First-of-its-kind study identifies novel genetic markers of type 2 diabetes in East Asians

In the largest non-European diabetes genetics study, an international team of researchers identified 61 new genetic variants associated with Type 2 Diabetes (T2D) in East Asians.

Findings include discovery of variants near genes involved in skeletal muscle and pancreatic functions, as well as in alcohol metabolism, and also in genes linked to higher levels of fat around the belly in East Asian individuals.

These genes had not been linked with T2D before and may help explain why — among people of similar body mass index (BMI) or waist circumference — the prevalence of T2D is greater in East Asian populations than in European populations.

“We know diabetes is caused by a complex set of risk factors, such as BMI, that have varying effects on the disease across ancestries,” said Assistant Professor Sim Xueling. “These findings expand the number of genetic variants associated with diabetes and highlight the importance of studying different ancestries.”

The study involved 433,540 diabetic and non-diabetic East Asian individuals from China, Hong Kong, Japan, the Philippines, Singapore, South Korea, Taiwan and the United States.

The international team of more than 100 researchers was led by scientists at five institutions, all co-senior authors of the Nature paper:

  • Assistant Professor Sim Xueling Sim, SSHSPH;
  • Dr Karen Mohlke, Department of Genetics, University of North Carolina at Chapel Hill School of Medicine;
  • Dr Kim Bong-Jo, Center for Genome Science, National Institute of Health, Cheongjusi, South Korea;
  • Dr Robin Walters, Nuffield Department of Population Health, University of Oxford, United Kingdom;
  • Dr Takashi Kadowaki, Department of Diabetes and Metabolic Diseases, University of Tokyo, Japan.

This research, published in prestigious journal Nature, shows how different populations of people share most of the genetic susceptibilities to developing T2D but do have some different genetic variations that can make them more or less susceptible to developing the condition.

“While a recent study of 900,000 European individuals discovered many new genetic variants linked to T2D, we were still able to make novel findings as we were studying such a large number of East Asian individuals, where these variants are more common. The identified variants are relatively rare in Europeans and thus missed in the European studies,” said Dr Sim.

The researchers made another striking observation: genetic variants can act through multiple close-by genes in different tissues to influence T2D development. For example, one gene may influence the production of insulin in the pancreas, while another gene close by could affect the use of insulin in the muscle.

“These results help further our understanding of the genetic basis for T2D across populations and provide new targets for T2D drug discovery,” said Dr Karen Mohlke of the University of North Carolina, one of the co-senior authors.

“Genetic variants are present in all our genomes, some of which predispose individuals to disease like T2D. Due to differences in population history, some variants are more common in one population than another. This study emphasizes the importance of including large numbers of individuals from different parts of the world in these studies so that we can better understand the cause of diseases. Singapore, with its multi-ethnic populations from different parts of the work, is an ideal environment for studying this.”

— Professor Tai E Shyong, Senior Consultant of the Division of Endocrinology at the National University Hospital, and Professor at SSHSPH

Ultimately, the goal of such studies is to identify potential genetic targets to treat or even cure the chronic metabolic disorder that affects more than 400 million adults worldwide, according to the International Diabetes Federation.

These results serve as a valuable public resource for precision medicine efforts in diabetes. The next steps are to identify which genes are altered by the genetic variants, how those alterations lead to disease, and to determine which of these genes may be targeted for new diabetes drugs and treatments.

The large scale study brought together 23 cohort studies from the Asian Genetic Epidemiology Network (AGEN), a consortium with over 10 years of collaborative history. It includes local cohort studies such as the Singapore Population Health Studies (SPHS), the Singapore Chinese Health Studies (SCHS) from NUS SSHSPH, and the Singapore Epidemiology of Eye Diseases (SEED) studies from the Singapore Eye Research Institute (SERI).

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