Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, 20892, MD, USA.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, 21201, MD, USA.
Nat Commun. 2019 Jul 19;10(1):3195. doi: 10.1038/s41467-019-10967-7.
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). 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.
对不同人类群体的基因组分析有助于确定对主要临床和公共卫生有重大影响的疾病的新基因组位点。在这里，我们报告了对撒哈拉以南非洲人的 2 型糖尿病（T2D）的全基因组分析，这是一个研究不足的祖先群体。我们分析了来自尼日利亚、加纳和肯尼亚的 5231 个人的约 1800 万个常染色体 SNP。我们确定了一个以前未报告的全基因组显著位点：ZRANB3（锌指 RANBP2 型包含 3，先导 SNP p = 2.831×10）。斑马鱼同源物的敲低或基因组敲除导致胰腺 β 细胞数量减少，我们证明这是由于胰岛中细胞凋亡增加所致。MIN6 β 细胞中鼠 Zranb3 的 siRNA 转染导致对高葡萄糖的胰岛素分泌受损，表明 Zranb3 参与 β 细胞对高葡萄糖条件的功能反应。我们还在对 32 个已建立的 T2D 位点的研究中显示了可转移性。我们的发现增进了对非欧洲血统人群 T2D 遗传的理解。
