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

Sci Rep. 2021 Aug 2;11(1):15652. 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 < 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Biomarkers
  • C-Reactive Protein
  • Inflammation
  • Kynurenine*
  • Male
  • Mice
  • Polymorphism, Single Nucleotide*
  • Tryptophan / metabolism


  • Biomarkers
  • Kynurenine
  • Tryptophan
  • C-Reactive Protein