4-year PhD Studentship: Characterising the heterogeneity of type 1 diabetes across Bristol

Islet autoantibodies (iAabs) are established markers for type 1 diabetes (T1D) risk and classification. The European Reference Laboratory testing for a broad panel of iAabs (not all routinely available to the NHS) for a series of international studies, is based in Bristol. These studies, largely in children of northern European descent, show heterogeneity in iAabs, genetic risk, and rate of progression with half of T1D diagnosed in adulthood [1, 2]. In addition, our group and others showed that the iAab profile in people with T1D in some sub-Saharan African and Asian populations is different to that in Europe with altered frequencies of iAabs [3] and more idiopathic diabetes in young people. Following diagnosis there is also variation in endogenous insulin secretion, measured by C-peptide [4], and glucose management [5], which impact risks of complications. Early identification and treatment could help delay or prevent cardiovascular and renal complications of diabetes. The growing diversity of Bristol makes it an ideal location to test the hypothesis that a precision medicine approach, including broader testing to classify T1D and risks of complications at and after diagnosis, will lead to improved treatment including in non-Caucasians and older people.

Aims and objectives

This project will define iAab characteristics (level, epitopes, affinity), genetic profile, and endogenous insulin secretion in people with newly-diagnosed and longstanding T1D in Bristol.

Objectives:

1. Collect samples for analysis of iAabs, genetic risk, and urinary C-peptide, using established remote postal sampling methods, from people attending diabetes clinics in Bristol.
2. Collect clinical data including age and presentation at diagnosis, ethnicity, family history, HbA1c and complications of diabetes.
3. Compare characteristics of people with T1D (iAab profile, genetic risk, C-peptide) with respect to clinical characteristics.
4. Assay development to continue to improve remote sampling and classification.

Methodology

There are approximately 100 new cases of T1D/year in Bristol, and 35,000 existing cases. We will recruit 50% of new cases/year and at least 1000 longstanding cases (equal representation across ethnic backgrounds). In the 2011 census, Bristol’s population was 6% Black, 5.5% Asian, 84% White, and 4.5% mixed or other racial group. Video and social media strategies will be employed to aid recruitment as well as support from local NHS teams [5]. Participants will be recruited during routine diabetes clinics for remote postal sampling, currently successfully employed by our team [6].

We will collect; 1) Capillary blood serum and saliva for iAab analysis using luciferase immunoprecipitation system (LIPS) assays [7]. Epitopes and affinity will be determined using established protocols. Assay development will include multiplexing strategies and detection of iAabs in saliva (a more acceptable sample for participants), 2) mouth brush samples to generate a genetic risk score based on 67 SNPs [8], 3) Urine to measure urinary C-peptide Creatinine ratio [9].

Analysis will consider the association of age and ethnicity with iAabs, genetic risk, and C-peptide individually, and combined using multiple linear/ordinal regression, as appropriate. In Year 3, data will be linked to the National Diabetes Audits (NDA).

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol.

Please visit the Faculty of Health Sciences website for details of how to apply