The Autoimmune Risk R262W Variant of the Adaptor SH2B3 Improves Survival in Sepsis.

The single-nucleotide polymorphism (SNP) rs3184504 is broadly associated with increased risk for multiple autoimmune and cardiovascular diseases. Although the allele is uniquely enriched in European descent, the mechanism for the widespread selective sweep is not clear. In this study, we find the rs3184504*T allele had a strong association with reduced mortality in a human sepsis cohort. The rs3184504*T allele associates with a loss-of-function amino acid change (p.R262W) in the adaptor protein SH2B3, a likely causal variant. To better understand the role of SH2B3 in sepsis, we used mouse modeling and challenged SH2B3-deficient mice with a polymicrobial cecal-ligation puncture (CLP) procedure. We found SH2B3 deficiency improved survival and morbidity with less organ damage and earlier bacterial clearance compared with control mice. The peritoneal infiltrating cells exhibited augmented phagocytosis in Sh2b3 -/- mice with enriched recruitment of Ly6Chi inflammatory monocytes despite equivalent or reduced chemokine expression. Rapid cycling of monocytes and progenitors occurred uniquely in the Sh2b3 -/- mice following CLP, suggesting augmented myelopoiesis. To model the hypomorphic autoimmune risk allele, we created a novel knockin mouse harboring a similar point mutation in the murine pleckstrin homology domain of SH2B3. At baseline, phenotypic changes suggested a hypomorphic allele. In the CLP model, homozygous knockin mice displayed improved mortality and morbidity compared with wild-type or heterozygous mice. Collectively, these data suggest that hypomorphic SH2B3 improves the sepsis response and that balancing selection likely contributed to the relative frequency of the autoimmune risk variant.

Allenspach EJ ，Shubin NJ ，Cerosaletti K ，Mikacenic C ，Gorman JA ，MacQuivey MA ，Rosen ABI ，Timms AE ，Wray-Dutra MN ，Niino K ，Liggitt D ，Wurfel MM ，Buckner JH ，Piliponsky AM ，Rawlings DJ ... -  《-》

A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage.

Alexander MR ，Hank S ，Dale BL ，Himmel L ，Zhong X ，Smart CD ，Fehrenbach DJ ，Chen Y ，Prabakaran N ，Tirado B ，Centrella M ，Ao M ，Du L ，Shyr Y ，Levy D ，Madhur MS ... -  《-》

Reduced function of the adaptor SH2B3 promotes T1D via altered gc cytokine-regulated, T cell intrinsic immune tolerance.

Watson TK ，Rosen ABI ，Drow T ，Medjo JA ，MacQuivey MA ，Ge Y ，Liggitt HD ，Grosvenor DA ，Dill-McFarland KA ，Altman MC ，Concannon PJ ，Buckner JH ，Rawlings DJ ，Allenspach EJ ... -  《-》

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

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.

Bagheri M ，Wang C ，Shi M ，Manouchehri A ，Murray KT ，Murphy MB ，Shaffer CM ，Singh K ，Davis LK ，Jarvik GP ，Stanaway IB ，Hebbring S ，Reilly MP ，Gerszten RE ，Wang TJ ，Mosley JD ，Ferguson JF ... -  《Scientific Reports》

A2B adenosine receptor blockade enhances macrophage-mediated bacterial phagocytosis and improves polymicrobial sepsis survival in mice.

Belikoff BG ，Hatfield S ，Georgiev P ，Ohta A ，Lukashev D ，Buras JA ，Remick DG ，Sitkovsky M ... -  《-》