Oral Presentation GENEMAPPERS 2024

Polygenic prediction of response to interventions related to sodium and potassium in the clinical management of hypertension (#28)

William R Reay 1 2 3 , Erin D Clarke 2 3 , Shaun Eslick 4 , Carlos Riveros 3 , Elizabeth G Holliday 2 3 , Mark A McEvoy 5 , Stephen Hancock 3 , Roseanne Peel 2 3 , Rodney J Scott 2 3 , John R Attia 2 3 , Clare E Collins 2 3 , Murray J Cairns 2 3
  1. Menzies Institute for Medical Research, University of Tasmania, Hobart, TASMANIA, Australia
  2. The University of Newcastle, Callaghan, NSW, Australia
  3. Hunter Medical Research Institute, New Lambton, NSW, Australia
  4. Macquarie University, Macquarie Park, NSW, Australia
  5. La Trobe University, Bendigo, Victoria, Australia

Hypertension is an ongoing public health challenge and remains difficult to treat in many individuals. Dietary interventions are an effective approach to lower blood pressure but are not equally effective across all individuals. Blood pressure is heritable, and genetics may be a useful tool to overcome treatment response heterogeneity. We investigated whether the genetic architecture of blood pressure could be used to identify individuals with hypertension who may receive a particular benefit from lowering sodium intake and boosting potassium levels. Data were leveraged up to 296,475 genotyped participants from the UK Biobank (UKBB) for whom both blood pressure and urinary electrolytes (sodium and potassium) were measured, with these electrolytes objective biomarkers of sodium/potassium intake. Conventional genome-wide polygenic scores for blood pressure were generated in this cohort, as well as biologically directed genetic scores for blood pressure constructed specifically amongst pathways related to sodium/potassium biology (pharmagenic enrichment scores [1-3]). We then tested whether there was a gene-by-environment interaction between urinary electrolytes and these genetic scores on blood pressure. Genetic risk and urinary electrolytes both independently correlated with blood pressure. However, there was evidence of a non-additive interaction between blood pressure associated genetic variation in sodium/potassium pathways and urinary sodium on measured blood pressure. In other words, urinary sodium was associated with a larger blood increase among individuals with higher sodium/potassium pathway genetic burden than in those with comparatively lower genetic risk – a finding not seen for a genome-wide polygenic score.  These data suggest that genetic risk in sodium and potassium pathways could with further clinical characterisation be useful in a precision medicine model to direct interventions more specifically to lower blood pressure. A prospective clinical trial of this approach in hypertension has recently been funded to further explore efficacy.

  1. Reay, W.R., et al. Pharmacological enrichment of polygenic risk for precision medicine in complex disorders. Scientific Reports 10, 879 (2020). https://doi.org/10.1038/s41598-020-57795-0
  2. Reay, W.R., Cairns, M.J. Advancing the use of genome-wide association studies for drug repurposing. Nature Reviews Genetics 22, 658–671 (2021).
  3. Reay WR, et al. Genetics-informed precision treatment formulation in schizophrenia and bipolar disorder. The American Journal of Human Genetics. 2022 Sep 1;109(9):1620-1637. doi: 10.1016/j.ajhg.2022.07.011