应用BITOLA系统筛选腹主动脉瘤与2型糖尿病相互作用的候选基因

doi:10.24920/003711

摘要/Abstract

摘要：

目的应用生物信息学方法识别并挖掘腹主动脉瘤和糖尿病相互作用的候选基因。

方法采用封闭的生物医学发现支持系统（Biomedical Discovery Support System,BITOLA）,筛选与腹主动脉瘤和糖尿病有关的“基因或基因产物”作为候选中间分子（candidate intermediate molecules,CIMs）。通过GSE13760,GSE7084,GSE57691,GSE47472数据集筛选分别与腹主动脉瘤和糖尿病发病相关的差异表达基因（differentially expressed genes,DEGs）。然后,我们通过Venny2.1在线工具,辅以人工阅读文献,筛选出与CIMs重合的差异性表达基因。最后,应用基因表达人体电子荧光可视化浏览器（Human eFP Browser）观测所筛选出的基因的组织特异性表达,确定在动脉和胰腺组织均高表达的候选基因。

结果应用封闭的生物医学发现支持系统筛选出86个CIMs。在GSE13760,GSE7084,GSE57691,GSE47472数据集与腹主动脉瘤和糖尿病相关的差异表达基因中,我们发现GSE7084数据集中的8个基因（ISG20,ITGAX,DSTN,CCL5,CCR5,AGTR1,CD19,CD44）和GSE13760数据集中的2个基因（PSMD12,FAS）与86个CIMs交叉重叠。通过电子荧光可视化人体基因表达象形图进行组织特异性验证发现,基因PSMD12在主动脉和胰腺组织中均有高表达。

结论通过生物信息文本挖掘技术我们提出假说,PSMD12可能参与腹主动脉瘤与糖尿病的相互作用,这可能成为研究这两种疾病新型治疗手段的新线索。

关键词: 腹主动脉瘤, 2型糖尿病, 生物医学发现支持系统, 文本挖掘, 基因表达谱

Abstract:

Objective To explore the candidate genes that play significant roles in the interconnection between abdominal aortic aneurysm (AAA) and type 2 diabetes mellitus (DM).

Methods We used the Biomedical Discovery Support System (BITOLA) to screen out the candidate intermediate molecular (CIM) “Gene or Gene Product” that are related to AAA and DM. The dataset of GSE13760, GSE7084, GSE57691, GSE47472 were used to analyze the differentially expressed genes (DEGs) of AAA and DM compared to the healthy status. We used the online tool of Venny 2.1 assisted by manual checking to identify the overlapped DEGs with the CIMs. The Human eFP Browser was applied to examine the tissue specific expression levels of the detected genes in order to recognize strong expressed genes in both human artery and pancreatic tissue.

Results There were 86 CIMs suggested by the closed BITOLA system. Among all the DEGs of AAA and DM, 8 genes in GSE7084 (ISG20, ITGAX, DSTN, CCL5, CCR5, AGTR1, CD19, CD44) and 2 genes in GSE13760 (PSMD12, FAS) were found to be overlapped with the 86 CIMs. By manual checking and comparing with tissue-specific gene data through Human eFP Browser, the gene PSMD12 (proteasome 26S subunit, non-ATPase 12) was recognized to be strongly expressed in both the aorta and pancreatic tissue.

Conclusion We proposed a hypothesis through text mining that PSMD12 might be involved or potentially involved in the interconnection between AAA and DM, which may provide a new clue for studies on novel therapeutic strategies for the two diseases.

Key words: abdominal aortic aneurysm, diabetes mellitus, Biomedical Discovery Support System, text mining, gene expression profile

Honglin Zu,Likun Hou,Hongwei Liu,Yuanbo Zhan,Ju He. Identify Candidate Genes in the Interaction between Abdominal Aortic Aneurysm and Type 2 Diabetes Mellitus by Using Biomedical Discovery Support System[J].Chinese Medical Sciences Journal, 2021, 36(1): 50-56.

图/表 3

参考文献 44.

1.	Guirguis-Blake JM, Beil TL, Senger CA, et al. Primary care screening for abdominal aortic aneurysm: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA 2019; 322(22):2219-38. doi: 10.1001/jama.2019.17021. doi: 10.1001/jama.2019.17021 pmid: 31821436
2.	Bird AN, Davis AM. Screening for abdominal aortic aneurysm. JAMA 2015; 313(11):1156-7. doi: 10.1001/jama.2015.0996. doi: 10.1001/jama.2015.0996 pmid: 25781445
3.	Gloviczki P, Lawrence PF, Forbes TL. Update of the Society for Vascular Surgery abdominal aortic aneurysm guidelines. J Vasc Surg 2018; 67(1):1. doi: 10.1016/j.jvs.2017.11.022. doi: 10.1016/j.jvs.2017.11.022 pmid: 29268911
4.	Jalalzadeh H, Indrakusuma R, Planken RN, et al. Inflammation as a predictor of abdominal aortic aneurysm growth and rupture: a systematic review of imaging biomarkers. Eur J Vasc Endovasc Surg 2016; 52(3):333-42. doi: 10.1016/j.ejvs.2016.05.002. doi: 10.1016/j.ejvs.2016.05.002 pmid: 27283346
5.	Wanhainen A, Verzini F, Van Herzeele I, et al. Editor’s Choice - European Society for Vascular Surgery (ESVS) 2019 clinical practice guidelines on the management of abdominal aorto-iliac artery aneurysms. Eur J Vasc Endovasc Surg 2019; 57(1):8-93. doi: 10.1016/j.ejvs.2018.09.020. doi: 10.1016/j.ejvs.2018.09.020 pmid: 30528142
6.	Liu X, Li Y, Li L, et al. Prevalence, awareness, treatment, control of type 2 diabetes mellitus and risk factors in Chinese rural population: the Rural Diab study. Sci Rep 2016; 6:31426. doi: 10.1038/srep31426. doi: 10.1038/srep31426 pmid: 27510966
7.	Yang L, Shao J, Bian Y, et al. Prevalence of type 2 diabetes mellitus among inland residents in China (2000-2014): a meta-analysis. J Diabetes Investig 2016; 7(6):845-52. doi: 10.1111/jdi.12514. doi: 10.1111/jdi.12514 pmid: 27181391
8.	Abid A, Ahmad S, Waheed A. Screening for type II diabetes mellitus in the United States: the present and the future. Clin Med Insights Endocrinol Diabetes 2016; 9:19-22. doi: 10.4137/CMED.S38247. doi: 10.4137/CMED.S38247 pmid: 27330335
9.	Scirica BM. Use of biomarkers in predicting the onset, monitoring the progression, and risk stratification for patients with type 2 diabetes mellitus. Clin Chem 2017; 63(1):186-95. doi: 10.1373/clinchem.2016.255539. doi: 10.1373/clinchem.2016.255539 pmid: 28062618
10.	He M, Gao J, Liu W, et al. Case management of patients with Type 2 diabetes mellitus: a cross-sectional survey in Chongqing, China. BMC Health Serv Res 2017; 17(1):129. doi: 10.1186/s12913-017-2039-0. doi: 10.1186/s12913-017-2039-0 pmid: 28187724
11.	Tsai CL, Lin CL, Wu YY, et al. Advanced complicated diabetes mellitus is associated with a reduced risk of thoracic and abdominal aortic aneurysm rupture: a population-based cohort study. Diabetes Metab Res Rev 2015; 31(2):190-7. doi: 10.1002/dmrr.2585. doi: 10.1002/dmrr.2585 pmid: 25066630
12.	Xiong J, Wu Z, Chen C, et al. Association between diabetes and prevalence and growth rate of abdominal aortic aneurysms: a meta-analysis. Int J Cardiol 2016; 221:484-95. doi: 10.1016/j.ijcard.2016.07.016. doi: 10.1016/j.ijcard.2016.07.016 pmid: 27414727
13.	Pafili K, Gouni-Berthold I, Papanas N, et al. Abdominal aortic aneurysms and diabetes mellitus. J Diabetes Complications 2015; 29(8):1330-6. doi: 10.1016/j.jdiacomp.2015.08.011. doi: 10.1016/j.jdiacomp.2015.08.011 pmid: 26440573
14.	Cohen T, Widdows D, Stephan C, et al. Predicting high-throughput screening results with scalable literature-based discovery methods. CPT Pharmacometrics Syst Pharmacol 2014; 3(10):e140. doi: 10.1038/psp.2014.37.
15.	Preiss J, Stevenson M. The effect of word sense disambiguation accuracy on literature based discovery. BMC Med Inform Decis Mak 2016; 16(Suppl 1):57. doi: 10.1186/s12911-016-0296-1. doi: 10.1186/s12911-016-0296-1
16.	Hristovski D, Kastrin A, Dinevski D, et al. Using literature-based discovery to explain adverse drug effects. J Med Syst 2016; 40(8):185. doi: 10.1007/s10916-016-0544-z. doi: 10.1007/s10916-016-0544-z pmid: 27318993
17.	Hristovski D, Kastrin A, Dinevski D, et al. Constructing a graph database for semantic literature-based discovery. Stud Health Technol Inform 2015; 216:1094. pmid: 26262393
18.	Swanson DR. Fish oil, Raynaud’s syndrome, and undiscovered public knowledge. Perspect Biol Med 1986; 30(1):7-18. doi: 10.1353/pbm.1986.0087. doi: 10.1353/pbm.1986.0087 pmid: 3797213
19.	Petric I, Urbancic T, Cestnik B, et al. Literature mining method RaJoLink for uncovering relations between biomedical concepts. J Biomed Inform 2009; 42(2):219-27. doi: 10.1016/j.jbi.2008.08.004. doi: 10.1016/j.jbi.2008.08.004
20.	Kostoff RN. Validating discovery in literature-based discovery. J Biomed Inform 2007; 40(4):448-52. doi: 10.1016/j.jbi.2007.05.001. doi: 10.1016/j.jbi.2007.05.001 pmid: 17616484
21.	Weeber M, Kors JA, Mons B. Online tools to support literature-based discovery in the life sciences. Brief Bioinform 2005; 6(3):277-86. doi: 10.1093/bib/6.3.277. doi: 10.1093/bib/6.3.277 pmid: 16212775
22.	Srinivasan M, Blackburn C, Mohamed M, et al. Literature-based discovery of salivary biomarkers for type 2 diabetes mellitus. Biomark Insights 2015; 10:39-45. doi: 10.4137/BMI.S22177. doi: 10.4137/BMI.S22177 pmid: 26005324
23.	Ahlers CB, Hristovski D, Kilicoglu H, et al. Using the literature-based discovery paradigm to investigate drug mechanisms. AMIA Annu Symp Proc 2007; 2007:6-10.
24.	Hristovski D, Peterlin B, Mitchell JA, et al. Using literature-based discovery to identify disease candidate genes. Int J Med Inform 2005; 74(2-4):289-98. doi: 10.1016/j.ijmedinf.2004.04.024. doi: 10.1016/j.ijmedinf.2004.04.024 pmid: 15694635
25.	Saratzis N, Saratzis A, Melas N, et al. Aortoduodenal fistulas after endovascular stent-graft repair of abdominal aortic aneurysms: single-center experience and review of the literature. J Endovasc Ther 2008; 15(4):441-8. doi: 10.1583/08-2377.1. doi: 10.1583/08-2377.1 pmid: 18729556
26.	Indrakusuma R, Jalalzadeh H, Planken RN, et al. Biomechanical imaging markers as predictors of abdominal aortic aneurysm growth or rupture: a systematic review. Eur J Vasc Endovasc Surg 2016; 52(4):475-86. doi: 10.1016/j.ejvs.2016.07.003. doi: 10.1016/j.ejvs.2016.07.003 pmid: 27558090
27.	Skov V, Knudsen S, Olesen M, et al. Global gene expression profiling displays a network of dysregulated genes in non-atherosclerotic arterial tissue from patients with type 2 diabetes. Cardiovasc Diabetol 2012; 11:15. doi: 10.1186/1475-2840-11-15. doi: 10.1186/1475-2840-11-15 pmid: 22340758
28.	Lenk GM, Tromp G, Weinsheimer S, et al. Whole genome expression profiling reveals a significant role for immune function in human abdominal aortic aneurysms. BMC Genomics 2007; 8:237. doi: 10.1186/1471-2164-8-237. doi: 10.1186/1471-2164-8-237 pmid: 17634102
29.	Biros E, Gäbel G, Moran CS, et al. Differential gene expression in human abdominal aortic aneurysm and aortic occlusive disease. Oncotarget 2015; 6(15):12984-96. doi: 10.18632/oncotarget.3848. doi: 10.18632/oncotarget.3848 pmid: 25944698
30.	Biros E, Moran CS, Rush CM, et al. Differential gene expression in the proximal neck of human abdominal aortic aneurysm. Atherosclerosis 2014; 233(1):211-8. doi: 10.1016/j.atherosclerosis.2013.12.017. doi: 10.1016/j.atherosclerosis.2013.12.017
31.	Ma XD, Chen ZA, Zheng JP. Phenotypic modulation of vascular smooth muscle cells in diabetes mellitus and intervention of traditional Chinese medicines. Zhongguo Zhong Yao Za Zhi 2014; 39(24):4723-7. pmid: 25898567
32.	De Rango P, Farchioni L, Fiorucci B, et al. Diabetes and abdominal aortic aneurysms. Eur J Vasc Endovasc Surg 2014; 47(3):243-61. doi: 10.1016/j.ejvs.2013.12.007. doi: 10.1016/j.ejvs.2013.12.007 pmid: 24447529
33.	Weiss JS, Sumpio BE. Review of prevalence and outcome of vascular disease in patients with diabetes mellitus. Eur J Vasc Endovasc Surg 2006; 31(2):143-50. doi: 10.1016/j.ejvs.2005.08.015. doi: 10.1016/j.ejvs.2005.08.015 pmid: 16203161
34.	Miller CM, Rindflesch TC, Fiszman M, et al. A closed literature-based discovery technique finds a mechanistic link between hypogonadism and diminished sleep quality in aging men. Sleep 2012; 35(2):279-85. doi: 10.5665/sleep.1640. doi: 10.5665/sleep.1640 pmid: 22294819
35.	Yen HC, Espiritu C, Chang EC. Rpn5 is a conserved proteasome subunit and required for proper proteasome localization and assembly. J Biol Chem 2003; 278(33):30669-76. doi: 10.1074/jbc.M302093200. doi: 10.1074/jbc.M302093200 pmid: 12783882
36.	Kumar S, Jang IH, Kim CW, et al. Functional screening of mammalian mechanosensitive genes using Drosophila RNAi library- Smarcd3/Bap60 is a mechanosensitive pro-inflammatory gene. Sci Rep 2016; 6:36461. doi: 10.1038/srep36461. doi: 10.1038/srep36461 pmid: 27819340
37.	Mi T, Nie B, Zhang C, et al. The elevated expression of osteopontin and NF-κB in human aortic aneurysms and its implication. J Huazhong Univ Sci Technolog Med Sci 2011; 31(5):602. doi: 10.1007/s11596-011-0568-z. doi: 10.1007/s11596-011-0568-z pmid: 22038347
38.	Saito T, Hasegawa Y, Ishigaki Y, et al. Importance of endothelial NF-κB signalling in vascular remodelling and aortic aneurysm formation. Cardiovasc Res 2013; 97(1):106-14. doi: 10.1093/cvr/cvs298. doi: 10.1093/cvr/cvs298
39.	Casella S, Bielli A, Mauriello A, et al. Molecular pathways regulating macrovascular pathology and vascular smooth muscle cells phenotype in type 2 diabetes. Int J Mol Sci 2015; 16(10):24353-68. doi: 10.3390/ijms161024353. doi: 10.3390/ijms161024353 pmid: 26473856
40.	Yen HC, Gordon C, Chang EC. Schizosaccharomyces pombe Int6 and Ras homologs regulate cell division and mitotic fidelity via the proteasome. Cell 2003; 112(2):207-17. doi: 10.1016/s0092-8674(03)00043-6. doi: 10.1016/s0092-8674(03)00043-6 pmid: 12553909
41.	Livneh I, Cohen-Kaplan V, Cohen-Rosenzweig C, et al. The life cycle of the 26S proteasome: from birth, through regulation and function, and onto its death. Cell Res 2016; 26(8):869-85. doi: 10.1038/cr.2016.86. doi: 10.1038/cr.2016.86 pmid: 27444871
42.	Barac YD, Emrich F, Krutzwakd-Josefson E, et al. The ubiquitin-proteasome system: A potential therapeutic target for heart failure. J Heart Lung Transplant 2017; 36(7):708-14. doi: 10.1016/j.healun.2017.02.012. doi: 10.1016/j.healun.2017.02.012 pmid: 28341100
43.	Bugliani M, Liechti R, Cheon H, et al. Microarray analysis of isolated human islet transcriptome in type 2 diabetes and the role of the ubiquitin-proteasome system in pancreatic beta cell dysfunction. Mol Cell Endocrinol 2013; 367(1-2):1-10. doi: 10.1016/j.mce.2012.12.001. doi: 10.1016/j.mce.2012.12.001 pmid: 23246353
44.	Fan T, Huang Z, Chen L, et al. Associations between autophagy, the ubiquitin-proteasome system and endoplasmic reticulum stress in hypoxia-deoxygenation or ischemia-reperfusion. Eur J Pharmacol 2016; 791:157-67. doi: 10.1016/j.ejphar.2016.08.026. doi: 10.1016/j.ejphar.2016.08.026 pmid: 27568838

Disease	Series	Tissue	Subjects		Array platform	Overlap with CIM
Disease	Series	Tissue	Control	study	Array platform	Overlap with CIM
Abdominal Aortic Aneurysm	GSE7084	Human abdominal aorta	2	2	Affymetrix	ISG20, ITGAX, DSTN, CCL5, CCR5, AGTR1, CD19, CD44
	GSE57691	Human abdominal aorta	10	49	Illumina	None
	GSE47472	Full thickness aorta biopsy	8	14	Illumina	None
Diabetes Mellitus	GSE13760	Arterial intima-media	11	10	Affymetrix	PSMD12, FAS

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