MICA: Ancestry and biological Informative Markers for stratification of HYpertension: The AIM HY study

High blood pressure (hypertension) is extremely common within the general population in the UK and worldwide and is a major cause of heart disease, kidney disease and stroke. It is recognised to be the single biggest contributor to the global burden of disease. In most people with hypertension, a healthy lifestyle alone is not enough to control blood pressure, and drug treatment is required. There are a wide variety of drugs available and although these are effective and safe, it is often necessary to try different types of drugs and often to use a combination of two or more drugs. Delay in choosing the right kind of tablet or combination of tablets through "trial and error" is a major problem and, in a large proportion of people with hypertension, blood pressure is not adequately controlled. Relatively little is known about why some people respond better to one kind of tablet or combination of tablets than others. It is know that response to treatment differs in different ethnic groups in the UK and may differ between populations in Europe, Asia and Africa. The objective of this research proposal is to determine if we can use genetic markers of ancestry (which predict the proportion of a person's ancestors from Europe, Asia and Africa) and a detailed measure of chemical "metabolites" circulating in the blood that characterise the biochemical processes in each person to predict the best type of drug or combination of drugs for that person. If a combination of drugs is required we can use a new technology to put these into a single tablet. We hope that this will provide a more effective simpler approach to single tablet treatment of hypertension both in the UK and in other countries.

Hypertension treatment within the UK is currently stratified according to age and self-defined ethnicity (SDE). Limitations of this are well recognised: wide inter-individual response to drug classes despite stratification by age/ethnicity; uncertainty in stratification of ethnic minorities other than those of African ancestry and in an increasingly admixed population; uncertainty in stratification to combination treatment required in most patients; This proposal aims to exploit ethnic variation in drug response to: 1) Determine whether ancestry informative markers (AIM) and metabolomic profiling can be used to effectively personalize anti-hypertensive treatment. 2) Provide evidence for selecting the best first-line and combination treatments. 3) Determine mechanisms that define the response to existing treatments and hence inform future approaches to resistant hypertension using non-standard combinations of existing drugs and/or new drugs. Prediction of response to treatment by AIM / metabolites (previously identified in a discovery program in Twins UK) will be examined in existing randomised clinic trial (RCT) cohorts. A RCT in a multi-ethnic cohort of newly diagnosed hypertensive subjects in the UK will prospectively test this prediction and provide definitive evidence for optimal drug regimes. Multi-dimensional 'omics data (genomics, transcriptomics and metabolomics) from Twins UK will be used to identify potential gene pathways determining metabolite signatures associated with drug responses. Specific pathways will then be tested using interventional studies in participants from the RCT. A final phase of the study will examine whether the predictors of response can be utilised in centres in in lower and middle-income countries (LMIC). The consortium and project thus supports the 3 strategic aims of the MRC to translate advances in basic science, apply it to individuals and to build global collaborations to address inequality in health care.

The project will have impact on the general population, scientific community and on industry.

General population
Outcomes from the clinical trial in the UK will provide evidence for the best treatment according to self defined ethnicity and will have immediate impact for ethnic minorities with hypertension (> 6 million subjects in the UK) in whom need for improved hypertension management is greatest. This can be translated into guidelines through the British Hypertension Society which has an established pathway for the immediate translation of research findings of clinical relevance to primary and secondary care physicians managing hypertension. In the medium term implementation of a stratification based upon genomic and metabolomic biomarkers will have impact on the one in three of the general population requiring treatment for hypertension. The project is also likely to have short-term impacts in selecting optimal treatment for lower and middle-income countries (LMIC) such as Africa and India in whom populations may be sufficiently homogeneous to benefit from selection of treatment according to population characteristics. This guidance can be disseminated through the American and International Hypertension Societies.

Scientific community
Within the scientific community, the project will have impacts in identifying mechanisms of resistance to conventional hypertension treatment and new targets for treatment of hypertension. These will be of interest to both basic and clinical scientists in industry and academia and will be disseminated through scientific conferences at the Hypertension Societies and in the scientific literature.

Industry
Demonstrating that biomarker stratification of hypertension through a single additional blood test could lead to more effective yet simplified treatment of hypertension opens a global market in excess of 1 billion people. The project thus has huge potential to contribute to the wealth agenda through the diagnostic, informatics and pharmaceutical sectors of the health care industry required for seamless delivery of this new approach to hypertension management in primary care. This is likely to be realised in the relatively short term since our industry partners in these sectors are already committed to the development of the relevant technologies in more specialist areas. The application to hypertension provides added value with the opportunity to benefit from large global markets.