The genetic basis for type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin-producing beta-cells in the pancreas resulting from the action of environmental factors on genetically predisposed individuals. The increasing incidence over recent decades remains unexplained, but the capacity of identifying infants at highest genetic risk has become an increasing requirement for potential therapeutic intervention trials. SOURCES OF DATA: Literature searches on T1D and genes were carried out, and key papers since the 1970s were highlighted for inclusion in this review. AREAS OF AGREEMENT: Early genetic studies identified the most important region for genetic susceptibility to T1D-the human leukocyte antigen genes on chromosome 6; later shown to contribute approximately half of the genetic determination of T1D. The other half is made up of multiple genes, each having a limited individual impact on genetic susceptibility. AREAS OF CONTROVERSY: Historically, there have been many controversial genetic associations with T1D, mostly caused by underpowered case-control studies but these are now decreasing in frequency. AREAS OF GROWTH: The functional effect of each gene associated with T1D must be investigated to determine its usefulness both in risk assessment and as a potential therapeutic target. AREAS TIMELY FOR DEVELOPING RESEARCH: Recently identified copy number variants in DNA and epigenetic modifications (heritable changes not associated with changes in the DNA sequence) are also likely to play a role in genetic susceptibility to T1D.