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Targeting XDH mutations to deliver precision medicine therapeutics for hypertension addressing a major unmet need in East London

Code: BC-DTP_2026_05

Title: Targeting XDH mutations to deliver precision medicine therapeutics for hypertension addressing a major unmet need in East London

Primary Supervisor: Prof Amrita Ahluwalia

Email: a.ahluwalia@qmul.ac.uk

Institute: William Harvey Research Institute

Secondary Supervisor: Patricia Munroe

Email: p.b.munroe@qmul.ac.uk

Institute: William Harvey Research Institute

Lay Summary:

The aim of this project is to identify genetic variants in a gene called XDH that might influence hypertension and additionally heart disease. Furthermore, this research will highlight whether an approach based upon genetic profiling of this gene might identify those individuals that would benefit most from targeting the protein this gene makes using dietary therapies (through delivery of a substance called inorganic nitrate found in certain vegetables) that are easy to administer and cost‑effective for both prevention and treatment of hypertension. Current estimates indicate that ~30% of the population are set to have high blood pressure worldwide in the next few years, and this is worrying since high blood pressure is also the biggest risk factor for further heart disease and ultimately mortality. This is relevant for the East End of London since the region has some of the highest rates of both hypertension and consequent heart disease in the UK. Our research has identified some genetic variants in large genetic studies that are linked with blood pressure. In this project, the student will study the effect of these genetic variants in cell systems relevant to blood pressure control to identify whether people with these genetics could adopt lifestyles that prevent development or treat hypertension.

Aim:

The aim of this studentship is to identify variants in XDH that influence XOR activity relevant to hypertension and CAD, and to determine whether genetic profiling might identify those individuals who would benefit most from targeting XOR NO‑generating activity using dietary therapies (through delivery of inorganic nitrate).

Impact:

Current estimates indicate that ~30% of the population are set to have CVD worldwide in the next few years. Studying relatively rare variants in XDH with allele frequencies between 0.1 and 1% suggests that between 78,000 and 23.4 million people could ultimately benefit from our studies.

To achieve this aim, the student will conduct a series of experiments delivering on the following objectives:

  1. Identify the functional impact of identified rare variants in XDH upon biochemical enzyme activity in vitro using established methods.
  2. Determine the BP and vascular effects in vivo of the lead rare SNPs identified from the GWAS studies and with confirmed effects upon XOR biochemical activity.
  3. Conduct further analyses of both common and rare functional variants with hypertension, CHD and other cardiovascular traits across ancestries.

References:

  • Roth, et al. JACC. 2020;76:2982–3021
  • GBD 2019 Diseases and Injuries Collaborators. Lancet. 2020;396:1205–1222
  • Circulation Research. 2018;122:1302–1315
  • Kapil, et al. Pharmacol Rev. 2020;72:692–766
  • Moncada, Higgs. New England Journal of Medicine. 1993;329:2002–2012
  • Journal of Cell Science. 2003;116:9–15
  • Lundberg, Weitzberg. Cell. 2022;185:2853–2878
  • Anderson, et al. Journal of the American College of Cardiology. 1995;26:1235–1241
  • Brunner, et al. Journal of Hypertension. 2005;23:233–246
  • Gori, et al. European Heart Journal. 2012;33:363–371
  • Heiss, et al. Cardiovascular Research. 2022:cvac095
  • Farah, et al. Nature Reviews Cardiology. 2018;15:292–316
  • Münzel, et al. Vascular Pharmacology. 2014;63:105–113
  • Roy, et al. International Journal of Molecular Sciences. 2023;24
  • Jones, et al. Circulation Research. 2015;116:437–447
  • Kapil, et al. Hypertension. 2015;65:320–327
  • Jones, et al. European Heart Journal. 2024;45:1647–1658
  • Kim-Shapiro, Gladwin. Nitric Oxide. 2014;38:58–68
  • Berry, Hare. J Physiol. 2004;555:589–606
  • Bortolotti, et al. Redox Biology. 2021;41:101882
  • Mackenzie, et al. The Lancet. 2022;400:1195–1205
  • Givertz, et al. Circulation. 2015;131:1763–1771
  • Massimo, et al. Redox Biol. 2023;67:102864
  • Wu, et al. Mol Med Rep. 2015;12:5685–5690
  • Scheepers, et al. Journal of Hypertension. 2016;34
  • Chaves, et al. Pharmacogenet Genomics. 2007;17:589–596
  • Surendran, et al. Nature Genetics. 2020;52:1314–1332
  • Beckman, et al. Free Radic. Biol. Med. 1989;6:607–615
  • Munzel, et al. Arterioscler Thromb Vasc Biol. 2002;22:1761–1768
  • Ghosh, et al. Hypertension. 2013;61:1091–1102
  • Gee, et al. British Journal of Pharmacology. 2022;179:4757–4777
  • Khambata, et al. Proc Natl Acad Sci U S A. 2017;114:E550–E559
  • Denny, et al. Bioinformatics. 2010;26:1205–1210
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