Side Effects of BP Drugs Genetically Determined

Thiazide diuretics are one of the most widely used and effective class of medications used to treat high blood pressure, and is highly effective at preventing heart attacks and strokes in patients with hypertension.

Although the vast majority of patients do not experience side effects, a small minority do, of which Thiazide Induced Hypernatraemia (TIH) is amongst the most common and medically serious. TIH is the most common drug-induced cause of hypernatraemia requiring hospital admission in the UK.

Scientists at the Queen’s Medical Centre at University of Nottingham (UK) and their colleagues used a combination of genetic analysis and biochemical characterization of blood and urine samples of 157 patients admitted to the Queen’s Medical Centre with severe thiazide induced hyponatremia. This has enabled them to determine what is different about these individuals compared to the 246 patients they also studied who take thiazide medication but who had normal sodium levels in the blood.

Most of the clinical chemistry analyses were performed on Beckman AU clinical chemistry analyzer. Genome Wide Association Studies (GWAS) was performed using 48 TIH cases genotyped using the Illumina Omni1quad array and 2,922 general population controls from the British 1958 birth cohort were genotyped using the Illumina 1.2M chip. Controls were all aged 44 to 45 years at the time of DNA collection (2002 to 2004) and 48% were female.

The investigators found that some patients who developed TIH have a genetic abnormality, which causes excessive water retention by the kidneys. Patients who experienced this side effect continue to display more subtle differences in their blood and urine tests long after the thiazide medication has been stopped, suggesting that such abnormalities may be present before medication was started.

The team identified a suggestive association with a variant in the Solute Carrier Organic Anion Transporter Family Member 2A1(SLCO2A1) gene, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro.

Mark Glover, PhD, a clinical pharmacologist and senior author of the study said, “This study suggests that in the future we may be able to personalise the treatment of patients with hypertension; we may be able to predict who is at high risk of experiencing this side effect of thiazide tablets and either choose alternative anti-hypertensive medication or focus additional safety blood test monitoring in those at particularly high risk.” The study was published on August 7, 2017, in the Journal of Clinical Investigation.