Genetic susceptibility to type 2 diabetes and associated metabolic phenotypes
Ann’s current research is focused on identifying the genetic factors that underlie the development of type 2 diabetes, associated metabolic phenotypes (such as hypertension, dyslipidaemia and obesity) and long-term complications in South Asian populations. Individuals of South Asian ancestry have a two-to-four-fold greater risk of developing type 2 diabetes compared with white European subjects, are more likely to be centrally obese and are also more likely to suffer from kidney disease and cardiovascular disease as a result of their diabetes. In collaboration with clinical colleagues from the United Kingdom Asian Diabetes Study (UKADS) group (based in Birmingham and Coventry), University Hospitals Leicester, the Diabetic Association of Pakistan and the Baqai Institute of Diabetology and Endocrinology, Karachi, Pakistan, Ann and her research group have created a large DNA resource for studying the inherited factors underlying the increased risk of these phenotypes. Alongside the studies carried out in Birmingham, the research group is also involved in collaborative investigations with researchers from Exeter and Karachi and are part of the South Asian Type 2 Diabetes Study group, an international consortium of scientists from the UK, India, Pakistan, Singapore, Sri Lanka, Australia, Japan, China and the USA. They are also participating in a global research effort to fine-map diabetes genes in different ethnic groups.
Genetics of autoimmune diabetes
Ann worked on the genetics of autoimmune diabetes for over fifteen years and still has an interest in this area. Recently, her research group and colleagues from Sweden showed that latent autoimmune diabetes in adulthood (LADA) is an uncommon phenotype in South Asians, but is associated with a similar genetic profile to that seen in white Europeans. Her earlier research focused mainly on the role of HLA genes in susceptibility to type 1 diabetes, in particular alleles of the DQA1 and DQB1 loci. She was involved in many of the transracial studies carried out in Professor Barnett’s laboratory in the 1990s, identifying alleles and haplotypes associated with the disease in multiple ethnic groups. Her early postdoctoral work involved the creation of an in vitro model of the HLA-DQ6.2 molecule to investigate its role in conferring strong protection against type 1 diabetes. This research identified several amino acid residues that are critical to the stability and function of the molecule. She subsequently went on to investigate the differential expression of DQ alleles associated with susceptibility to, and protection from, diabetes. Her interest in HLA-DQ-encoded protection led to a collaborative study with colleagues at Harvard Medical School, which identified variants in the HLA-DQA2 gene that distinguished between healthy individuals and type 1 diabetes patients carrying the protective DQ6.2 genotype. This suggested that disease susceptibility may map centromeric of the DQB1 locus.
Genetics of multiple sclerosis (MS)
Ann’s PhD was based mainly on her studies of genetic susceptibility to multiple sclerosis. She and her colleagues were the first to use a transracial approach to identify the HLA alleles underlying the disease in multiple ethnic groups. She also showed that HLA genotype could be used alongside MRI scanning to improve prediction of progression to multiple sclerosis following presentation with a clinically isolated neurological syndrome of the optic nerve, brainstem or spinal cord. Ann collaborated with colleagues in Denmark and the USA to continue her research on MS after completion of her PhD and participated in the first genetic admixture scan to identify susceptibility loci for the disease in individuals of African heritage (Reich et al, Nature Genetics 2005; 37: 1113-1118).
Rees, S.D., Hydrie, M.Z.I., Shera, A.S., Kumar, S., O’Hare, J.P., Barnett, A.H., Basit, A., Kelly, M.A. (2011) Replication of thirteen GWA-validated risk variants for type 2 diabetes in Pakistani populations. Diabetologia; 54: 1368-1374.
Rees, S.D., Islam, M., Hydrie, M.Z.I., Chaudhary, B., Bellary, S., Hashmi, S., O’Hare, J.P., Kumar, S., Sanghera, D.K., Chaturvedi, N., Barnett, A.H., Shera, A.S., Weedon, M.N., Basit, A., Frayling, T.M., Kelly, M.A., Jafar, T.H. (2011) An FTO variant is associated with type 2 diabetes in South Asian populations after accounting for body mass index and waist circumference. Diabetic Medicine; 28: 673-680.
Patel, A., Rees, S.D., Kelly, M.A., Bain, S.C., Barnett, A.H., Thalitaya, D., Prasher, V.P. (2011) Association of variants within APOE, SORL1, RUNX1, BACE1 and ALDH18A1 with dementia in Alzheimer’s disease in subjects with Down syndrome. Neuroscience Letters; 487: 144-148.
Rees, S.D., Britten, A.C., Bellary, S., O'Hare, J.P., Kumar, S., Barnett, A.H., Kelly, M.A. (2009) The promoter polymorphism -232C/G of the PCK1 gene is associated with type 2 diabetes in a UK-resident South Asian population. BMC Medical Genetics; 10: 83.
Britten, A.C., Mijovic, C.H., Barnett, A.H., Kelly, M.A. (2009) Differential expression of HLA-DQ alleles in peripheral blood mononuclear cells; alleles associated with susceptibility to and protection from autoimmune type 1 diabetes. International Journal of Immunogenetics; 36: 47-57.
Rees, S.D., Bellary, S., Britten, A.C., O’Hare, J.P., Kumar, S., Barnett, A.H., Kelly, M.A. (2008) Common variants of the TCF7L2 gene are associated with increased risk of type 2 diabetes mellitus in a UK-resident South Asian population. BMC Medical Genetics; 9: 8.
Husain, Z., Kelly, M.A., Eisenbarth, G.S., Pugliese, A., Awdeh, Z.L., Larsen, C.E., Alper, C.A. The MHC type 1 diabetes susceptibility gene is centromeric to HLA-DQB1 (2008) Journal of Autoimmunity; 30: 266-272.
Britten, A.C., Jones, K., Törn, C., Hillman, M., Eckholm, B., Kumar, S., Barnett, A.H., Kelly, M.A. (2007) Latent autoimmune diabetes in adults in a South Asian population of the UK. Diabetes Care; 30: 3088-3090.