Type 1 diabetes (T1D) is an autoimmune disorder where the immune system mistakenly attacks and destroys the insulin-producing beta cells in the pancreas. This destruction leads to a deficiency of insulin, which is necessary for regulating blood sugar. The inheritance pattern of T1D is not simple; it does not follow a predictable, single-gene pattern like Mendelian diseases. Instead, the risk of developing T1D arises from a complex interaction between multiple inherited genes and environmental factors.
Understanding Polygenic Inheritance
Type 1 diabetes is classified as a polygenic or multifactorial condition, meaning its development depends on the cumulative effect of many different genes. Researchers have identified over 50 regions in the human genome that contribute to T1D susceptibility, each adding a small degree of risk. No single “diabetes gene” is responsible for the disease; rather, the combined influence of these susceptibility genes creates a genetic predisposition.
Genetic susceptibility alone is not sufficient to cause the disease, highlighting the role of external triggers. The autoimmune process is initiated when a genetically susceptible individual encounters environmental factors, such as viral infections or changes in the gut microbiome. Genetic factors contribute approximately 50% to the risk of developing T1D. This is supported by studies of identical twins, where if one twin has T1D, the other has only a 30% to 50% chance of developing the condition, demonstrating that other elements are required for disease manifestation.
The Role of the HLA Gene Complex
The single greatest genetic contributor to T1D risk is the Human Leukocyte Antigen (HLA) gene complex, accounting for roughly 40% to 50% of the total genetic susceptibility. Located on chromosome 6, these genes encode proteins that present foreign and self-proteins to T-cells. In T1D, specific variations in HLA genes lead to a breakdown in the immune system’s ability to distinguish between its own cells and foreign invaders.
The HLA Class II genes, specifically HLA-DR and HLA-DQ, are the major determinants of T1D risk. Particular combinations of alleles, known as haplotypes, confer the highest risk, such as the co-inheritance of HLA-DR3-DQ2 and HLA-DR4-DQ8. Conversely, some HLA haplotypes are considered protective and can substantially lower the risk. While HLA genes are the strongest predictors, other non-HLA genes also contribute to the overall polygenic risk. Genes like INS and PTPN22 are recognized as secondary contributors, collectively completing the picture of genetic predisposition.
Calculating Risk Based on Family History
The lifetime risk of developing Type 1 diabetes for the general population is low (0.3% to 0.4%). This risk increases substantially when a first-degree relative (parent, sibling, or child) has the condition, raising the individual’s risk up to approximately 5%.
When a child has one parent with T1D, the risk is not equal. If the father has T1D, the risk is estimated between 3.6% and 8%; if the mother has T1D, the risk is lower (1.7% to 4%). This difference is not fully understood.
A sibling of a person with T1D has an increased risk, ranging from 8% to 10%, particularly if they share high-risk HLA haplotypes. The risk is also influenced by the affected family member’s age at diagnosis, with the highest risk conferred when diagnosis occurred at a very young age. The risk is highest when both parents have T1D, increasing the child’s likelihood to between 10% and 25%.
Genetic Screening for Predisposition
Genetic screening identifies individuals who have inherited a high-risk genetic profile for T1D, often focusing on first-degree relatives. This process involves calculating a Genetic Risk Score (GRS), which assesses the cumulative risk conferred by multiple susceptibility gene variants, including high-risk HLA types. The GRS is a statistical measure, not a diagnostic tool, that helps determine who should be monitored more closely.
The primary goal of genetic screening is to identify individuals who should proceed to autoantibody screening, a direct marker of the ongoing autoimmune process. Autoantibodies are proteins that target the beta cells, and their presence indicates the preclinical stage of T1D. Screening looks for multiple autoantibodies, such as those targeting GAD65, insulin, and IA-2. The risk of developing T1D increases significantly with the number of autoantibodies detected. Individuals testing positive for two or more autoantibodies have a high likelihood of developing clinical diabetes, with a lifetime risk approaching 100%. Identifying these high-risk individuals allows for participation in clinical trials aimed at delaying or preventing the onset of the disease.