Body mass index is a mediumiator of the genetic association between STK39 and blood pressure in Mexican women

Abstract Background Although obesity causally relates to hypertension, the underlying genetic mechanisms are not completely understood. STK39 gene, encoding the SPAK kinase, associates with both hypertension and body mass index (BMI). In a murine model, we previously showed that the inactivation of SPAK resulted in a hypotensive and obesity-resistant phenotype. Methods We analyzed the mediator effect of BMI on the association between STK39 and systolic blood pressure (SBP) in a sample of 2,853 Mexican adults. We also assessed the STK39 expression patterns in human adipose tissue, a relevant tissue determining BMI. Results We found that a STK39 locus, tagged by rs6749447 genetic variant, has a positive and significant direct effect on blood pressure in women (B(SE) = 0.073(0.028), P = 0.010), as well as an indirect effect through the BMI (B(SE) = 0.010(0.004), P = 0.024), therefore showing that BMI is a mediator of STK39 and SBP. None of the effects were significant in men (direct effect: B(SE) = 0.030(0.031), P = 0.329; indirect effect: B(SE) = 0.124(0.255), P = 0.626). Additionally, we found that STK39 is expressed in subcutaneous adipose tissue with similar steady-state levels to PPARG and LIPE genes, and its expression is higher in women than in men (P = 0.0008). Conclusions Our results shed light on the genetic basis of obesity-induced hypertension and outline a specific locus within STK39 as an important modulator of this process.