A new study has revealed a novel gene associated with Type 2 diabetes. The study, which was published in the July 19, 2019 issue of Nature Communications, included genomic data from more than 5,000 people of Sub-Saharan African origin with the disease. According to its authors, it is the largest genomic study of Type 2 diabetes in people from Nigeria, Ghana and Kenya. The study confirmed known genomic variants associated with the disease, as well as identified ZRANB3, which may influence susceptibility to the disease in that population—and beyond.
“Africa is the original cradle of all humanity, to which all humans can trace their genetic origin,” said Francis S. Collins, M.D., Ph.D., co-author of the paper in a press release. “Thus, studying the genomes of Africans offers important opportunities to understand genetic variation across all human populations,” said Collins, who is a senior investigator with the National Human Genome Research Institute’s Medical Genomics and Metabolic Genetics Branch.
The Centers for Disease Control and Prevention estimates that 30 million Americans suffer from Type 2 diabetes. Nearly 9 percent of the world’s population has it, according to the World Health Organization’s 2014 statistics, a disease in which the body’s cells become resistant to the sugar-regulating hormone insulin. Long-term effects of high blood sugar levels include kidney disease, blindness and stroke.
In the current study, researchers analyzed genomic data available on participants through the Africa America Diabetes Mellitus study, the single largest diabetes genome-wide association study conducted on the continent. Using the information available from 5,231 people, they confirmed many of the variants which other research studies have already implicated in Type 2 diabetes in mostly European ancestry populations. But they also identified ZRANB3, a gene previously unknown to be associated with the disease.
The researchers took their findings one step further by studying the gene’s effects on zebrafish pancreas. They wanted to know more about the role ZRANB3 played in the development of the disease. The pancreas gives rise to the β-cells that release insulin as a response to rising glucose in the bloodstream.
“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, NHGRI researcher and first author of the paper in the press release. “But with the availability of new genomic tools, our next step was to ask: What does ZRANB3 do? How does it confer risk for Type 2 diabetes, and by what mechanisms does it act? That is the knowledge that will help the results become actionable for patients.”
The team of researchers used a CRISPR-Cas9 DNA editing system to make the ZRANB3 gene inoperative in zebrafish (called a ‘knockout’). They also used biological tools to reduce the expression of the ZRANB3 gene in different zebrafish. In both cases, researchers observed a reduction in β-cell numbers in the developing zebrafish embryo. They concluded the β-cells were being destroyed by the inactivation of ZRANB3.
To follow up on these results and identify the consequence of such β-cell death, the researchers took β-cell cells from mice and performed a similar knockdown of the ZRANB3 gene as in the zebrafish model. They found that cells with ZRANB3 knockdown released much less insulin in the presence of high glucose than normal mouse β-cells.
The identification of ZRANB3, a previously unidentified diabetes gene, researchers wrote, “provides further support for the notion that genome analysis studies in diverse global populations have the potential to discover novel (associated genes) and improve our knowledge of the genetic architecture of many common complex disorders.”