ZRANB3 is an African-specific type 2 diabetes locus associated with beta-cell mass and insulin response
AuthorZaghloul, Norann A.
Doumatey, Ayo P.
Hostelley, Timothy L.
Nesmith, Jessica E.
Bentley, Amy R.
Leitch, Carmen C.
Adeyemo, Adelbowale A.
PublisherNature Publishing Group
MetadataShow full item record
AbstractGenome 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.
SponsorsThe study was supported in part by the Intramural Research Program of the National Institutes of Health in the Center for Research on Genomics and Global Health (CRGGH). The CRGGH is supported by the National Human Genome Research Institute (NHGRI), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the Center for Information Technology, and the Office of the Director at the National Institutes of Health (1ZIAHG200362). Support for participant recruitment and initial genetic studies of the AADM study was provided by NIH grant No. 3T37TW00041-03S2 from the Office of Research on Minority Health. Additional support from the NIH includes grants R01DK102001 (N.A.Z.), P30DK072488 (N.A.Z.), T32DK098107 (T.L.H. and J.E.N.), and F31DK115179 (T.L.H.).
KeywordAfrica America Diabetes Mellitus (AADM) Study
African Continental Ancestry Group--genetics
Diabetes Mellitus, Type 2--genetics
Identifier to cite or link to this itemhttps://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85069469543&origin=inward; http://hdl.handle.net/10713/10142