Molecular Genetics - Monogenic
This group principally work on defining monogenic and polygenic genetic determinants of human disease. The polygenic work is led by Professor Tim Frayling and is detailed below under "Genetics Type 2 Diabetes". The monogenic analysis involves the discovery of novel genes causing human syndromes (Turnpenny et al, American Journal of Human Genetics 1999, Bulman et al Nature Genetics 2000). Work centres on monogenic diabetes, permanent neonatal diabetes, familial hypoglycaemia, developmental spinal disorders and developmental eye movement disorders. This work is in close liaison with NHS colleagues who identify families enabling gene localisation and identification.
Monogenic genetic analysis has led to improved patient care. Close collaboration with the NHS diagnostic lab in the Royal Devon & Exeter laboratory and has led to the introduction of new diagnostic molecular genetic tests which are available worldwide. Research has also looked at the interpretation of genetic information by patients and has led international thinking on how to develop genetic counselling and diagnostic genetic testing in monogenic diabetes. Studying subjects with mutations is a crucial way of defining the function of the specific gene in man. We have shown the key role of glucokinase in fetal growth and the sensing of hypoglycaemia.
The present work is centering on pharmacogenetics showing specific sensitivity to sulphonylureas in patients with hepatic nuclear factor mutations. We are collecting samples from appropriate patient and normal subject populations in whom the role of polygenic genes can be defined. This work is centred on Type 2 diabetes (EXTRA study, MRC Trios) and fetal growth (the Exeter Family Study).
Genetics of Type 2 Diabetes
Type 2 Diabetes is caused by a combination of genetic and environmental factors. Despite this the aetiology of type 2 diabetes is still very poorly understood and clinicians are forced to treat the symptoms rather than the causes of the disorder. Finding the genes that predispose to this condition will help define the underlying pathophysiological pathways involved and lead to improved preventative and therapeutic measures. Our group is aiming to identify type 2 diabetes genes using some of the best and largest clinical resources worldwide. Through the UK Warren 2 consortium and local collections we have access to DNA from over 3000 subjects with type 2 diabetes, including 450 parent offspring ‘trios’ and ‘duos’, 850 sib-pairs and 350 subjects diagnosed <45 years. These resources have led to the identification of common alleles in the insulin promoter factor-1 (D76N) (1), Kir6.2 (E23K) (Gloyn et al Diabetes 2003), and Glucokinase (-30G/A) (Weedon et al, unpublished) genes as influencing type 2 diabetes risk or intermediate traits. Further work has revealed evidence for variation in the Calpain 10 (2) and Wolframs syndrome (3) genes influencing type 2 diabetes risk.
We are also investigating the role of common variation in monogenic diabetes genes, with particular focus on the beta-cell transcription factors (HNF-1 alpha and HNF4 alpha). These transcription factors are part of a complex network of gene regulation in the beta-cell and liver. We are using bioinformatic techniques to examine regions upstream of these genes for transcription factor binding sites (Lockwood and Frayling, submitted).
Using the latest linkage software (Allegro, Genehunter 2.0) we are also performing linkage studies on type 2 patients diagnosed young (<55) from the Warren 2 sibpair cohort. These studies have revealed evidence that younger subjects have an increased family history of type 2 diabetes and provide disproportionate amounts of evidence to linkage peaks. Loci on chromosomes 1, 5, 8, 10 and 22 have been identified in young onset subjects (4).
In addition we are looking at the role of type 2 diabetes genes in fetal growth. Insulin is a key regulator of fetal growth. This work aims to test the ‘fetal insulin hypothesis’ (5; 6) that proposes that genes altering insulin action or secretion may also alter fetal growth.
More details of our monogenic and polygenic work can be found on our website, which includes a list of publications.
We will be part of the UK BioBank project.