Decoding Diabetes in Asia

The largest meta-analysis of people of East Asian origin to date is adding to a growing genetics resource on type 2 diabetes and bolstering precision medicine efforts in the region.

In the early 20th century, diabetes was a death sentence, leaving sufferers an average of just one year to live. But in 1921, the discovery of insulin, the hormone that helps cells turn sugar into energy, turned this fatal disease into a manageable one.

Yet, one century later, diabetes is posing new challenges. Type 2 diabetes, a particular type linked to obesity and insulin resistance, has risen to epidemic proportions—with cases more than tripling worldwide over the past 20 years[1]. This explosion in cases is revealing striking disparities in risk, especially between Asian and Caucasian populations. Not only are East Asian individuals more likely to develop type 2 diabetes, but they do so at a lower body mass index (BMI) than their European counterparts.

To understand and combat these emerging trends, scientists are turning to genetics. While Asian genetics studies have historically lagged behind those in Europe, they have started catching up over the past decade.

In 2020, a collaboration by 113 scientists combined data from 23 cohort studies from the Asian Genetic Epidemiology Network, a decade-old consortium of genetic studies of type 2 diabetes in East Asia, to perform the largest meta-analysis of East Asian individuals to date [2]. The study, published in Nature, compares the genetic risk of type 2 diabetes between East Asian and European populations.

“Studying East Asian individuals at such an unprecedented collaborative scale allows us to expand the number of genetic variants associated with diabetes to understand population differences in the development of type 2 diabetes,” said corresponding author Xueling Sim, Assistant Professor at the National University of Singapore’s Saw Swee Hock School of Public Health.

Small changes, big impact

At our core, humans are more similar than we are different. The genome of all humans, for instance, contains about three billion base pairs and 20,000 protein-coding genes. While we all harbour genetic variants, or changes in the sequences of our genes, that make us unique, these account for just 0.001 percent of our DNA.

The similarity in our genomes appears to extend somewhat to our genetic susceptibility to type 2 diabetes. When Sim and colleagues compared genetic variants that were present in both people of East Asian and European origin, they found that the effect size, or the link between these variants and type 2 diabetes, was very similar, indicating that the two populations had a substantial shared genetic susceptibility to the disease.

However, it turns out that some variants have different effects in different populations. When there were large differences in effect sizes, the variants involved were often rare in Europeans but common or present at low frequency in people of East Asian origin.

“While East Asian individuals share some similar genetic susceptibility, certain genetic variants predisposing to type 2 diabetes risk have arisen and occur at higher frequency in East Asian individuals that are very rare in Europeans,” Sim explained. This highlights the importance of studying diverse populations so as to better understand the cause of the disease.

A growing resource

Aside from comparing common variants, the researchers took advantage of their large-scale study—which included 433,540 East Asian individuals from China, Hong Kong, Japan, Korea, Philippines, Singapore, Taiwan and USA—to look for unique genetic links to type 2 diabetes in East Asian people. They found 61 novel regions of the genome, known as loci, associated with the disease that had never before been reported in Europeans.

Among the new variants was a pair located in two nearby genes involved in glucose uptake in skeletal muscle and pancreatic cell development. What struck the researchers about these variants was that while they were located in the same locus, the ANK1/NKX6-3 locus, these two variants appear to act via genes with distinct functions in different tissues of the body. This, according to Sim, tells us that the underlying biology of type 2 diabetes may be more complex than we think.

The study also provides insight into the intriguing link between BMI and type 2 diabetes in East Asian individuals. When they accounted for BMI, the researchers discovered that there were associations between type 2 diabetes and loci found only in East Asian populations linked to body fat distribution and lipodystrophy, a dysfunction in the way the body uses and stores fat. These associations may explain why East Asian people develop the disease even at lower BMIs.

“These results serve as a valuable public resource for precision medicine efforts in diabetes,” Sim said. Not only will these data be useful for developing early risk stratification strategies, they will also form the foundations upon which researchers can discover new pathways and develop novel drugs to combat the challenges posed by type 2 diabetes in the 21st century.

References:

[1] IDF Diabetes Atlas [Online].  https://www.diabetesatlas.org/en/sections/worldwide-toll-of-diabetes.html

[2] Spracklen, C.N., Horikoshi, M., Kim, Y.J., Lin, K., Bragg, F., et al. Identification of type 2 diabetes loci in 433,540 East Asian individuals. Nature 582, 240–245 (2020).