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

• Published in: Scientific reports 2021-08, Vol.11 (1), p.15652-10, Article 15652
• Main Authors: Bagheri, Minoo, Wang, Chuan, Shi, Mingjian, Manouchehri, Ali, Murray, Katherine T., Murphy, Matthew B., Shaffer, Christian M., Singh, Kritika, Davis, Lea K., Jarvik, Gail P., Stanaway, Ian B., Hebbring, Scott, Reilly, Muredach P., Gerszten, Robert E., Wang, Thomas J., Mosley, Jonathan D., Ferguson, Jane F.
• Format: Article
• Language: English
• Subjects: 631/208/200; 631/208/2489/144; 692/53/2422; 692/699/75; Adaptor Proteins, Signal Transducing - genetics; Adult; Animals; Biomarkers; Biomarkers - blood; C-reactive protein; Cardiovascular Diseases - blood; Cardiovascular Diseases - genetics; Electronic medical records; Endotoxemia; Endotoxemia - blood; Endotoxemia - genetics; Female; Gene mapping; Genetic Predisposition to Disease; Genetics; Health risks; Humanities and Social Sciences; Humans; Inflammation; Inflammation - blood; Inflammation - genetics; Intracellular Signaling Peptides and Proteins - genetics; Kynurenine - blood; Kynurenine - metabolism; Lipopolysaccharides; Male; Metabolites; Mice; Mice, Knockout; Middle Aged; multidisciplinary; Phenotypes; Plasma; Plasma levels; Polymorphism, Single Nucleotide; Science; Science (multidisciplinary); Single-nucleotide polymorphism; Tryptophan
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-95154-9

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