Rare gene variants linked to type 2 diabetes discovered in Asian Indian families

Rare gene variants linked to type 2 diabetes discovered in Asian Indian families

A new study published inCommunication medicineANatureThe publication describes the discovery of rare gene variants that increase the prevalence of type 2 diabetes in multiple generations of Asian Indians. The unusual finding is a step toward more targeted treatment for all people with type 2 diabetes, a disease with complex genetic influences.

"We wanted to study multiple generations of Asian Indians because understanding genetics in families can give us better information, and Asian Indians are up to six times more likely to develop type 2 diabetes than Europeans. Additionally, Asian Indians tend to live together and marry in the same caste system." from the Oklahoma College of Medicine.

“Our study found that the participants have their own rare genetic changes that are not found in other unrelated populations around the world,” Sanghera added. "This is important because it helps us understand the different causes of diabetes. It also gives us ideas to create new drugs that target specific proteins or pathways. Treating diabetes in a tailored way is important because not everyone does not respond well to metformin or other drugs that lower blood sugar. We also need to prevent or delay diabetes in children that alter many of these genes."

When people develop type 2 diabetes, their genes contribute about 50% to the onset of the disease, and the other 50% is due to lifestyle factors such as poor diet and lack of physical activity. There are three main ways that genes can influence: monogenic, where one gene causes the disease; Oligogenic, where some genes have a large influence regardless of diet or exercise; and polygenic, where a proportion of many genes (over 400) each contribute a small effect, combined with lifestyle factors. Scientists found these genes by studying millions of people, mostly of European descent. The rare gene variations Sanghera's team found are an example of oligogenic diabetes, she said.

Sanghera and her team also made an unexpected finding: the gene variants did not code. While coding genes are like a “recipe” for building a protein, non-coding gene variants are like “instructions” for when to use the recipe, therefore controlling when and where a protein is made.

Because these families have multiple generations of diabetes, we thought we would discover coding genes because they directly influence a person's susceptibility to diabetes. By finding rare non-coding variants in a handful of genes that are highly correlated with diabetes, we determined that this is an example of oligogenic diabetes. “

Dharambir Sanghera, Ph.D., professor of pediatric genetics, University of Oklahoma College of Medicine

In a serendipitous finding, the researchers found that three of the genes with many rare variations were mody genes (maturity-related diabetes in adolescents). A single Mody gene can cause diabetes (monogenic) no matter how healthy a person's lifestyle is, Sanghera said. There are approximately 14 Mody genes that cause this type of diabetes in young adults, but their connection to type 2 diabetes is not well understood.

“These results suggest that we need to study the role of Mody genes in type 2 diabetes in more detail by looking at the family genes affected by it,” Sanghera said. "The most interesting part of this study was that families with many cases of late-onset type 2 diabetes and a number of rare non-coding gene changes had less common genetic risk factors, called a 'polygenic risk score.' Typically, people with higher polygenic scores have rarer, more rare genetic changes.

“The genetic component of diabetes is very complex because the disease is so heterogeneous (has multiple causes), just as there are different types of breast cancer and different treatments based on the subtypes of breast cancer,” Sanghera added. “The more we understand about the genetics of diabetes, the closer we are to moving toward precision medicine and treating people based on the specific type of diabetes they have.”

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