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Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood(1,2). Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts,...

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Autores principales: Zekavat, Seyedeh M., Lin, Shu-Hong, Bick, Alexander G., Liu, Aoxing, Paruchuri, Kaavya, Uddin, Md Mesbah, Ye, Yixuan, Yu, Zhaolong, Liu, Xiaoxi, Kamatani, Yoichiro, Pirruccello, James P., Pampana, Akhil, Loh, Po-Ru, Kohli, Puja, McCarroll, Steven A., Neale, Benjamin, 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., Ganna, Andrea, Machiela, Mitchell J., Genovese, Giulio, Natarajan, Pradeep
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685330/
https://www.ncbi.nlm.nih.gov/pubmed/33236019
http://dx.doi.org/10.1101/2020.11.12.20230821
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author Zekavat, Seyedeh M.
Lin, Shu-Hong
Bick, Alexander G.
Liu, Aoxing
Paruchuri, Kaavya
Uddin, Md Mesbah
Ye, Yixuan
Yu, Zhaolong
Liu, Xiaoxi
Kamatani, Yoichiro
Pirruccello, James P.
Pampana, Akhil
Loh, Po-Ru
Kohli, Puja
McCarroll, Steven A.
Neale, Benjamin
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.
Ganna, Andrea
Machiela, Mitchell J.
Genovese, Giulio
Natarajan, Pradeep
author_facet Zekavat, Seyedeh M.
Lin, Shu-Hong
Bick, Alexander G.
Liu, Aoxing
Paruchuri, Kaavya
Uddin, Md Mesbah
Ye, Yixuan
Yu, Zhaolong
Liu, Xiaoxi
Kamatani, Yoichiro
Pirruccello, James P.
Pampana, Akhil
Loh, Po-Ru
Kohli, Puja
McCarroll, Steven A.
Neale, Benjamin
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.
Ganna, Andrea
Machiela, Mitchell J.
Genovese, Giulio
Natarajan, Pradeep
author_sort Zekavat, Seyedeh M.
collection PubMed
description Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood(1,2). Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality(3–11). Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.
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spelling pubmed-76853302020-11-25 Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer Zekavat, Seyedeh M. Lin, Shu-Hong Bick, Alexander G. Liu, Aoxing Paruchuri, Kaavya Uddin, Md Mesbah Ye, Yixuan Yu, Zhaolong Liu, Xiaoxi Kamatani, Yoichiro Pirruccello, James P. Pampana, Akhil Loh, Po-Ru Kohli, Puja McCarroll, Steven A. Neale, Benjamin 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. Ganna, Andrea Machiela, Mitchell J. Genovese, Giulio Natarajan, Pradeep medRxiv Article Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood(1,2). Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality(3–11). Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction >10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses. Cold Spring Harbor Laboratory 2020-11-16 /pmc/articles/PMC7685330/ /pubmed/33236019 http://dx.doi.org/10.1101/2020.11.12.20230821 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Zekavat, Seyedeh M.
Lin, Shu-Hong
Bick, Alexander G.
Liu, Aoxing
Paruchuri, Kaavya
Uddin, Md Mesbah
Ye, Yixuan
Yu, Zhaolong
Liu, Xiaoxi
Kamatani, Yoichiro
Pirruccello, James P.
Pampana, Akhil
Loh, Po-Ru
Kohli, Puja
McCarroll, Steven A.
Neale, Benjamin
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.
Ganna, Andrea
Machiela, Mitchell J.
Genovese, Giulio
Natarajan, Pradeep
Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
title Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
title_full Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
title_fullStr Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
title_full_unstemmed Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
title_short Hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
title_sort hematopoietic mosaic chromosomal alterations and risk for infection among 767,891 individuals without blood cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685330/
https://www.ncbi.nlm.nih.gov/pubmed/33236019
http://dx.doi.org/10.1101/2020.11.12.20230821
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