A genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan African populations, which have been vastly underrepresented in genomics research, resulted in the discovery of a previously-unreported gene, ZRANB3 (Zinc Finger RANBP2-Type Containing 3), that may influence susceptibility to the disease.

https://www.flickr.com/photos/nihgov/19838394254
Francis Collins, MD, PhD

“Africa is the original cradle of all humanity, to which all humans can trace their genetic origin,” said Francis S. Collins, MD, PhD, senior investigator with the NHGRI Medical Genomics and Metabolic Genetics Branch and co-author of the paper. “Thus, studying the genomes of Africans offers important opportunities to understand genetic variation across all human populations.”

The team analyzed roughly 18 million autosomal SNPs using data from 5,231 individuals from Nigeria, Ghana, and Kenya making this the largest genomic study of T2D in sub-Saharan Africans. The participants were obtained through the Africa America Diabetes Mellitus study, the single largest diabetes genomic association study conducted on the continent.

The paper, “ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response” is published today in Nature Communications.

“In the early days of large-scale genomic studies, we did not know the effect of genes we found through our statistical tests,” said Adebowale Adeyemo, MD, deputy director of the Center for Research on Genomics and Global Health (CRHHG) at the National Human Genome Research Institute (NHGRI), National Institutes of Health and first author of the paper. “But with the availability of new genomic tools, our next step was to ask: What does ZRANB3 do? How does it confer risk for T2D, and by what mechanisms does it act? That is the knowledge that will help the results become actionable for patients.”

To better understand how ZRANB3 was involved in T2D, the researchers studied its effects on the pancreas—a key organ involved in T2D—of zebrafish. Working with Norann Zaghloul, PhD, associate professor at the University of Maryland School of Medicine, they used a CRISPR-Cas9 DNA editing system to knock out the ZRANB3 in zebrafish. A lack in ZRANB3 resulted in a reduction in pancreatic β-cell number in the developing zebrafish embryo. They found that β-cells were being destroyed when the ZRANB3 gene was inactive due to increased apoptosis in islets.

To follow up on these results and identify the consequence of such β-cell death, the researchers showed that siRNA transfection of murine ZRANB3 in MIN6 β-cells results in impaired insulin secretion in response to high glucose, implicating ZRANB3 in β-cell functional response to high glucose conditions.

“The findings of this study further demonstrate why it is important to study all human populations. By doing so, we have the opportunity to make novel discoveries that will not only help the specific population but also people all around the globe,” said Charles Rotimi, PhD, director of the Trans-National Institutes of Health center for research in genomics and global health and senior author of the paper. “The biology then becomes generalizable, and that much more impactful.” Indeed, although the role of ZRANB3 in T2D was discovered in African populations, it is possible that the same gene may also influence the development of T2D in other populations.

The next steps for the researchers will be to return to the human participants who have T2D as well as the variant for ZRANB3. One question that they would like to ask is, could the presence of the ZRANB3 variant in T2D patients help predict whether these individuals will require insulin early in the course of their diabetes treatment? Providing insulin to such people early may be advantageous because that could help delay the exhaustion of their β-cells over time. This could someday be a simple, yet vastly effective way of treating T2D in a personalized manner.

The findings replicate results for many of the variants which other research studies have already implicated in T2D in mostly European ancestry populations. But, they importantly advance the understanding of the genetics of T2D in non-European ancestry populations.

 

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