadi J; Tomaszewski, Maciej.
Affiliation
  • Eales JM; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Jiang X; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Xu X; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Saluja S; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Akbarov A; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Cano-Gamez E; Department of Human Genetics, Wellcome Sanger Institute, Cambridge, UK.
  • McNulty MT; Division of Nephrology, Boston Children's Hospital, Boston, MA, USA.
  • Finan C; The Broad Institute, Cambridge, MA, USA.
  • Guo H; Institute of Cardiovascular Science, University College London, London, UK.
  • Wystrychowski W; Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Szulinska M; Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Poland.
  • Thomas HB; Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
  • Pramanik S; Division of Evolution and Genomic Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Chopade S; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Prestes PR; East Lancashire Hospitals NHS Trust, Blackburn, UK.
  • Wise I; Institute of Cardiovascular Science, University College London, London, UK.
  • Evangelou E; Health Innovation and Transformation Centre, School of Science, Psychology and Sport, Federation University Australia, Ballarat, Victoria, Australia.
  • Salehi M; Australian Institute of Tropical Health & Medicine, James Cook University, Cairns, Queensland, Australia.
  • Shakanti Y; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.
  • Ekholm M; Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
  • Denniff M; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Nazgiewicz A; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Eichinger F; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Godfrey B; Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden.
  • Antczak A; Department of Cardiovascular Sciences, University of Leicester, Leicester, UK.
  • Glyda M; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Król R; Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
  • Eyre S; Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
  • Brown J; Department of Urology and Uro-oncology, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
  • Berzuini C; Department of Transplantology and General Surgery Poznan, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland.
  • Bowes J; Department of General, Vascular and Transplant Surgery, Medical University of Silesia, Katowice, Poland.
  • Caulfield M; Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Zukowska-Szczechowska E; Division of Research and Innovation, Manchester University NHS Foundation Trust, Manchester, UK.
  • Zywiec J; Centre for Biostatistics, School of Health Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Bogdanski P; Division of Musculoskeletal and Dermatological Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Kretzler M; William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Woolf AS; National Institute for Health Research, Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London, UK.
  • Talavera D; Department of Health Care, Silesian Medical College, Katowice, Poland.
  • Keavney B; Department of Internal Medicine, Diabetology and Nephrology, Zabrze, Medical University of Silesia, Katowice, Poland.
  • Maffia P; Department of Obesity, Metabolic Disorders Treatment and Clinical Dietetics, Karol Marcinkowski University of Medical Sciences, Poznan, Poland.
  • Guzik TJ; Department of Medicine, University of Michigan, Ann Arbor, MI, USA.
  • O'Keefe RT; Division of Cell Matrix Biology and Regenerative Medicine, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Trynka G; Royal Manchester Children's Hospital and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
  • Samani NJ; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Hingorani A; Division of Cardiovascular Sciences, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK.
  • Sampson MG; Division of Cardiology and Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, Manchester, UK.
  • Morris AP; Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
  • Charchar FJ; Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
  • Tomaszewski M; Department of Pharmacy, University of Naples Federico II, Naples, Italy.
Nat Genet ; 53(5): 630-637, 2021 05.
Article in En | MEDLINE | ID: mdl-33958779
ABSTRACT
The kidney is an organ of key relevance to blood pressure (BP) regulation, hypertension and antihypertensive treatment. However, genetically mediated renal mechanisms underlying susceptibility to hypertension remain poorly understood. We integrated genotype, gene expression, alternative splicing and DNA methylation profiles of up to 430 human kidneys to characterize the effects of BP index variants from genome-wide association studies (GWASs) on renal transcriptome and epigenome. We uncovered kidney targets for 479 (58.3%) BP-GWAS variants and paired 49 BP-GWAS kidney genes with 210 licensed drugs. Our colocalization and Mendelian randomization analyses identified 179 unique kidney genes with evidence of putatively causal effects on BP. Through Mendelian randomization, we also uncovered effects of BP on renal outcomes commonly affecting patients with hypertension. Collectively, our studies identified genetic variants, kidney genes, molecular mechanisms and biological pathways of key relevance to the genetic regulation of BP and inherited susceptibility to hypertension.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Predisposition to Disease / Genomics / Hypertension / Kidney Type of study: Clinical_trials / Prognostic_studies Limits: Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2021 Document type: Article Affiliation country: Reino Unido
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Genetic Predisposition to Disease / Genomics / Hypertension / Kidney Type of study: Clinical_trials / Prognostic_studies Limits: Humans Language: En Journal: Nat Genet Journal subject: GENETICA MEDICA Year: 2021 Document type: Article Affiliation country: Reino Unido