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

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

Author information

1
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
2
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, 21201, MD, USA.
3
Program in Personalized and Genomic Medicine, University of Maryland School of Medicine, Baltimore, 21201, MD, USA.
4
University of Lagos, Lagos, Nigeria.
5
University of Nigeria Teaching Hospital, Enugu, Nigeria.
6
University of Science and Technology, Kumasi, Ghana.
7
National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
8
College of Medicine, University of Ibadan, Ibadan, Nigeria.
9
University of Ghana Medical School, Accra, Ghana.
10
Department of Epidemiology and Public Health; Institute of Human Virology; Greenebaum Comprehensive Cancer Center, School of Medicine, University of Maryland, Baltimore, 21201, MD, USA.
11
National Institutes of Health, Bethesda, 20892, MD, USA.
12
National Human Genome Center at Howard University, Washington, 20059, DC, USA.
13
Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, MD, USA. rotimic@mail.nih.gov.

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.

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