Linking inflammation and hypertension via LNK/SH2B3

Abstract

Purpose of review Hypertension is a leading cause of cardiovascular and renal morbidity and mortality. Genome wide association studies identified a single nucleotide polymorphism in the gene SH2B3 encoding the lymphocyte adaptor protein, LNK, but until recently, little was known about how LNK contributes to hypertension. This review summarizes recent work highlighting a central role for LNK in inflammation and hypertension. Recent findings Using a systems biology approach that integrates genomic data with whole blood transcriptomic data and network modeling, LNK/SH2B3 was identified as a key driver gene for hypertension in humans. LNK is an intracellular adaptor protein expressed predominantly in hematopoietic and endothelial cells that negatively regulates cell proliferation and cytokine signaling. Genetic animal models with deletion or mutation of LNK revealed an important role for LNK in renal and vascular inflammation, glomerular injury, oxidative stress, interferon gamma (IFNγ) production, and hypertension. Bone marrow transplantation experiments revealed that LNK in hematopoietic cells is primarily responsible for blood pressure regulation. Summary LNK/SH2B3 is a key driver gene for human hypertension, and alteration of LNK in animal models has a profound effect on inflammation and hypertension. Thus, LNK is a potential therapeutic target for this disease and its devastating consequences.

Genome‐wide mapping of plasma protein QTLs identifies putatively causal genes and pathways for cardiovascular disease

“…For example, we found decreased SH2B3 expression to be causal for higher circulating B2M levels. This extends prior knowledge of the associations of SH2B3 24 and B2M 25 with hypertension as we demonstrate a unidirectional causal association between SH2B3 expression and plasma B2M levels, and thus provide plausible evidence for a causal role of the SH2B3 -B2M axis in hypertension (Supplementary Fig. 2b ).…”

Human longevity: 25 genetic loci associated in 389,166 UK biobank participants

“…The variant is also highly correlated (R 2 =0.91) with an exonic variant in SH2B3 , previously linked to CAD, blood pressure, TNF-α, cell counts and colorectal cancer [ 14 ]. SH2B3 encodes the lymphocyte adapter protein (LNK), which plays a key role linking inflammation and hypertension, particularly in the kidney and blood vessels [ 26 ].…”

Dietary inflammatory index and risk of renal cancer in the Iowa Women’s Health Study

“…Smoking [44] and long-term hypertension [45] are among established risk factor for renal cancer and are also known to increase level of inflammation [46, 47]. Thus, it may be possible that diet-associated inflammation amplifies these effects resulting in increased risk of renal cancer.…”