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A Single Nucleotide Polymorphism in SH2B3/LNK Promotes Hypertension Development and Renal Damage
Matthew R Alexander1,2,3,4, Samuel Hank1, Bethany L Dale5
1Division of Clinical Pharmacology (M.R.A., S.H., D.J.F., M.C., M.A., M.S.M.), Vanderbilt University Medical Center, Nashville, TN.
Circulation Research
|September 28, 2022
Summary
The SH2B3 (SH2B adaptor protein 3) Trp variant (rs3184504) increases hypertension and kidney damage by impairing T cell cytokine signaling. This variant causes higher blood pressure and renal dysfunction through reduced SH2B3 repression of IL-12 signaling.
Area of Science:
- Genetics
- Immunology
- Cardiovascular Disease
Background:
- SH2B3 (SH2B adaptor protein 3) negatively regulates cytokine signaling.
- A common SH2B3 polymorphism (rs3184504) is linked to hypertension.
- The causal role and mechanism of this variant in hypertension are unknown.
Purpose of the Study:
- To investigate the causal role of the SH2B3 rs3184504 polymorphism in hypertension.
- To elucidate the mechanism by which this variant impacts blood pressure and renal pathology.
Main Methods:
- CRISPR-Cas9 was used to create mice with different SH2B3 alleles (Arg/Arg and Trp/Trp).
- Mice underwent angiotensin II infusion to assess blood pressure and organ damage.
- T cell cytokine production and Stat4 phosphorylation were analyzed.
Main Results:
- Trp/Trp mice showed higher systolic blood pressure and exacerbated renal injury after angiotensin II infusion.
- Trp/Trp T cells produced more interferon gamma (IFNg) due to enhanced IL-12 signaling and Stat4 phosphorylation.
- Increased SH2B3 expression in lymphocytes was inversely associated with hypertension in humans.
Conclusions:
- The Trp allele of rs3184504 is causal for elevated blood pressure and renal dysfunction.
- This occurs partly through loss of SH2B3-mediated repression of T cell IL-12 signaling, enhancing IFNg production.
- The findings highlight a novel mechanism linking genetic variation in SH2B3 to hypertension pathogenesis.
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