Title: Genetics of Type 2 Diabetes
Funder: Medical Research Council

Abstract: Diabetes is a major health problem globally with an estimated 382 million people affected in 2013 with a projected 592 million by 2035. In the UK 3 million people (approximately 4.6% of the population) are currently diagnosed with diabetes and a further estimated 850k undiagnosed. Around 90% of the people affected by diabetes have type 2 (T2D), which is characterized by defects in insulin action and insulin secretion and is generally a later onset disease (risk increasing with age). Risk factors for diabetes include ethnicity, obesity (accounting for 80-85% of the risk), genetics and deprivation. Diabetes causes significant mortality and morbidity as a result of complications that develop over prolonged periods of time and costs the UK NHS an estimated £27 million/day. Treatment for diabetes mitigates these complications but there are a limited number of drugs available with varying efficacy and therefore there is a need for new and better treatments to improve glycaemic control. Novel insights into mechanisms underlying disease can come from genetic approaches such as the mapping and identification of genetic loci that give rise to diabetes or related metabolic traits. The characterization of mutations and polymorphisms in particular genes and pathways linked to disease traits can then yield novel information about basic biology and physiology that may ultimately be translatable for therapeutic benefit. My main research focus is the functional characterization of genes within genome wide association (GWA) loci for type 2 diabetes and obesity. In order to select genes and sequences within loci we make use of tissue specific chromatin maps from ENCODE and the Roadmap epigenomic project, expression-QTL data and close collaboration with human geneticists. Our approach is to functionally test genes and putative non-coding regulatory elements using the mouse. To do this we make conditional knockout and overexpression alleles, as well as editing the genome using CRISPR/Cas9 technology and in the latter case targeting enhancer elements that may be marked by human functional SNPs. Mice carrying these alleles are then metabolically phenotyped in detail and tissues and cells used for mechanistic studies. Three GWAS loci are of particular interest (FTO/IRX/RPGRIP1L, ARL15 and TBX15/WARS2) because they have in common that their T2D risk is mediated by changes in body composition and in particular on their effects on adipose tissue mass. The aim of these studies is to (1) functionally test conserved candidate SNPs/regulatory elements (2) functionally test genes for a role in traits linked to the GWAS signals and (3) to understand the mechanism by which they exert these effects on traits. We are also characterizing new models, from past work, of insulin resistance, insulin secretory defects and obesity. This work includes detailed physiological and molecular phenotyping and mapping and cloning of the underlying mutations. Once genes are cloned they are investigated in more detail to determine their function particularly where their role in diabetes was not previously known. I am interested in developing further projects around metabolic GWAS loci in collaboration with human geneticists and clinicians, particularly where there is access to patients recalled by genotype for further characterization.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: METABOLIC AND ENDOCRINE