1. ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response.
- Author
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Adeyemo AA, Zaghloul NA, Chen G, Doumatey AP, Leitch CC, Hostelley TL, Nesmith JE, Zhou J, Bentley AR, Shriner D, Fasanmade O, Okafor G, Eghan B Jr, Agyenim-Boateng K, Chandrasekharappa S, Adeleye J, Balogun W, Owusu S, Amoah A, Acheampong J, Johnson T, Oli J, Adebamowo C, Collins F, Dunston G, and Rotimi CN
- Subjects
- Africa, Northern, Animals, Apoptosis, Base Sequence, Blood Glucose, CRISPR-Cas Systems, Disease Models, Animal, Female, Gene Editing, Gene Knockout Techniques, Genotype, Ghana, Glucose metabolism, Homozygote, Humans, Kenya, Male, Mice, Middle Aged, Mutation, Nigeria, Polymorphism, Single Nucleotide, RNA, Small Interfering, Transcription Factor 7-Like 2 Protein genetics, Transcriptome, Zebrafish, DNA Helicases genetics, DNA Helicases metabolism, Diabetes Mellitus, Type 2 genetics, Genetic Association Studies, Genetic Predisposition to Disease genetics, Insulin metabolism, Insulin-Secreting Cells metabolism
- Abstract
Genome analysis of diverse human populations has contributed to the identification of novel genomic loci for diseases of major clinical and public health impact. Here, we report a genome-wide analysis of type 2 diabetes (T2D) in sub-Saharan Africans, an understudied ancestral group. We analyze ~18 million autosomal SNPs in 5,231 individuals from Nigeria, Ghana and Kenya. We identify a previously-unreported genome-wide significant locus: ZRANB3 (Zinc Finger RANBP2-Type Containing 3, lead SNP p = 2.831 × 10
-9 ). Knockdown or genomic knockout of the zebrafish ortholog results in reduction in pancreatic β-cell number which we demonstrate to be due to increased apoptosis in islets. 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. We also show transferability in our study of 32 established T2D loci. Our findings advance understanding of the genetics of T2D in non-European ancestry populations.- Published
- 2019
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