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Hematopoietic mosaic chromosomal alterations increase the risk for diverse types of infection.
Zekavat, Seyedeh M; Lin, Shu-Hong; Bick, Alexander G; Liu, Aoxing; Paruchuri, Kaavya; Wang, Chen; Uddin, Md Mesbah; Ye, Yixuan; Yu, Zhaolong; Liu, Xiaoxi; Kamatani, Yoichiro; Bhattacharya, Romit; Pirruccello, James P; Pampana, Akhil; Loh, Po-Ru; Kohli, Puja; McCarroll, Steven A; Kiryluk, Krzysztof; Neale, Benjamin; Ionita-Laza, Iuliana; Engels, Eric A; Brown, Derek W; Smoller, Jordan W; Green, Robert; Karlson, Elizabeth W; Lebo, Matthew; Ellinor, Patrick T; Weiss, Scott T; Daly, Mark J; Terao, Chikashi; Zhao, Hongyu; Ebert, Benjamin L; Reilly, Muredach P; Ganna, Andrea; Machiela, Mitchell J; Genovese, Giulio; Natarajan, Pradeep.
Afiliação
  • Zekavat SM; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
  • Lin SH; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Bick AG; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Liu A; Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Paruchuri K; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Wang C; Division of Genetic Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • Uddin MM; Institute for Molecular Medicine Finland, Helsinki, Finland.
  • Ye Y; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Yu Z; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Liu X; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Kamatani Y; Department of Biostatistics, Mailman School of Public Health, Columbia University, New York City, NY, USA.
  • Bhattacharya R; Division of Nephrology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University, New York City, NY, USA.
  • Pirruccello JP; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Pampana A; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Loh PR; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
  • Kohli P; Computational Biology and Bioinformatics Program, Yale University, New Haven, CT, USA.
  • McCarroll SA; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
  • Kiryluk K; Laboratory for Statistical and Translational Genetics, RIKEN Center for Integrative Medical Sciences, RIKEN, Yokohama, Japan.
  • Neale B; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Ionita-Laza I; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Engels EA; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Brown DW; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Smoller JW; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Green R; Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
  • Karlson EW; Medical and Population Genetics and Cardiovascular Disease Initiative, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Lebo M; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • Ellinor PT; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
  • Weiss ST; Vertex Pharmaceuticals, Boston, MA, USA.
  • Daly MJ; Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Terao C; Irving Institute for Clinical and Translational Research, Columbia University, New York City, NY, USA.
  • Zhao H; Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Ebert BL; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
  • Reilly MP; Department of Biostatistics, Mailman School of Public Health, Columbia University, New York City, NY, USA.
  • Ganna A; Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Machiela MJ; Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
  • Genovese G; Stanley Center, Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Natarajan P; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nat Med ; 27(6): 1012-1024, 2021 06.
Article em En | MEDLINE | ID: mdl-34099924
ABSTRACT
Age is the dominant risk factor for infectious diseases, but the mechanisms linking age to infectious disease risk are incompletely understood. Age-related mosaic chromosomal alterations (mCAs) detected from genotyping of blood-derived DNA, are structural somatic variants indicative of clonal hematopoiesis, and are associated with aberrant leukocyte cell counts, hematological malignancy, and mortality. Here, we show that mCAs predispose to diverse types of infections. We analyzed mCAs from 768,762 individuals without hematological cancer at the time of DNA acquisition across five biobanks. Expanded autosomal mCAs were associated with diverse incident infections (hazard ratio (HR) 1.25; 95% confidence interval (CI) = 1.15-1.36; P = 1.8 × 10-7), including sepsis (HR 2.68; 95% CI = 2.25-3.19; P = 3.1 × 10-28), pneumonia (HR 1.76; 95% CI = 1.53-2.03; P = 2.3 × 10-15), digestive system infections (HR 1.51; 95% CI = 1.32-1.73; P = 2.2 × 10-9) and genitourinary infections (HR 1.25; 95% CI = 1.11-1.41; P = 3.7 × 10-4). A genome-wide association study of expanded mCAs identified 63 loci, which were enriched at transcriptional regulatory sites for immune cells. These results suggest that mCAs are a marker of impaired immunity and confer increased predisposition to infections.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pneumonia / Envelhecimento / Doenças Transmissíveis / Sepse Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Aged80 Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Adicionar na Minha BVS
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pneumonia / Envelhecimento / Doenças Transmissíveis / Sepse Tipo de estudo: Etiology_studies / Prognostic_studies Limite: Aged80 Idioma: En Revista: Nat Med Assunto da revista: BIOLOGIA MOLECULAR / MEDICINA Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos