ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response

Nat Commun. 2019 Jul 19;10(1):3195. doi: 10.1038/s41467-019-10967-7.

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.

Publication types

  • Meta-Analysis
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Africa, Northern
  • Animals
  • Apoptosis
  • Base Sequence
  • Blood Glucose
  • CRISPR-Cas Systems
  • DNA Helicases / genetics*
  • DNA Helicases / metabolism*
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Models, Animal
  • Female
  • Gene Editing
  • Gene Knockout Techniques
  • Genetic Association Studies*
  • Genetic Predisposition to Disease / genetics*
  • Genotype
  • Ghana
  • Glucose / metabolism
  • Homozygote
  • Humans
  • Insulin / metabolism*
  • Insulin-Secreting Cells / metabolism*
  • Kenya
  • Male
  • Mice
  • Middle Aged
  • Mutation
  • Nigeria
  • Polymorphism, Single Nucleotide
  • RNA, Small Interfering
  • Transcription Factor 7-Like 2 Protein / genetics
  • Transcriptome
  • Zebrafish

Substances

  • Blood Glucose
  • Insulin
  • RNA, Small Interfering
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • DNA Helicases
  • ZRANB3 protein, human
  • Glucose