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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes
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Expression-based genome-wide association study links the receptor CD44 in adipose tissue with type 2 diabetes

机译:基于表达的全基因组关联研究将脂肪组织中的受体CD44与2型糖尿病联系起来

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摘要

Type 2 diabetes (T2D) is a complex, polygenic disease affecting nearly 300 million people worldwide. T2D is primarily characterized by insulin resistance, and growing evidence has indicated the causative link between adipose tissue inflammation and the development of insulin resistance. Genetic association studies have successfully revealed a number of important genes consistently associated with T2D to date. However, these robust T2D-associated genes do not fully elucidate the mechanisms underlying the development and progression of the disease. Here, we report an alternative approach, gene expression-based genome-wide association study (eGWAS): searching for genes repeatedly implicated in functional microarray experiments (often publicly available). We performed an eGWAS across 130 independent experiments (totally 1,175 T2D case-control microarrays) to find additional genes implicated in the molecular pathogenesis of T2D and identified the immune-cell receptor CD44 as our top candidate (P = 8.5 x 1CT20). We found CD44 deficiency in a diabetic mouse model ameliorates insulin resistance and adipose tissue inflammation and also found that anti-CD44 antibody treatment decreases blood glucose levels and adipose tissue macrophage accumulation in a high-fat, diet-fed mouse model. Further, in humans, we observed CD44 is expressed in inflammatory cells in obese adipose tissue and discovered serum CD44 levels were positively correlated with insulin resistance and glycemic control. CD44 likely plays a causative role in the development of adipose tissue inflammation and insulin resistance in rodents and humans. Genes repeatedly implicated in publicly available experimental data may have unique functionally important roles in T2D and other complex diseases.
机译:2型糖尿病(T2D)是一种复杂的多基因疾病,影响了全球近3亿人。 T2D的主要特征是胰岛素抵抗,越来越多的证据表明脂肪组织炎症与胰岛素抵抗的发展之间存在因果关系。遗传关联研究成功地揭示了迄今为止与T2D始终相关的许多重要基因。但是,这些健壮的T2D相关基因不能完全阐明疾病发展和进程的机制。在这里,我们报告了一种替代方法,基于基因表达的全基因组关联研究(eGWAS):寻找在功能性微阵列实验中反复牵连的基因(通常是公开可用的)。我们通过130个独立实验(总共1,175个T2D病例对照微阵列)进行了eGWAS,以发现与T2D分子发病机理有关的其他基因,并将免疫细胞受体CD44鉴定为我们的最佳候选药物(P = 8.5 x 1CT20)。我们发现糖尿病小鼠模型中CD44缺乏症改善了胰岛素抵抗和脂肪组织炎症,并且还发现抗CD44抗体治疗可降低高脂饮食饮食小鼠模型中的血糖水平和脂肪组织巨噬细胞蓄积。此外,在人类中,我们观察到CD44在肥胖脂肪组织的炎症细胞中表达,并且发现血清CD44水平与胰岛素抵抗和血糖控制呈正相关。 CD44可能在啮齿动物和人类的脂肪组织炎症和胰岛素抵抗的发展中起着致病作用。在公众可获得的实验数据中反复牵涉的基因在T2D和其他复杂疾病中可能具有独特的功能重要作用。

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  • 作者单位

    Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 Lucile Packard Children's Hospital, Palo Alto, CA 94304;

    Departments of Metabolic Diseases and Biomedical Laboratory, Kitasato Institute Hospital, Kitasato University, Tokyo 108-8642, Japan;

    Departments of Division of Basic Research, Biomedical Laboratory, Kitasato Institute Hospital, Kitasato University, Tokyo 108-8642, Japan;

    Diabetes Center, Kitasato Institute Hospital, Tokyo 108-8642, Japan;

    Departments of Metabolic Diseases and Biomedical Laboratory, Kitasato Institute Hospital, Kitasato University, Tokyo 108-8642, Japan;

    Diabetes Center, Kitasato Institute Hospital, Tokyo 108-8642, Japan Department of Internal Medicine, Keio University School of Medicine, Tokyo 160-8582, Japan;

    Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 Lucile Packard Children's Hospital, Palo Alto, CA 94304;

    Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 Lucile Packard Children's Hospital, Palo Alto, CA 94304;

    Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 Lucile Packard Children's Hospital, Palo Alto, CA 94304;

    Clinical Trial Data Management, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655,Japan;

    Laboratory for Endocrinology and Metabolism, Center for Genomic Medicine, RIKEN, Yokohama City, Kanagawa 230-0045, Japan;

    Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 Lucile Packard Children's Hospital, Palo Alto, CA 94304;

    Division of Systems Medicine, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305 Lucile Packard Children's Hospital, Palo Alto, CA 94304;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    bioinformatics; meta-analysis; integration; obesity; hyperglycemia;

    机译:生物信息学荟萃分析积分;肥胖;高血糖症;

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