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Master of Public Health

A Single Nucleotide Polymorphism in Promotes Hypertension Development and Renal Damage

AUTHORS

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 , . Circulation research. 2022 9 28; (). 101161CIRCRESAHA121320625

ABSTRACT

RATIONALE: SH2B3 (SH2B adaptor protein 3) is an adaptor protein that negatively regulates cytokine signaling and cell proliferation. A common missense single-nucleotide polymorphism in (rs3184504) results in substitution of tryptophan for arginine 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.

OBJECTIVES: Test the hypothesis that the tryptophan-encoding allele of rs3184504 promotes hypertension development and end-organ damage through loss of SH2B3-mediated repression of cytokine signaling to enhance T-cell activation.

METHODS AND RESULTS: We used CRISPR-Cas9 technology to create mice homozygous for the major (arginine/arginine) and minor (tryptophan/tryptophan) alleles of this polymorphism. Tryptophan/tryptophan mice exhibited 10 mm Hg higher systolic blood pressure during chronic Ang II (angiotensin II) infusion compared with arginine/arginine controls. Renal injury and perivascular fibrosis were exacerbated in tryptophan/tryptophan mice compared with arginine/arginine controls following Ang II infusion. In addition, renal and ex vivo stimulated splenic CD8 T cells from Ang II-infused tryptophan/tryptophan mice produced significantly more IFN (interferon)-γ compared with arginine/arginine controls. IL (Interleukin)-12-induced IFN-γ production was greater in tryptophan/tryptophan compared with arginine/arginine CD8 T cells. In addition, IL-12 enhanced Stat4 (signal transducer and activator of transcription 4) phosphorylation to a greater degree in tryptophan/tryptophan compared with arginine/arginine CD8 T cells, suggesting that tryptophan-encoding SH2B3 exhibits less negative regulation of IL-12 signaling to promote IFN-γ production. Finally, we demonstrated that a multi-single-nucleotide polymorphism model genetically predicting increased expression in lymphocytes is inversely associated with hypertension and hypertensive chronic kidney disease in humans.

CONCLUSIONS: Taken together, these results suggest that the tryptophan-encoding allele of rs3184504 is causal for blood pressure elevation and renal dysfunction, in part through loss of SH2B3-mediated repression of T-cell IL-12 signaling leading to enhanced IFN-γ production.

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