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Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits

Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individ...

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Autores principales: Liu, Lili, Khan, Atlas, Sanchez-Rodriguez, Elena, Zanoni, Francesca, Li, Yifu, Steers, Nicholas, Balderes, Olivia, Zhang, Junying, Krithivasan, Priya, LeDesma, Robert A., Fischman, Clara, Hebbring, Scott J., Harley, John B., Moncrieffe, Halima, Kottyan, Leah C., Namjou-Khales, Bahram, Walunas, Theresa L., Knevel, Rachel, Raychaudhuri, Soumya, Karlson, Elizabeth W., Denny, Joshua C., Stanaway, Ian B., Crosslin, David, Rauen, Thomas, Floege, Jürgen, Eitner, Frank, Moldoveanu, Zina, Reily, Colin, Knoppova, Barbora, Hall, Stacy, Sheff, Justin T., Julian, Bruce A., Wyatt, Robert J., Suzuki, Hitoshi, Xie, Jingyuan, Chen, Nan, Zhou, Xujie, Zhang, Hong, Hammarström, Lennart, Viktorin, Alexander, Magnusson, Patrik K. E., Shang, Ning, Hripcsak, George, Weng, Chunhua, Rundek, Tatjana, Elkind, Mitchell S. V., Oelsner, Elizabeth C., Barr, R. Graham, Ionita-Laza, Iuliana, Novak, Jan, Gharavi, Ali G., Kiryluk, Krzysztof
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9651905/
https://www.ncbi.nlm.nih.gov/pubmed/36369178
http://dx.doi.org/10.1038/s41467-022-34456-6
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author Liu, Lili
Khan, Atlas
Sanchez-Rodriguez, Elena
Zanoni, Francesca
Li, Yifu
Steers, Nicholas
Balderes, Olivia
Zhang, Junying
Krithivasan, Priya
LeDesma, Robert A.
Fischman, Clara
Hebbring, Scott J.
Harley, John B.
Moncrieffe, Halima
Kottyan, Leah C.
Namjou-Khales, Bahram
Walunas, Theresa L.
Knevel, Rachel
Raychaudhuri, Soumya
Karlson, Elizabeth W.
Denny, Joshua C.
Stanaway, Ian B.
Crosslin, David
Rauen, Thomas
Floege, Jürgen
Eitner, Frank
Moldoveanu, Zina
Reily, Colin
Knoppova, Barbora
Hall, Stacy
Sheff, Justin T.
Julian, Bruce A.
Wyatt, Robert J.
Suzuki, Hitoshi
Xie, Jingyuan
Chen, Nan
Zhou, Xujie
Zhang, Hong
Hammarström, Lennart
Viktorin, Alexander
Magnusson, Patrik K. E.
Shang, Ning
Hripcsak, George
Weng, Chunhua
Rundek, Tatjana
Elkind, Mitchell S. V.
Oelsner, Elizabeth C.
Barr, R. Graham
Ionita-Laza, Iuliana
Novak, Jan
Gharavi, Ali G.
Kiryluk, Krzysztof
author_facet Liu, Lili
Khan, Atlas
Sanchez-Rodriguez, Elena
Zanoni, Francesca
Li, Yifu
Steers, Nicholas
Balderes, Olivia
Zhang, Junying
Krithivasan, Priya
LeDesma, Robert A.
Fischman, Clara
Hebbring, Scott J.
Harley, John B.
Moncrieffe, Halima
Kottyan, Leah C.
Namjou-Khales, Bahram
Walunas, Theresa L.
Knevel, Rachel
Raychaudhuri, Soumya
Karlson, Elizabeth W.
Denny, Joshua C.
Stanaway, Ian B.
Crosslin, David
Rauen, Thomas
Floege, Jürgen
Eitner, Frank
Moldoveanu, Zina
Reily, Colin
Knoppova, Barbora
Hall, Stacy
Sheff, Justin T.
Julian, Bruce A.
Wyatt, Robert J.
Suzuki, Hitoshi
Xie, Jingyuan
Chen, Nan
Zhou, Xujie
Zhang, Hong
Hammarström, Lennart
Viktorin, Alexander
Magnusson, Patrik K. E.
Shang, Ning
Hripcsak, George
Weng, Chunhua
Rundek, Tatjana
Elkind, Mitchell S. V.
Oelsner, Elizabeth C.
Barr, R. Graham
Ionita-Laza, Iuliana
Novak, Jan
Gharavi, Ali G.
Kiryluk, Krzysztof
author_sort Liu, Lili
collection PubMed
description Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease.
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spelling pubmed-96519052022-11-14 Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits Liu, Lili Khan, Atlas Sanchez-Rodriguez, Elena Zanoni, Francesca Li, Yifu Steers, Nicholas Balderes, Olivia Zhang, Junying Krithivasan, Priya LeDesma, Robert A. Fischman, Clara Hebbring, Scott J. Harley, John B. Moncrieffe, Halima Kottyan, Leah C. Namjou-Khales, Bahram Walunas, Theresa L. Knevel, Rachel Raychaudhuri, Soumya Karlson, Elizabeth W. Denny, Joshua C. Stanaway, Ian B. Crosslin, David Rauen, Thomas Floege, Jürgen Eitner, Frank Moldoveanu, Zina Reily, Colin Knoppova, Barbora Hall, Stacy Sheff, Justin T. Julian, Bruce A. Wyatt, Robert J. Suzuki, Hitoshi Xie, Jingyuan Chen, Nan Zhou, Xujie Zhang, Hong Hammarström, Lennart Viktorin, Alexander Magnusson, Patrik K. E. Shang, Ning Hripcsak, George Weng, Chunhua Rundek, Tatjana Elkind, Mitchell S. V. Oelsner, Elizabeth C. Barr, R. Graham Ionita-Laza, Iuliana Novak, Jan Gharavi, Ali G. Kiryluk, Krzysztof Nat Commun Article Immunoglobulin A (IgA) mediates mucosal responses to food antigens and the intestinal microbiome and is involved in susceptibility to mucosal pathogens, celiac disease, inflammatory bowel disease, and IgA nephropathy. We performed a genome-wide association study of serum IgA levels in 41,263 individuals of diverse ancestries and identified 20 genome-wide significant loci, including 9 known and 11 novel loci. Co-localization analyses with expression QTLs prioritized candidate genes for 14 of 20 significant loci. Most loci encoded genes that produced immune defects and IgA abnormalities when genetically manipulated in mice. We also observed positive genetic correlations of serum IgA levels with IgA nephropathy, type 2 diabetes, and body mass index, and negative correlations with celiac disease, inflammatory bowel disease, and several infections. Mendelian randomization supported elevated serum IgA as a causal factor in IgA nephropathy. African ancestry was consistently associated with higher serum IgA levels and greater frequency of IgA-increasing alleles compared to other ancestries. Our findings provide novel insights into the genetic regulation of IgA levels and its potential role in human disease. Nature Publishing Group UK 2022-11-11 /pmc/articles/PMC9651905/ /pubmed/36369178 http://dx.doi.org/10.1038/s41467-022-34456-6 Text en © The Author(s) 2022, corrected publication 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Liu, Lili
Khan, Atlas
Sanchez-Rodriguez, Elena
Zanoni, Francesca
Li, Yifu
Steers, Nicholas
Balderes, Olivia
Zhang, Junying
Krithivasan, Priya
LeDesma, Robert A.
Fischman, Clara
Hebbring, Scott J.
Harley, John B.
Moncrieffe, Halima
Kottyan, Leah C.
Namjou-Khales, Bahram
Walunas, Theresa L.
Knevel, Rachel
Raychaudhuri, Soumya
Karlson, Elizabeth W.
Denny, Joshua C.
Stanaway, Ian B.
Crosslin, David
Rauen, Thomas
Floege, Jürgen
Eitner, Frank
Moldoveanu, Zina
Reily, Colin
Knoppova, Barbora
Hall, Stacy
Sheff, Justin T.
Julian, Bruce A.
Wyatt, Robert J.
Suzuki, Hitoshi
Xie, Jingyuan
Chen, Nan
Zhou, Xujie
Zhang, Hong
Hammarström, Lennart
Viktorin, Alexander
Magnusson, Patrik K. E.
Shang, Ning
Hripcsak, George
Weng, Chunhua
Rundek, Tatjana
Elkind, Mitchell S. V.
Oelsner, Elizabeth C.
Barr, R. Graham
Ionita-Laza, Iuliana
Novak, Jan
Gharavi, Ali G.
Kiryluk, Krzysztof
Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
title Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
title_full Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
title_fullStr Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
title_full_unstemmed Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
title_short Genetic regulation of serum IgA levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
title_sort genetic regulation of serum iga levels and susceptibility to common immune, infectious, kidney, and cardio-metabolic traits
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9651905/
https://www.ncbi.nlm.nih.gov/pubmed/36369178
http://dx.doi.org/10.1038/s41467-022-34456-6
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