Evidence for a Causal Role of the SH2B3-2M Axis in Blood Pressure Regulation: Framingham Heart Study

Genetic variants at SH2B3 are associated with blood pressure and circulating M-2 (-2 microglobulin), a well-characterized kidney filtration biomarker. We hypothesize that circulating M-2 is an independent risk predictor of hypertension and may causally contribute to its development. The study sample consisted of 7065 Framingham Heart Study participants with measurements of plasma M-2. Generalized estimating equations were used to test the association of M-2 with prevalent and new-onset hypertension. There were 2145 (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 M-2 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 M-2 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 M-2 levels, and in a hypertensive mouse model, knockout of Sh2b3 increased M-2 gene expression. In a community-based study of healthy individuals, higher plasma M-2 levels are associated with increased risk of prevalent and incident hypertension independent of chronic kidney disease status. Overlapping genetic signals for hypertension and M-2, in conjunction with mouse knockout experiments, suggest that the SH2B3-M-2 axis plays a causal role in hypertension.