Type 1 diabetes (T1D) develops when the immune system damages the insulin-producing beta cells of the pancreas. Both genetic susceptibility and environmental factors take part in that process.
Family history and genetic susceptibility
When the genetic basis of a disease is discussed, people tend to think of it as running in families, but that is not always true, and T1D is a good example. Two facts matter here:
- More than 85% of patients with T1D do not have any family history of diabetes mellitus.
- Having a relative with T1D still increases the relative risk of T1D, by about 15-fold.
Despite that raised risk, most relatives never develop the disease. The prevalence of T1D at age 20 in someone with an affected relative depends on who that relative is:
| Relative with T1D | Prevalence at age 20 |
|---|---|
| Mother | 2% |
| Father | 6% |
| Non-twin sibling | 6% |
| Dizygotic (fraternal) twin | 10% |
| Monozygotic (identical) twin | >50% |
The jump to over 50% in identical twins shows how strong the genetic contribution is, while the fact that it stops short of 100% shows that genes alone are not sufficient.
The HLA genes and other genetic factors
The most important genes in T1D pathogenesis are the human leukocyte antigen (HLA) genes, the same region that presents antigens to the immune system. Patients who carry the HLA class II DR3 and DR4 haplotypes — the serological names for the haplotypes that carry the DQ2 and DQ8 risk alleles — have the highest risk of T1D progression. These genes are involved in the formation of autoantibodies by the adaptive immune system, and so make a person genetically more susceptible to forming T1D-related autoantibodies. Other, non-HLA genes are believed to have a minor effect by comparison.
The strength of that genetic effect seems to be changing. It is believed that in the past the effect of high-risk HLA genes was more pronounced than it is now, which again points to environmental factors becoming relatively more important over time. The effect of carrying one or two risk haplotypes is measurable: two susceptible polymorphisms of HLA raise the risk of T1D up to about 6.5, while one of them gives about 2.5.
Where environmental factors fit
The environmental factors, together with the non-HLA genes, are believed to act in the course of T1D pathogenesis as the factors that progress established autoimmunity to overt clinical disease. Genetics set the susceptibility and start the autoimmune process; the environment is what tilts it toward clinical diabetes, which is why identical twins differ and why incidence changes faster than any gene pool could.