• Queen Mary University of London
  • Barts Health NHS
  • Bradford NHS
  • Manchester Uni

S00014: A recall by genotype study of coronary artery disease risk genes carrying loss of function mutations

S00014: A recall by genotype study of coronary artery disease risk genes carrying loss of function mutations and functional follow-up.

Investigators: Prof Panos Deloukas, Miss Konain Fatima Bhatti

Lay summary

a. Please provide information on the aims of the proposed research including the research question(s) that you are aiming to answer and the health condition(s) under investigation

We aim to investigate genes associated with lipid levels, blood pressure and heart disease in people recruited to Genes and Health. To this end, we will use the latest results from genetic studies in hundreds of thousands of people to select and prioritise candidate genes. We will then look at the Genes and Health Stage I genetic data to select genes that have mutations (DNA changes) affecting protein function and also play a role in the 3 traits. We will identify the Genes and Health participants who are carriers of such DNA changes, and based on the information from their electronic health records refine the selection of candidate genes. For the selected genes, we will recall participants who are carriers of the DNA changes described above (those with 1 and/or 2 copies of a relevant DNA change) and a group of individuals free of any of the investigated DNA changes (controls), for further analyses (tests available in the Genes and Health Facility and some additional cardiovascular measurements). Based on the results obtained from these analyses, we will select 2-3 target genes to establish induced stem cell lines from a few individuals for each gene. We will then use these (naïve) cells in the laboratory to derive relevant heart cell types to study in more depth the function of the target genes and how they cause heart disease.

b. How will your research improve health?

Genes and Health participants are of Pakistani and Bangladeshi heritage which are ethnic groups known to have a higher rate of cardiovascular disease (CV) and diabetes compared to European descent individuals which is also reflected in the UK population. These Prioritising CAD risk genes for functional studies will aid us to better understand disease pathophysiology and provide new targets for drug development.

c. How does your research meet the other purposes of Genes and Health?

The information from the research study which includes CV phenotyping of participants, will be linked to their genetic data and health records to help investigate the role of selected genes in CAD. The study’s research outputs have the potential to be translated to medical benefits for the South Asian community in the UK and demonstrate the value of Genes and Health Study Project Data efficacy for the purpose of biomedical research.

d. Please give a non-technical description of how the research will be undertaken

We will analyse the DNA information of the ELGH participants to select individuals that have specific DNA changes affecting protein function in genomic regions known from other studies to be associated with lipid levels, blood pressure and heart disease. We will then use available information from participants’ health records to prioritise relevant genes in these regions. We will recall participants who carry such loss of function DNA variants in the selected genes for deeper phenotyping through the ELGH Centre for Population Genomic Medicine Clinical Research Facility. Potential participants will be contacted with the help of the ELGH research team by telephone, email or post. Individuals willing to participate will be invited at the ELGH research centre for consenting followed by a short visit lasting approximately 30mins. During this time, consented participants will be subjected to a few cardiovascular phenotyping tests and asked to donate a blood sample of 50ml. The blood sample taken from the participants in this study will be used to establish ‘naïve’ cell lines which we will then differentiate to suitable cell types e.g. endothelial cells for functional studies in the laboratory. We will ensure the rules of ELGH are followed carefully and that all the results from our genetic analysis and laboratory work are anonymous. The participants in the study will not be identified through our results.

e. Please state the approximate number of volunteers to be included (i.e. whether the full cohort or a subset)

We will include 200–300 volunteers i.e. those who carry Loss of Function (LoF) in CAD risk genes and a ‘universal’ control group (i.e. people with none of the investigated LoFs). We note that recall of individuals with heart disease variants will be coordinated with other groups to avoid any duplication. We also anticipate collaborative work in the context of the Genes & Health Cardiovascular Researchers Consortium.