overview:
- Research shows that type 2 diabetes in adolescents appears to result from a combination of rare and common genetic mutations.
- This discovery could pave the way for more nuanced diagnosis and precisely targeted treatments for this form of the condition.
The field of diabetes has long classified the disease into two distinct groups: type 1 and type 2. But new genetics research focusing on a type of type 2 diabetes that is becoming more common among young people suggests a more complicated picture.
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The study, led by researchers at Harvard Medical School, the Broad Institute of Massachusetts Institute of Technology and Harvard University, and Boston Children’s Hospital, found that adolescent-onset type 2 diabetes is a form genetically intermediate to adult-onset diabetes. It turns out that there is something. There are also rare forms of the disorder caused by a single gene.
This study natural metabolismwas based on DNA analysis of more than 3,000 people with type 2 diabetes and nearly 9,800 adults between the ages of 12 and 18, more than three-quarters of whom were African American and Hispanic.
Adult-onset type 2 diabetes is affected by thousands of common genetic mutations, but a rare form known as monogenic diabetes is caused by a single mutation. But new research reveals that type 2 diabetes, which occurs in young people, shares some genetic features with both types of the disease, and is characterized by common and rare genetic variations. Became.
Furthermore, young people carry more of these mutations than those with adult-onset type 2 diabetes, suggesting that genetics plays a greater role in the etiology of young-onset type 2 diabetes than in adult-onset cases. It has been.
The study also showed that specific combinations of different types of genetic variants in an individual are associated with a specific set of symptoms in that person. For example, those with the more common mutation showed more symptoms of adult-onset type 2 diabetes, such as high insulin levels.
The findings challenge current thinking about type 2 diabetes and suggest that there is greater genetic overlap between different forms of diabetes than previously thought.
“Currently, the way clinicians subdivide patients with diabetes is based on symptoms, but in this study, the frequency of genetic risk factors appears to vary among patients with juvenile type 2 diabetes,” said the study’s lead author. Ta. Jason FrannickHe is an assistant professor in the HMS Department of Pediatrics at Boston Children’s Hospital and an associate member of the Broad Institute.
“We didn’t expect the frequency of genetic mutations to correlate with clinical symptoms, but surprisingly that seems to be what we’re seeing.”
According to the researchers, this finding challenges current thinking about type 2 diabetes and other complex diseases, which lacks nuance and treats patients as highly ill defined by symptoms alone. It is classified into clear categories.
“Until this study, there was no clear idea about the genetic makeup of youth-onset type 2 diabetes. Our study provides insight into the overall genetics of diabetes,” said the study’s authors. said lead author Soo-Hong Kwak, a visiting researcher at the Broad Institute in Franik’s lab and now a clinician based at Seoul National University Hospital in South Korea.
Risk factor warning
Genetic mutations that cause disease are generally classified as common, occurring in 5 percent or more of the population. It is rare, found in less than 5 percent of the population. Even rarer are single-gene variants that cause disease on their own.
Genetic data from thousands of patients are needed to clarify how these different types of mutations contribute to the risk of young-onset type 2 diabetes.
Kwak and Franik turned to ProDiGY (Advances in Diabetes Genetics in Youth), a research consortium funded by the National Institutes of Health. The organization also collected data by sequencing the exome, or protein-coding region of the genome, of thousands of young adults with type 2 diabetes. Common genetic variation data from thousands of healthy adults.
Their analysis demonstrated that in youth-onset type 2 diabetes, a combination of common and rare genetic variants has a greater impact on disease risk than in adult-onset cases. Juvenile diabetics were three times more likely to carry the common mutation than adult diabetics. They were also five times more likely to carry rare genetic mutations than adults.
Building on previously published research from the ProDiGY consortium, Kwak and Flannick found that 2.4 percent of patients with early-onset type 2 diabetes have monogenic diabetes, resulting from a single gene. MC4R, a gene strongly associated with monogenic obesity. Researchers say patients with early-onset type 2 diabetes may be worth screening for monogenic forms of the disease, which may help decide what treatment to receive. said.
“Even though it doesn’t look exactly like typical monogenic diabetes, there are many areas where it’s worth getting screened for monogenic diabetes,” says Franik.
Aiming for precision medicine
Researchers have long believed that common mutations are the most important genetic risk factor for diabetes, but this study may change that belief.
“There has been a long debate about the genetic makeup of type 2 diabetes, and the field tends to lean towards the common mutation hypothesis,” Professor Kwak said. “But we found that rare variants were important even after excluding cases of monogenic diabetes.”
Kwak and Flannick hope their research will help develop new diabetes treatments based on the specific combinations of genetic mutations involved. They added that this approach could also be used to better understand the genetic causes of other diseases.
“I think this could have a major impact on other studies of early-onset complex diseases,” Professor Kwak said. “There is a lot of heterogeneity in the different forms of common diseases. This model can be used to understand the genetic architecture of other diseases.”
Authors, funding, and disclosures
Additional authors of this study: Shylaja Srinivasan, Ling Chen, Jennifer Todd, Josep M. Mercader, Elizabeth T. Jensen, Jasmin Divers, Amy K. Mottl, Catherine Pihoker, Rachelle G. Gandica, Lori M. Laffel, Elvira Isganaitis, Morey W. Haymond, Lynn L. Levitsky, Toni I. Pollin, Jose C. Flores.
This research was supported by the National Research Foundation of Korea, the National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases, National Human Genome Research Institute, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Heart and Lung Institute). ) was funded by. , and Blood Institute), American Diabetes Association, etc. A complete list of funders can be found in the “Acknowledgements” section of this paper.
Mr. Mottle has received consulting fees from Bayer, Chinook, and Prokidney. research support from Alexion, Bayer, Boehringer Ingelheim, and Chinook; Mr. Frannick received speaking fees from Nordisk and AstraZeneca for his scientific lectures, the content of which he had full control over. His wife has received consulting honoraria from Novartis. The other authors declare no competing interests.
