Evidence for a Causal Role of the SH2B3 -β ₂ M Axis in Blood Pressure Regulation

Genetic variants at SH2B3 are associated with blood pressure and circulating β 2 M (β-2 microglobulin), a well-characterized kidney filtration biomarker. We hypothesize that circulating β 2 M is an independent risk predictor of hypertension and may causally contribute to its development. The study sample consisted of 7 065 Framingham Heart Study participants with measurements of plasma β 2 M. Generalized estimating equations were used to test the association of β 2 M with prevalent and new-onset hypertension. There were 2 145 (30%) cases of prevalent hypertension at baseline and 886 (21%) cases of incident hypertension during 6 years of follow-up. A 1-SD increase in baseline plasma β 2 M was associated with a greater risk of prevalent (odds ratio 1.14, 95% CI 1.05–1.24) and new-onset (odds ratio 1.18, 95% CI 1.07–1.32) hypertension. Individuals within the top β 2 M quartile had a greater risk than the bottom quartile for prevalent (odds ratio 1.29, 95% CI 1.05−1.57) and new-onset (odds ratio 1.59, 95% CI 1.20–2.11) hypertension. These associations remained essentially unchanged in analyses restricted to participants free of albuminuria and chronic kidney disease. Mendelian randomization demonstrated that lower SH2B3 expression is causal for increased circulating β 2 M levels, and in a hypertensive mouse model, knockout of Sh2b3 increased β 2 M gene expression. In a community-based study of healthy individuals, higher plasma β 2 M levels are associated with increased risk of prevalent and incident hypertension independent of chronic kidney disease status. Overlapping genetic signals for hypertension and β 2 M, in conjunction with mouse knockout experiments, suggest that the SH2B3 -β 2 M axis plays a causal role in hypertension.