AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism

a.
Laboratory of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing 100871, China
b.
State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing 100871, China
c.
Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China
d.
Laboratory of Nucleic Acid Technology, Institute of Molecular Medicine, Peking University, Beijing 100871, China
e.
Human Population Genetics, Human Aging Research Institute and School of Life Sciences, Nanchang University, Nanchang 330006, China
f.
Institute of Life Science and School of Life Science, Nanchang University, Nanchang 330031, China
g.
School of Basic Medical Sciences, Nanchang University, Nanchang 330006, China
h.
Institute of Translational Medicine, Nanchang University, Nanchang 330031, China
i.
Shanghai Key Laboratory of Diabetes Mellitus and Center for Translational Medicine, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China

More Information

Corresponding author: E-mail address: tianxiaoli@pku.edu.cn (Xiao-Li Tian)

摘要

- /
- /
Abstract: Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream ofAQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3β, and restored the insulin sensitivity. Furthermore, the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process. Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.
- Type 2 diabetes /
- Glucose metabolism /
- Ubiquitination

HTML全文

参考文献(36)

[1]	1000 Genomes Project Consortium, Auton, A., Brooks, L.D., Durbin, R.M. et al. A global reference for human genetic variation Nature, 526 (2015),pp. 68-74
[2]	Claussnitzer, M., Dankel, S.N., Kim, K.H. et al. FTO obesity variant circuitry and adipocyte browning in humans N. Engl. J. Med., 373 (2015),pp. 895-907
[3]	Danecek, P., Auton, A., Abecasis, G. et al. The variant call format and VCFtools Bioinformatics, 27 (2011),pp. 2156-2158
[4]	DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium, Mexican American Type 2 Diabetes (MAT2D) Consortium, Type 2 Diabetes Genetic Exploration by Nex-generation sequencing in muylti-Ethnic Samples (T2D-GENES) Consortium, Mahajan, A., Go, M.J., Zhang, W. et al. Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility Nat. Genet., 46 (2014),pp. 234-244
[5]	Evangelou, E., Ioannidis, J.P. Meta-analysis methods for genome-wide association studies and beyond Nat. Rev. Genet., 14 (2013),pp. 379-389
[6]	Fuchsberger, C., Flannick, J., Teslovich, T.M. et al. The genetic architecture of type 2 diabetes Nature, 536 (2016),pp. 41-47
[7]	GTEx Consortium The genotype-tissue expression (GTEx) project Nat. Genet., 45 (2013),pp. 580-585
[8]	Herrera, B.M., Lockstone, H.E., Taylor, J.M. et al. MicroRNA-125a is over-expressed in insulin target tissues in a spontaneous rat model of Type 2 Diabetes BMC Med. Genomics, 2 (2009),p. 54
[9]	Hirose, T., Ideue, T., Nagai, M. et al. A spliceosomal intron binding protein, IBP160, links position-dependent assembly of intron-encoded box C/D snoRNP to pre-mRNA splicing Mol. Cell, 23 (2006),pp. 673-684
[10]	Hsu, P.P., Kang, S.A., Rameseder, J. et al. The mTOR-regulated phosphoproteome reveals a mechanism of mTORC1-mediated inhibition of growth factor signaling Science, 332 (2011),pp. 1317-1322
[11]	Huang da, W., Sherman, B.T., Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources Nat. Protoc., 4 (2009),pp. 44-57
[12]	Ishii, M., Maeda, A., Tani, S. et al. Palmitate induces insulin resistance in human HepG2 hepatocytes by enhancing ubiquitination and proteasomal degradation of key insulin signaling molecules Arch. Biochem. Biophys., 566 (2015),pp. 26-35
[13]	Jiang, F., Yan, H., Wu, C. et al. A novel block at chromosome 12q24.1 is associated with coronary artery disease in Han Chinese populations Pharmacogenet. Genom., 26 (2016),pp. 497-504
[14]	Kim, D., Langmead, B., Salzberg, S.L. HISAT: a fast spliced aligner with low memory requirements Nat. Methods, 12 (2015),pp. 357-360
[15]	Koegl, M., Hoppe, T., Schlenker, S. et al. A novel ubiquitination factor, E4, is involved in multiubiquitin chain assembly Cell, 96 (1999),pp. 635-644
[16]	Krzywinski, M., Schein, J., Birol, I. et al. Circos: an information aesthetic for comparative genomics Genome Res., 19 (2009),pp. 1639-1645
[17]	Li, H., Handsaker, B., Wysoker, A. et al. The sequence alignment/map format and SAMtools Bioinformatics, 25 (2009),pp. 2078-2079
[18]	Ma, R.C., Hu, C., Tam, C.H. et al. Diabetologia, 56 (2013),pp. 1291-1305
[19]	Modaressi, S., Christ, B., Bratke, J. et al. Molecular cloning, sequencing and expression of the cDNA of the mitochondrial form of phosphoenolpyruvate carboxykinase from human liver Biochem. J., 315 (1996),pp. 807-814
[20]	Morris, A.P. Transethnic meta-analysis of genomewide association studies Genet. Epidemiol., 35 (2011),pp. 809-822
[21]	Neel, J.V. The “thrifty genotype” in 1998 Nutr. Rev., 57 (1999),pp. S2-S9
[22]	Purcell, S., Neale, B., Todd-Brown, K. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses Am. J. Hum. Genet., 81 (2007),pp. 559-575
[23]	Rich, S.S. Diabetes: still a geneticist's nightmare Nature, 536 (2016),pp. 37-38
[24]	Scott, R.A., Scott, L.J., Magi, R. et al. An expanded genome-wide association study of type 2 diabetes in Europeans Diabetes, 66 (2017),pp. 2888-2902
[25]	Srivastava, A.K., Pandey, S.K. Potential mechanism(s) involved in the regulation of glycogen synthesis by insulin Mol. Cell. Biochem., 182 (1998),pp. 135-141
[26]	Trapnell, C., Hendrickson, D.G., Sauvageau, M. et al. Differential analysis of gene regulation at transcript resolution with RNA-seq Nat. Biotechnol., 31 (2013),pp. 46-53
[27]	Weir, B.S., Cockerham, C.C. Estimating F-statistics for the analysis of population structure Evolution, 38 (1984),pp. 1358-1370
[28]	Wellcome Trust Case Control Consortium Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls Nature, 447 (2007),pp. 661-678
[29]	Welsh, G.I., Wilson, C., Proud, C.G. GSK3: a SHAGGY frog story Trends Cell Biol., 6 (1996),pp. 274-279
[30]	Westra, H.J., Peters, M.J., Esko, T. et al. Systematic identification of trans eQTLs as putative drivers of known disease associations Nat. Genet., 45 (2013),pp. 1238-1243
[31]	Xia, Q., Chesi, A., Manduchi, E. et al. The type 2 diabetes presumed causal variant within TCF7L2 resides in an element that controls the expression of ACSL5 Diabetologia, 59 (2016),pp. 2360-2368
[32]	Xu, K., Ma, L., Li, Y. et al. Hypertension, 66 (2015),pp. 641-646
[33]	Yi, J.S., Park, J.S., Ham, Y.M. et al. MG53-induced IRS-1 ubiquitination negatively regulates skeletal myogenesis and insulin signalling Nat. Commun., 4 (2013),p. 2354
[34]	Zhang, X., Zhang, R., Raab, S. et al. Rhesus macaques develop metabolic syndrome with reversible vascular dysfunction responsive to pioglitazone Circulation, 124 (2011),pp. 77-86
[35]	Zhang, Y., Zheng, W., Liu, Y. et al. Eplerenone restores 24-h blood pressure circadian rhythm and reduces advanced glycation end-products in rhesus macaques with spontaneous hypertensive metabolic syndrome Sci. Rep., 6 (2016),p. 23957
[36]	Zou, C., Wang, Y., Shen, Z. 2-NBDG as a fluorescent indicator for direct glucose uptake measurement J. Biochem. Biophys. Methods, 64 (2005),pp. 207-215