阿尔茨海默病自噬相关基因的筛选及其通路分析

doi:10.16138/j.1673-6087.2024.04.04

摘要/Abstract

摘要：

目的：基于微阵列分析筛选阿尔茨海默病（Alzheimer disease，AD）自噬相关基因，并进行通路分析，鉴定关键基因，以期探究潜在的发病机制与治疗靶点。方法：从GEO数据库下载GSE33000数据集，通过R软件limma包获取AD差异表达基因，从人类自噬基因数据库、人类自噬调节因子数据库及GeneCard数据库分别下载自噬相关基因，获得自噬相关基因集，将差异表达基因与自噬相关基因集取交集，获得AD自噬相关基因。使用R软件org.Hs.eg.db、clusterProfiler等程序包进行基因本体论（gene ontology，GO）分析、京都基因和基因组百科全书（Kyoto Encyclopedia of Genes and Genomes，KEGG）分析，利用在线软件STRING进行蛋白互作网络分析，并基于最大团中心性（maximal clique centrality，MCC）算法进行关键基因预测。结果：共获得66个AD自噬相关基因，其中41个基因上调，25个基因下调。基因富集分析显示，GO分析中细胞组分主要富集在吞噬小泡膜、分泌颗粒膜、膜微结构域、晚期内体等，分子功能主要富集在结合Toll样受体、结合泛素连接酶等，生物学过程富集在调节自噬、细胞分解代谢的调节、脂多糖诱导的反应、调节炎症反应、外部刺激的细胞反应等。在KEGG富集分析中，差异表达的自噬相关基因主要富集在NOD样受体信号通路、脂质与动脉粥样硬化、叉头框蛋白O（forkhead box protein O，FoxO）信号通路等。完成蛋白互作网络（protein-protein interaction，PPI）的构建，同时鉴定出10个关键基因，筛选出与AD关联较大的为白介素-6（interleukin -6，IL-6）、信号转导与转录激活因子3(signal transducer and activator of transcription 3, STAT3)。结论：本研究获得10个关键ADARG，其中与AD关联较大的为IL-6、STAT3。

关键词: 阿尔茨海默病, 自噬, 基因, 生物信息学

Abstract:

Objective Screen autophagy related genes of Alzheimer disease(AD) based on microarray analysis, conduct pathway analysis and identify key genes in order to explore potential pathogenesis and therapeutic targets. Methods The GSE33000 dataset was downloaded from GEO Database, and the differentially expressed genes of AD were obtained by R software limma package. Autophagy-related genes were downloaded from Human Autophagy Database, Human Autophagy Modulator Database and GeneCard Database, respectively, and the autophagy-related gene set was obtained. The AD autophagy-related genes were obtained through intersecting the differentially expressed genes with the autophagy-related gene set. The R software packages such as org.Hs.eg.db and clusterProfiler were used to perform gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, the online software Search Tool for the Retrieval of Interacting Genes (STRING) was used to conduct protein-protein interaction network analysis, and the key genes were predicted based on MCC algorithm. Results A total of 66 autophagy related genes were obtained, of which 41 genes were up-regulated and 25 genes were down-regulated. Gene enrichment analysis showed that cellular components in GO analysis were mainly enriched in phagocytic vesicle membrane, secretory granule membrane, membrane microdomain, late endosome, etc., and molecular functions were mainly enriched in Toll-like receptor binding, ubiquitin-like protein ligase binding, etc., and biological processes were enriched in regulation of autophagy, positive regulation of cellular catabolic process, response to lipopolysaccharide, regulation of inflammatory response, cellular response to external stimulus, etc. In KEGG enrichment analysis, the differentially expressed autophagy-related genes were mainly concentrated in NOD-like receptor signaling pathway, lipid and atherosclerosis, forkhead box protein O(FoxO) signaling pathway, etc. Our research completed the construction of protein-protein interaction (PPI), identified 10 key genes, and screened out that interleukin-6(IL-6) and signal transducer and activator of transcription 3(STAT3) were closely related to AD. Conclusions Ten key autophagy-related genes were obtained in this study, among which IL-6 and STAT3 are more closely related to AD.

Key words: Alzheimer disease, Autophagy, Genes, Bioinformatics

中图分类号:

R749.1

盛兆晴, 刘晓红. 阿尔茨海默病自噬相关基因的筛选及其通路分析[J]. 内科理论与实践, 2024, 19(04): 236-242.

SHENG Zhaoqing, LIU Xiaohong. Screening and pathway analysis of autophagy-related genes in Alzheimer disease[J]. Journal of Internal Medicine Concepts & Practice, 2024, 19(04): 236-242.

图/表 11

图1

表1

差异表达的ARG

基因	log₂FC	FDR	上调/下调
S100A8	0.734 430 653	1.294 75E-41	上调
S100A9	0.631 580 392	2.997 15E-41	上调
GFAP	0.609 292 049	4.453 38E-55	上调
BAG3	0.446 585 26	5.753 08E-48	上调
SPP1	0.419 081 46	2.439 46E-40	上调
DDIT4	0.387 251 516	5.005 39E-49	上调
CDKN1A	0.368 832 806	2.884 3E-44	上调
NFKBIA	0.363 802 97	8.647 81E-75	上调
IL6	0.359 681 502	3.796 82E-17	上调
CCL2	0.345 877 034	7.361 13E-31	上调
GJA4	0.334 011 564	1.492 26E-45	上调
TNFRSF10B	0.309 289 337	2.784 55E-69	上调
PDK4	0.283 985 514	1.619 89E-26	上调
CEBPB	0.282 784 748	4.097 13E-59	上调
CXCR4	0.274 577 193	4.684 29E-34	上调
TREM2	0.274 073 704	2.786 42E-35	上调
SERPINH1	0.270 492 92	3.114 4E-31	上调
CASP1	0.263 382 958	9.255 49E-51	上调
HMOX1	0.256 356 446	1.288 31E-36	上调
CASP4	0.253 136 162	1.349 79E-51	上调
IL10RA	0.252 086 766	7.222 95E-48	上调
TRIM22	0.251 133 782	6.561 9E-55	上调
VAMP8	0.249 623 31	9.593 4E-50	上调
MYD88	0.249 228 915	1.156 73E-51	上调
LAMP2	0.247 986 568	4.413 14E-40	上调
KDR	0.242 699 838	1.689 45E-17	上调
CYBB	0.241 577 351	1.078 61E-28	上调
ITGB4	0.236 962 537	1.708 02E-47	上调
NFE2L2	0.231 527 954	2.941 17E-59	上调
MCL1	0.231 458 541	1.725 39E-52	上调
DCN	0.228 229 134	2.220 71E-29	上调
RELA	0.224 802 04	1.358 85E-59	上调
SLC1A5	0.223 657 939	4.543 77E-50	上调
ITPR3	0.221 584 092	1.796 88E-42	上调
TCIRG1	0.219 778 682	5.358 93E-53	上调
PLCE1	0.219 757 497	5.667 72E-65	上调
NFKBIZ	0.217 692 335	1.087 39E-40	上调
MYC	0.213 477 663	2.334 41E-36	上调
NDRG1	0.211 367 782	2.057 29E-33	上调
LGALS3	0.209 718 41	1.968 45E-29	上调
STAT3	0.206 894 233	1.137 87E-56	上调
DUSP4	-0.499 845 019	1.766 41E-60	下调
CAMK4	-0.494 161 901	2.063 21E-74	下调
BDNF	-0.477 357 958	5.418 81E-81	下调
PAK1	-0.469 712 144	1.555 31E-70	下调
IGF1	-0.392 947 702	1.648 13E-67	下调
TBC1D9	-0.331 515 013	4.391 44E-54	下调
MAP2K1	-0.279 448 405	2.363 26E-32	下调
PLK2	-0.278 443 738	1.786 23E-46	下调
HSPA8	-0.255 422 758	6.227 56E-28	下调
GABBR2	-0.235 543 436	1.284 5E-48	下调
CAMKK2	-0.235 461 651	1.826 4E-67	下调
PRNP	-0.234 526 608	7.010 57E-35	下调
RALB	-0.231 614 543	3.131 96E-43	下调
MAPK8	-0.229 246 562	1.221 77E-29	下调
VDAC1	-0.229 196 778	4.274 23E-51	下调
SNCA	-0.226 627 217	2.682 88E-54	下调
HIVEP2	-0.225 398 91	2.151 41E-42	下调
KIAA1524	-0.224 809 135	1.178 74E-36	下调
CDKN2D	-0.221 703 258	1.496 62E-79	下调
GABARAPL1	-0.214 767 25	7.058 2E-60	下调
PIK3CB	-0.213 074 216	7.147 73E-27	下调
VDAC2	-0.210 329 444	7.610 65E-52	下调
FBXL2	-0.208 120 876	1.005 31E-49	下调
NRG3	-0.205 871 654	1.082 04E-42	下调
TBC1D7	-0.204 288 881	2.941 05E-43	下调

表1

图2

图3

图4

图5

图6

图7

图8

图9

表2

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基因	英文全称	MCC评分
IL-6	interleukin 6	244 380
STAT3	signal transducer and activator of transcription 3	244 225
NFKBIA	nuclear factor-kappaB inhibitor alpha	213 723
MAPK8	mitogen-activated protein kinase 8	184 714
CCL2	CC chemokine ligand 2	169 968
MYC	myelocytomatosis viral oncogene homolog	136 967
HMOX1	heme oxygenase 1	108 768
RELA	v-rel reticuloendotheliosis viral oncogene homolog A (avian)	107 766
CASP1	caspase-1	106 712
NFE2L2	nuclear factor erythroid2-like-2	90 721