Genetic and molecular characterisation of sodium reabsorption by thiazide-sensitive pathways in the kidney

High blood pressure (hypertension) affects one in three adults in the UK and causes heart attacks and strokes. Thiazide water tablets (diuretics) are one of the most widely used and cost-effective group of medicines to treat hypertension. They work by causing the kidneys to lose sodium salt into the urine but are usually only partly effective in lowering blood pressure and can cause debilitating side effects, such as confusion, falls and seizures due to low sodium levels in the blood (hyponatraemia).

We want to understand how thiazides cause sodium loss at a molecular level so that we may avoid their use in those at risk of hyponatraemia and also inform the design of new thiazide-like medicines which are more effective at lowering blood pressure and less likely to cause low sodium levels.

To do this we will conduct genetic studies and analyse blood and urine samples from two unique patient groups. The first group have a very rare, inherited and exquisitely thiazide-responsive syndrome of hypertension, known as Gordon syndrome but who do not carry mutations established for this condition. The second group of patients are those admitted to hospital with thiazide-induced hyponatraemia. Nine hospitals throughout the UK will help us recruit hyponatraemic patients and initial genetic results from Nottingham (candidate gene seqeuncing) are encouraging and require replication.

The role or function of identified genes from both patient groups will be studied in our laboratories. We will also investigate whether more subtle abnormalities in these genes may contribute to blood pressure and blood sodium regulation in the general population by collaboration with the UK Biobank.

Aims:
To advance understanding of the thiazide-sensitive pathway(s) of sodium reabsorption by studying two clinical manifestations of dysregulation of this pathway: Gordon syndrome (GS) and Thiazide-Induced Hyponatraemia (TIH).

Objectives
1.To establish the genetic basis for Gordon syndrome (GS) in patients without mutation in WNK1/4, CUL3 or KLHL3 mutation and explore phenotype-genotype correlations within GS

2.To build on pilot work in Nottingham to establish the genetic basis for predisposition to severe TIH and detailed description of the TIH phenotype

3.To investigate whether the identified genes are associated with blood pressure and sodium concentration in the general population using the UK Biobank

4. in vitro characterisation of identified genes and their variants, including novel CUL3, KLHL3 and TIH candidates already identified.

Methods
1.Recruitment of GS patients with Professors Gordon and Jeunemaitre and TIH patients through an ongoing multi-site programme in the UK

2.A variety of genetic methods will be used to investigate GS and TIH including:
-Whole exome reseqencing (GS)
-Exon-directed beadchip analysis (TIH)
-Targeted resequencing of candidate genes (TIH)

3. Association study of BP and serum sodium in the UK Biobank population.

4. Functional studies using Xenopus oocytes & cell culture.

Scientific/Medical value of results

1.Further understanding of the molecular mechanisms regulating sodium trafficking will advance the understanding of:
a.the regulation of human blood pressure
b.additional mechanisms of action of thiazide diuretics
c.predisposition to TIH

2.This will inform:
a.The discovery of new anti-hypertensive drug targets
b.The design of new diuretics less prone to induce hyponatraemia
c.Functional and pharmacogenetic characterisation of hypertensive patients to avoid thiazides in those susceptible to hyponatraemia

There are many potential beneficiaries of my research other than the academic community:

1) Patients and patient groups

The 30% of the adult population in the UK who are hypertensive would benefit from the design of more efficacious anti-hypertensive drugs by improved blood pressure control and so lower incidence of cardiovascular disease and events such as heart attacks and strokes. Patients would also benefit from drugs with fewer side effects or from avoiding drugs to which they were predisposed to develop side effects from. It is notable that the vast majority of patients with severe TIH (and mental capacity) we have approached have agreed to contribute to the TIH research project. Patients often comment us how debillitating being admitted to hospital with TIH is and as a patient group they are overwhelmingly in support of research into this severe side effect.

Patients will also benefit by understanding they have hypertension, and by better understanding how their medicines work and how and why they can cause side effects. The patients' 'Blood Pressure Association' is particularly well suited to convey developments in hypertension from researchers to patients.

2) Clinicians

Both doctors and nurses, specialist and non-specialist, would benefit from advances in understanding of the pathophysiology of hypertension as well as clinical and genetic associations with the development of hyponatraemia after prescription of thiazide diuretics. This would arise not only through changes to hypertension guidelines but more directly through continued professional development and engagement with developments in Medicine.

3) The Pharmaceutical industry

Identification of new anti-hypertensive drug targets and the design of thiazide-like agents with fewer side-effects would benefit the pharmaceutical industry. It would also contribute to the reputation of the UK as a centre of excellence and innovation in biomedical research. This in turn is valuable in determining where multi-national companies such as those in the pharmaceutical industry choose to locate their resources.

4) Policy makers and Government agencies

Bodies such as NICE and the British Society of Hypertension, who formulate clinical guides on the treatment of hypertension in the UK, may incorporate any beneficial new anti-hypertensive agents or pharmacogenomic prescribing algorithms informed by this research into treatment guidelines. This not only ensures that newly emerging medical evidence is used to benefit patients nationally but also maximises health gains with limited public resources, for example avoiding the costs of hospitalisation with thiazide-induced hyponatraemia or a cardiovascular event. These benefits would also apply to international counterparts.

Timescale of benefits:

Understanding of the mechanisms of hypertension and adverse effects of thiazide-diuretics will occur during the tenure of the Fellowship

It will however take many years for this to result in new anti-hypertensive agents. This does not diminish the final benefits of any such agents but reflects the complex and demanding process of developing new drugs. As the UK population ages and hypertension becomes more prevalent, the need for superior and innovative anti-hypertensive agents will be even greater in the future than at present.

Personalised prescribing based on pharmacogenomic risk prediction models may be realised sooner than the development of new drugs but would still be measured in years.