Prediction of Type 1 Diabetes
- 1Roche Molecular Systems, Pleasanton, California
- 2Department of Genetics and Molecular Medicine, School of Medicine, King’s College London, London, U.K.
- 3Children’s Hospital Oakland Research Institute, Oakland, California
- Corresponding author: Henry A. Erlich, .
Type 1 diabetes (T1D) is a chronic autoimmune disorder in which the destruction of the insulin-producing cells and resulting clinical symptoms are preceded by the appearance of a number of islet-cell specific autoantibodies. Linkage (1) and association analyses have demonstrated that type 1 diabetes has a very strong genetic component, with specific alleles and haplotypes at the HLA class II genes, as well as HLA-A and -B alleles, conferring either susceptibility to or protection from T1D (2–6). The ability to identify individuals at high risk for type 1 diabetes using genetic and/or autoantibody markers (7–10) has been a long-standing goal of the diabetes research and clinical community and a critical element in T1D prevention strategies. The role of prediction in prevention is twofold: 1) Clinical trials to evaluate potential preventative interventions are more efficient if the recruited subjects are at high T1D risk, and 2) interventions are likely to be more effective if administered early in disease progression or during the prediabetic phase, a stage identified by autoantibody markers in individuals who carry genetic risk alleles.
Although a large number of genetic variants associated with T1D have been identified by genome-wide association study analyses (11), the major genetic determinants remain specific alleles at the HLA class II and, to a lesser extent, class I loci. Because specific combinations of alleles at the HLA loci determine the genetic susceptibility, the risk for T1D is best captured by considering DR-DQ haplotypes and genotypes …