Epigenetic Factors Explain Variable Type 1 Diabetes Onset

Young diabetic patient checks blood sugar level
Cute elementary age girl checks her blood sugar level with a glaucometer. A senior pediatrician is helping her. The girl's mother is standing behind her.

Epigenetic factors likely explain why not all individuals with type 1 diabetes genetic risk variants go on to develop the condition, according to researchers based at Huazhong University of Science and Technology.

Type 1 diabetes is a heterogenous condition and is thought to have different causes in different people. Genetic variants in around 50 genes, such as several in the HLA region, have been linked with the condition, but carriage of these variants does not necessarily result in diabetes.

If one parent or a sibling has type 1 diabetes then the risk of a child developing the condition is 3-8%. Even if an identical twin develops the condition, then the other twin only has a 40-50% chance of also developing it, suggesting that factors other than genetics influence risk.

Environmental factors are known to influence whether or not a person develops type 1 diabetes. For example, breastfeeding and sufficient vitamin D levels seem to be protective and cow’s milk consumption and the early introduction of gluten seem to increase risk. Viral infections and exposure to stress or traumatic events have also been linked to type 1 diabetes onset.

Researchers now believe epigenetics –combining both genetic and environmental factors–may explain a large amount of the variation seen in the onset of this chronic condition. A team of researchers from the Huazhong University of Science and Technology in Wuhan, China led by Cong-Yi Wang and Fei Xiong set out to summarize how epigenetic factors influence the risks of type 1 diabetes in a new review paper published in the Chinese Medical Journal.

DNA methylation patterns influence whether or not a gene is expressed and are influenced by environmental factors. A number of methylation sites, thought to influence genes relevant to type 1 diabetes onset, have been discovered by researchers. These include several in HLA genes (eg. HLA-DQB1) and also in the insulin gene INS, among others.

Histones are proteins around which DNA is wrapped and they help store DNA in a compact and efficient way. Abnormal modifications in histones can also impact gene expression and are thought to contribute to type 1 diabetes risk. For example, modifications that increase inflammation and influence immune function.

Another epigenetic factor that can influence type 1 diabetes risk are non-coding RNAs such as micro RNAs or short-interfering RNAs. There are many types of these small genetic molecules and they have a range of functions including promoting or suppressing gene expression. Recent research suggests that they may influence type 1 diabetes onset by binding to genes influencing the immune system that subsequently result in beta cell dysfunction.

“Given the relationship between epigenetic changes and type 1 diabetes, various epigenetic changes could serve as markers for disease progression and treatment effects or even as targets for future therapeutics,” says Wang in a press statement.

“Noncoding RNAs can be measured noninvasively, while changes in DNA methylation levels and patterns for particular genes could indicate that a genetically predisposed person is developing type 1 diabetes.”

The researchers believe the current research in this area suggests that drugs that alter DNA methylation could have beneficial effects in patients who are susceptible to or who develop type 1 diabetes.

“A typical example is the DNA demethylation agent, 5-Aza-2′-deoxycytidine, which has been widely used in cancer models and patients but now is found to exert a powerful beneficial effect on T1D,” write the authors.

“Unlike genetic hardwiring, epigenetic changes following environmental exposures are a reversible process, and as a result, those changes could be erased through specific mechanisms,” they conclude.

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