ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response.
Adebowale A AdeyemoNorann A ZaghloulGuanjie ChenAyo P DoumateyCarmen C LeitchTimothy L HostelleyJessica E NesmithJie ZhouAmy R BentleyDaniel ShrinerOlufemi FasanmadeGodfrey OkaforBenjamin EghanKofi Agyenim-BoatengSettara ChandrasekharappaJokotade AdeleyeWilliam BalogunSamuel OwusuAlbert AmoahJoseph AcheampongThomas JohnsonJohnnie OliClement Adebamowonull nullFrancis CollinsGeorgia DunstonCharles N RotimiPublished in: Nature communications (2019)
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.
Keyphrases
- genome wide
- high glucose
- endothelial cells
- type diabetes
- public health
- copy number
- single cell
- dna methylation
- genome wide association study
- cell therapy
- induced apoptosis
- endoplasmic reticulum stress
- genome wide analysis
- stem cells
- cardiovascular disease
- gene expression
- metabolic syndrome
- glycemic control
- drug delivery
- cell death
- signaling pathway
- insulin resistance
- adipose tissue
- pi k akt
- genetic diversity
- weight loss
- oxide nanoparticles