The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene

Abstract Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with car...

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Autores principales:	Minoo Bagheri, Chuan Wang, Mingjian Shi, Ali Manouchehri, Katherine T. Murray, Matthew B. Murphy, Christian M. Shaffer, Kritika Singh, Lea K. Davis, Gail P. Jarvik, Ian B. Stanaway, Scott Hebbring, Muredach P. Reilly, Robert E. Gerszten, Thomas J. Wang, Jonathan D. Mosley, Jane F. Ferguson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/82d713fe6c8546188c145b33545e9251
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spelling	oai:doaj.org-article:82d713fe6c8546188c145b33545e92512021-12-02T17:06:10ZThe genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene10.1038/s41598-021-95154-92045-2322https://doaj.org/article/82d713fe6c8546188c145b33545e92512021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95154-9https://doaj.org/toc/2045-2322Abstract Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3 −/− mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.Minoo BagheriChuan WangMingjian ShiAli ManouchehriKatherine T. MurrayMatthew B. MurphyChristian M. ShafferKritika SinghLea K. DavisGail P. JarvikIan B. StanawayScott HebbringMuredach P. ReillyRobert E. GersztenThomas J. WangJonathan D. MosleyJane F. FergusonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Minoo Bagheri Chuan Wang Mingjian Shi Ali Manouchehri Katherine T. Murray Matthew B. Murphy Christian M. Shaffer Kritika Singh Lea K. Davis Gail P. Jarvik Ian B. Stanaway Scott Hebbring Muredach P. Reilly Robert E. Gerszten Thomas J. Wang Jonathan D. Mosley Jane F. Ferguson The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene
description	Abstract Inflammation increases the risk of cardiometabolic disease. Delineating specific inflammatory pathways and biomarkers of their activity could identify the mechanistic underpinnings of the increased risk. Plasma levels of kynurenine, a metabolite involved in inflammation, associates with cardiometabolic disease risk. We used genetic approaches to identify inflammatory mechanisms associated with kynurenine variability and their relationship to cardiometabolic disease. We identified single-nucleotide polymorphisms (SNPs) previously associated with plasma kynurenine, including a missense-variant (rs3184504) in the inflammatory gene SH2B3/LNK. We examined the association between rs3184504 and plasma kynurenine in independent human samples, and measured kynurenine levels in SH2B3-knock-out mice and during human LPS-evoked endotoxemia. We conducted phenome scanning to identify clinical phenotypes associated with each kynurenine-related SNP and with a kynurenine polygenic score using the UK-Biobank (n = 456,422), BioVU (n = 62,303), and Electronic Medical Records and Genetics (n = 32,324) databases. The SH2B3 missense variant associated with plasma kynurenine levels and SH2B3 −/− mice had significant tissue-specific differences in kynurenine levels.LPS, an acute inflammatory stimulus, increased plasma kynurenine in humans. Mendelian randomization showed increased waist-circumference, a marker of central obesity, associated with increased kynurenine, and increased kynurenine associated with C-reactive protein (CRP). We found 30 diagnoses associated (FDR q < 0.05) with the SH2B3 variant, but not with SNPs mapping to genes known to regulate tryptophan-kynurenine metabolism. Plasma kynurenine may be a biomarker of acute and chronic inflammation involving the SH2B3 pathways. Its regulation lies upstream of CRP, suggesting that kynurenine may be a biomarker of one inflammatory mechanism contributing to increased cardiometabolic disease risk.
format	article
author	Minoo Bagheri Chuan Wang Mingjian Shi Ali Manouchehri Katherine T. Murray Matthew B. Murphy Christian M. Shaffer Kritika Singh Lea K. Davis Gail P. Jarvik Ian B. Stanaway Scott Hebbring Muredach P. Reilly Robert E. Gerszten Thomas J. Wang Jonathan D. Mosley Jane F. Ferguson
author_facet	Minoo Bagheri Chuan Wang Mingjian Shi Ali Manouchehri Katherine T. Murray Matthew B. Murphy Christian M. Shaffer Kritika Singh Lea K. Davis Gail P. Jarvik Ian B. Stanaway Scott Hebbring Muredach P. Reilly Robert E. Gerszten Thomas J. Wang Jonathan D. Mosley Jane F. Ferguson
author_sort	Minoo Bagheri
title	The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene
title_short	The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene
title_full	The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene
title_fullStr	The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene
title_full_unstemmed	The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene
title_sort	genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the sh2b3 gene
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/82d713fe6c8546188c145b33545e9251
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The genetic architecture of plasma kynurenine includes cardiometabolic disease mechanisms associated with the SH2B3 gene

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