{"doi":"10.1161/circresaha.121.320625","title":"A Single Nucleotide Polymorphism in <i>SH2B3/LNK</i> Promotes Hypertension Development and Renal Damage","abstract":"Background: SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single nucleotide polymorphism in SH2B3 (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. Methods: We used CRISPR-Cas9 technology to create mice homozygous for the major (Arg/Arg) and minor (Trp/Trp) alleles of this SH2B3 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. Results: 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 + 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 + T cells. In addition, IL-12 enhances Stat4 phosphorylation to a greater degree in Trp/Trp compared to Arg/Arg CD8 + 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 SH2B3 expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans.. Conclusions: 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.","journal":"Circulation Research","year":2022,"id":242944,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":36,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9612,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":874594,"name":"Samuel Hank","orcid":null,"position":1,"is_corresponding":false},{"id":398250,"name":"Bethany L. Dale","orcid":"0000-0003-4984-5517","position":2,"is_corresponding":false},{"id":236806,"name":"Lauren E. Himmel","orcid":"0000-0002-0628-9998","position":3,"is_corresponding":false},{"id":441245,"name":"Xue Zhong","orcid":"0000-0002-7482-8471","position":4,"is_corresponding":false},{"id":16586,"name":"C. Duncan Smart","orcid":"0000-0003-0391-3916","position":5,"is_corresponding":false},{"id":16587,"name":"Daniel J. Fehrenbach","orcid":"0000-0003-3382-464X","position":6,"is_corresponding":false},{"id":398249,"name":"Yuhan Chen","orcid":"0000-0002-2950-2675","position":7,"is_corresponding":false},{"id":874595,"name":"Nitin Prabakaran","orcid":null,"position":8,"is_corresponding":false},{"id":793213,"name":"Brian Tirado","orcid":"0000-0001-6149-0232","position":9,"is_corresponding":false},{"id":298183,"name":"Mingfang Ao","orcid":"0000-0002-3639-8546","position":10,"is_corresponding":false},{"id":374832,"name":"Liping Du","orcid":"0000-0003-4926-2135","position":11,"is_corresponding":false},{"id":105129,"name":"Yu Shyr","orcid":"0000-0003-2086-9670","position":12,"is_corresponding":false},{"id":38114,"name":"Daniel Levy","orcid":"0000-0003-1843-8724","position":13,"is_corresponding":false},{"id":16598,"name":"Meena S. Madhur","orcid":"0000-0002-0407-634X","position":14,"is_corresponding":false},{"id":325637,"name":"Matthew R. Alexander","orcid":"0000-0003-4739-7204","position":0,"is_corresponding":true}],"reference_count":89,"raw_metadata":null,"created_at":"2026-07-19T00:23:10.218426Z","pmid":"36169218","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}