ZRANB3 in African Populations: New Type 2 Diabetes risk locus identified

August 03, 2019 – Africa is considered the original cradle of all humanity, to which all humans can trace their genetic origin. This may be very interesting in the context of diseases that are due to genetic predispositions both in todays African populations and in all the populations descendant of African origin worldwide.

In a very remarkable study along these lines, a research team led by investigators at the National Institutes of Health genotyped, as part of the Africa America Diabetes Mellitus (AADM) Study, some 18 million autosomal SNPs in 2,343 participants from Nigeria, Ghana, or Kenya with type 2 diabetes (T2D) and 2,889 unaffected controls from the same populations who had similar average body mass indexes. The team reported online in Nature Communications that it started previously with a genome-wide association study that included more than 5200 individuals from Nigeria, Ghana, and Kenya with or without T2D. There, they identified 32 loci linked to T2D in prior studies, which were mainly conducted in individuals of European descent, as well as a new association involving a locus near ZRANB3, that belongs to the SNF2 family of DNA-dependent ATPases that function in replication stress response and catalyze remodeling of stalled replication forks. Along with the already known T2D risk loci, the analyses highlighted two ZRANB3 SNPs, which were missing from the 1000 Genomes Project (1KGP) database and the Genome Aggregation Database (GnomAD) and are suspected of being specific to some African populations. In a validation analysis that included T2D cases and controls from a Zulu population in South Africa, which had lower population frequencies of both SNPs compared to the AADM cohort, the team noted consistent directional effects, though the ties to T2D appeared to be less pronounced.

The findings of this study further demonstrate why it is important to study all human populations. By doing so, novel discoveries that will not only help the specific population but also people all around the globe are going to be made. Moreover, in the early days of large-scale genomic studies, the effect of genes found through statistical tests were not known. Today, with the availability of new genomic tools, a logical step in the present case is to ask: What does ZRANB3 do? How does it confer risk for T2D, and by what mechanisms does it act? Are these mechanisms unique to individuals of African population descent only? What is (are) the resulting clinical phenotype(s)? Overall, this kind of studies only will eventually provide the knowledge that will help the results become actionable for patients in theragenomic medicine.

Thus, for those functional experiments, the team used RNA sequencing, CRISPR-Cas9-based gene knockouts, and other approaches for fiddling with the expression of ZRANB3 in a zebrafish pancreas model of T2D. Results from such experiments indicated that the number of insulin-producing beta cells in the pancreas decrease as ZRANB3 activity is dialed down, results confirmed with small interfering RNA-based gene knockdown experiments in mice. If confirmed in humans, these results may indicate the in the ZRANB3 affected African populations, regulation of insulin-producing beta cells may be one of the mechanisms behind T2D, and that, consequently, this regulation could become a target for therapeutic intervention.

When they looked for T2D associations with more than 100 SNPs implicated in the condition in the past, the researchers verified 32 of these risk loci in the Nigerian, Ghanaian, or Kenyan cases, among them TCF7L2rs7903146, MCM6, DARS, DGKB, GTF3AP5-AGMO, IL23R/IL12RB2, SLC44A4. A handful more risk loci came out of the GWAS meta-analysis, which included data for almost 8,600 participants from African, African American, and other populations.

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About the Author
Joseph Gut - thasso Ph.D.; Professor in Pharmacology and Toxicology. Senior expert in theragenomic and personalized medicine and individualized drug safety. Senior expert in pharmaco- and toxicogenetics. Senior expert in human safety of drugs, chemicals, environmental pollutants, and dietary ingredients.

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