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

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.