Researchers are still uncovering the genetics underlying type 2 diabetes. Image: Darryl Leja, National Human Genome Research Institute, National Institutes of Health
At a glance:
- Research shows that type 2 diabetes in adolescents appears to arise from a mix of rare and common gene variants.
- The findings can pave the way toward more nuanced diagnosis and precision-targeted treatments for this form of the condition.
The diabetes field has long classified the disorder into two distinct groups, type 1 and type 2. However, new genetics research focused on a form of type 2 diabetes that is becoming more common in adolescents suggests a more complicated picture.
The study, led by researchers at Harvard Medical School, the Broad Institute of MIT and Harvard, and Boston Children’s Hospital, found that youth-onset type 2 diabetes is a genetically intermediate form of the disorder that lies on a spectrum between adult-onset diabetes and rare forms of the disorder caused by a single gene.
The research, published in Nature Metabolism, is based on analysis of DNA from more than 3,000 patients with type 2 diabetes between 12 and 18 years of age and nearly 9,800 adults, more than three-quarters of whom were of African American and Hispanic ancestry.
Adult-onset type 2 diabetes is influenced by thousands of common genetic variants, whereas the rare forms, known as monogenic diabetes, are caused by a single variant. However, the new study revealed that youth-onset type 2 diabetes shares some of genetic features with both forms of the disorder, marked by common and rare genetic variants.
Moreover, younger individuals harbor more of these variants than people with adult-onset type 2 diabetes, suggesting that genetics plays a greater role in causing youth-onset type 2 diabetes than it does in the adult-onset form.
The work also showed that the specific mix of different types of gene variants an individual carried was linked to their particular set of symptoms. For example, those with more common variants 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 a greater genetic overlap between the different forms of diabetes than previously thought.
“The way that clinicians subdivide diabetes patients now is based on symptoms, but in this study, the frequency of genetic risk factors seems to vary among patients with youth-onset type 2 diabetes,” said study senior author Jason Flannick, HMS assistant professor of pediatrics at Boston Children’s and an associate member at the Broad Institute.
“We didn’t expect that frequency of genetic variants would correlate with clinical presentation, but that amazingly seems to be what we’re seeing.”
The findings challenge our current way of thinking about type 2 diabetes and other complex diseases, which lacks nuance and instead buckets patients into very distinct categories defined by symptoms alone, the researchers said.
“Before this study, there was no clear view on the genetic architecture of youth-onset type 2 diabetes. Our work provides a view of the overall genetics of diabetes,” said study first author Soo Heon Kwak, a visiting scientist at the Broad Institute in Flannick’s lab and now a clinician based at Seoul National University Hospital in Korea.
Flagging risk factors
Disease-causing genetic variants are generally classified as common, appearing in more than 5 percent of the population; rare, found in less than 5 percent of the population; and the even rarer, monogenic variants that cause disease on their own.
Teasing apart the contributions of these different types of variants to youth-onset type 2 diabetes risk requires genetic data from thousands of patients.
Kwak and Flannick turned to ProDiGY, Progress in Diabetes Genetics in Youth, a National Institutes of Health-funded research consortium that has sequenced the exome, or the protein-coding region of the genome, of thousands of adolescents with type 2 diabetes and also collected common genetic variant data from many thousands of healthy adults.
Their analyses demonstrated that the combination of common and rare genetic variants in youth-onset type 2 diabetes has a greater influence on disease risk than in the adult-onset form. Patients with youth-onset diabetes were three times more likely to harbor common variants, compared with adults with the disorder. They were also five times more likely to harbor rare gene variants than adults.
Kwak and Flannick, building upon work previously published by the ProDiGY consortium, also found that 2.4 percent of the patients with youth-onset type 2 diabetes had monogenic diabetes — arising from a single gene — including a significant number of patients who carried variants in MC4R, a gene strongly linked to monogenic obesity. The researchers said that patients with youth-onset type 2 diabetes may merit screening for monogenic forms of the disease, which might help determine what treatments they would receive.
“There’s a nontrivial fraction that is worth getting screened for monogenic forms of diabetes, even if they don’t exactly look like what typical monogenic cases look like,” said Flannick.
Toward precision medicine
Researchers have long thought that common variants are the most significant genetic risk factor for diabetes, but the study may change that thinking.
“There’s been a long debate on the genetic architecture for type 2 diabetes, and the field tends to lean toward the common variant hypothesis,” Kwak said. “But we show that rare variants are important even after excluding the monogenic diabetes cases.”
Kwak and Flannick hope that their study can inform the development of new diabetes treatments based on specific combination of gene variant involved. The approach, they add, can also be used to better understand the genetic causes of other diseases.
“I think this could have a huge impact on other studies of complex diseases with early-onset forms,” said Kwak. “There’s a lot of heterogeneity in the different forms of common diseases. With this model, we can understand other conditions’ genetic architecture.”
Authorship, funding, disclosures
Additional authors on the 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, Lynne L. Levitsky, Toni I. Pollin, Jose C. Florez.
This research was funded by the National Research Foundation of Korea, 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, and National Heart, Lung, and Blood Institute), American Diabetes Association, among others. The full list of funders is available in the paper under Acknowledgements.
Mottl receives consulting fees from Bayer, Chinook, and Prokidney; research support from Alexion, Bayer, Boehringer Ingelheim, and Chinook. Flannick has received speaking honoraria from AstraZeneca and Novo Nordisk for scientific talks over which he had full control of content; his wife has received a consulting honorarium from Novartis. The other authors declare no competing interests.
