{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:26:42Z","timestamp":1792070802327,"version":"4.4.0"},"reference-count":87,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2022,10,14]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism in\n                      <jats:italic toggle=\"yes\">SH2B3<\/jats:italic>\n                      (rs3184504) results in substitution of tryptophan (Trp) for arginine (Arg) at amino acid 262 and is a top association signal for hypertension in human genome-wide association studies. Whether this variant is causal for hypertension, and if so, the mechanism by which it impacts pathogenesis is unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg\/Arg) and minor (Trp\/Trp) alleles of this\n                      <jats:italic toggle=\"yes\">SH2B3<\/jats:italic>\n                      polymorphism. Mice underwent angiotensin II (Ang II) infusion to evaluate differences in blood pressure (BP) elevation and end-organ damage including albuminuria and renal fibrosis. Cytokine production and Stat4 phosphorylation was also assessed in Arg\/Arg and Trp\/Trp T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      Trp\/Trp mice exhibit 10 mmHg higher systolic BP during chronic Ang II infusion compared to Arg\/Arg controls. Renal injury and perivascular fibrosis are exacerbated in Trp\/Trp mice compared to Arg\/Arg controls following Ang II infusion. Renal and ex vivo stimulated splenic CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from Ang II-infused Trp\/Trp mice produce significantly more interferon gamma (IFNg) compared to Arg\/Arg controls. Interleukin-12 (IL-12)-induced IFNg production is greater in Trp\/Trp compared to Arg\/Arg CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp\/Trp compared to Arg\/Arg CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, suggesting that Trp-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFNg production. Finally, we demonstrated that a multi-SNP model genetically predicting increased\n                      <jats:italic toggle=\"yes\">SH2B3<\/jats:italic>\n                      expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans..\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Taken together, these results suggest that the Trp encoding allele of rs3184504 is causal for BP elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T cell IL-12 signaling leading to enhanced IFNg production.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.121.320625","type":"journal-article","created":{"date-parts":[[2022,9,28]],"date-time":"2022-09-28T08:03:30Z","timestamp":1664352210000},"page":"731-747","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"title":["A Single Nucleotide Polymorphism in\n                    <i>SH2B3\/LNK<\/i>\n                    Promotes Hypertension Development and Renal Damage"],"prefix":"10.1161","volume":"131","author":[{"given":"Matthew R.","family":"Alexander","sequence":"first","affiliation":[{"name":"Division of Clinical Pharmacology (M.R.A., S.H., D.J.F., M.C., M.A., M.S.M.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Division of Cardiovascular Medicine (M.R.A., M.S.M.), Vanderbilt University Medical Center, Nashville, TN."},{"name":"Vanderbilt Institute for Infection, Immunology, and Inflammation, Nashville, TN (M.R.A., M.S.M.)."},{"name":"Department of Molecular Physiology 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