Correlation between <i>ATG3</i> gene polymorphism and susceptibility and symptoms of tuberculosis patients in western China_West China Medical Journal

Authors：

LI Jing ^1,2 , WU Lijuan ¹ , HU Xuejiao ¹ , ZHAO Zhenzhen ¹ , LÜ Yanghua ^1,2 ,  YING Binwu ¹

1. Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Department of Clinical Laboratory, Central Hospital of Panzhihua City in Sichuan Province, Sichuan 617067, P. R. China;

Corresponding author：

YING Binwu, Email: binwuying@126.com

Keywords：

Tuberculosis; ATG3 gene; Single nucleotide polymorphisms; Susceptibility

DOI：

10.7507/1002-0179.201907071

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Objective To investigate the relationship between the gene polymorphism of autophagy-related gene 3 (ATG3) and the development and clinical symptoms of tuberculosis in tuberculosis patients in western China.Methods According to the inclusion and exclusion criteria, 476 tuberculosis patients (tuberculosis group) who were admitted to West China Hospital of Sichuan University from December 2014 to November 2015 and 475 healthy controls (healthy control group) who underwent health examination during the same period were finally included. High-throughput genotyping technology was used to detect genotypes of three single nucleotide polymorphisms (SNPs) (rs2638029, rs2638037, rs3732817) of ATG3 gene, and relevant clinical data of subjects were collected. The relationship between gene polymorphism and susceptibility to tuberculosis and clinical symptoms was analyzed by statistical methods such as χ² test and logistic regression model.Results Except for GA genotype [odds ratio (OR) =1.375, 95% confidence interval (CI) (1.048, 1.805), P=0.022] and dominant genetic model GG+GA [OR=1.326, 95%CI (1.024, 1.717), P=0.032] in rs2638037, there was no statistically significant difference in the allele frequency, genotype and genetic patterns of rs2638029, rs3732817 and rs2638037 between the two groups (P>0.05), after the adjustment of the gender and age. But after correction by Bonferroni, GA genotype and dominant genetic patterns GG+GA showed no statistical significance between the two groups (P=0.132, 0.201). Haplotype CGA was associated with tuberculosis susceptibility [OR=1.262, 95%CI (1.001,1.593), P=0.048]. There was a statistically significant difference in weight loss symptoms among rs2638037 genotypes (χ²=8.131, P=0.017).Conclusions The haplotype CGA of three SNPs of ATG3 gene may be involved in the development of tuberculosis. The rs2638037 single nucleotide polymorphism may be related to weight loss, and more research is needed in the future.

Citation： LI Jing, WU Lijuan, HU Xuejiao, ZHAO Zhenzhen, LÜ Yanghua, YING Binwu. Correlation between ATG3 gene polymorphism and susceptibility and symptoms of tuberculosis patients in western China. West China Medical Journal, 2019, 34(8): 850-856. doi: 10.7507/1002-0179.201907071 Copy

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31.	李芳, 黄果, 彭平, 等. 自噬相关基因3过表达促进乳腺癌细胞自噬并抑制盐霉素诱导的细胞凋亡. 南方医科大学学报, 2019, 39(2): 162-168.
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1. World Health Organization. Global tuberculosis report 2018. (2018-09-18)[2019-05-09]. https://www.who.int/tb/publications/global_report/en/.
2. Schurz H, Kinnear CJ, Gignoux C, et al. A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array. Front Genet, 2019, 9: 678.
3. Boisson-Dupuis S, Bustamante J, El-Baghdadi J, et al. Inherited and acquired immunodeficiencies underlying tuberculosis in childhood. Immunol Rev, 2015, 264(1): 103-120.
4. Vannberg FO, Chapman SJ, Hill AV. Human genetic susceptibility to intracellular pathogens. Immunol Rev, 2011, 240(1): 105-116.
5. Mboowa G, Sserwadda I, Amujal M, et al. Human genomic loci important in common infectious diseases: role of high-throughput sequencing and genome-wide association studies. Can J Infect Dis Med Microbiol, 2018, 2018: 1875217.
6. Möller M, Hoal EG. Current findings, challenges and novel approaches in human genetic susceptibility to tuberculosis. Tuberculosis (Edinb), 2010, 90(2): 71-83.
7. 江道斌, 胡昕, 李双, 等. 白细胞介素23受体基因单核苷酸多态性与肺结核和耐药肺结核易感性的相关性. 中华医学杂志, 2015, 95(20): 1576-1580.
8. 周汶静, 胡雪姣, 张晶雅, 等. Wnt信号通路基因单核苷酸多态性与中国西部藏族人群结核易感性研究. 四川大学学报(医学版), 2016, 47(6): 920-925.
9. Lindenau JD, Guimarães LS, Friedrich DC, et al. Cytokine gene polymorphisms are associated with susceptibility to tuberculosis in an Amerindian population. Int J Tuberc Lung Dis, 2014, 18(8): 952-957.
10. Faridgohar M, Nikoueinejad H. New findings of Toll-like receptors involved in Mycobacterium tuberculosis infection. Pathog Glob Health, 2017, 111(5): 256-264.
11. Sveinbjornsson G, Gudbjartsson DF, Halldorsson BV, et al. HLA classⅡsequence variants influence tuberculosis risk in populations of European ancestry. Nat Genet, 2016, 48(3): 318-322.
12. Hu X, Zhou J, Chen X, et al. Pathway analyses identify novel variants in the WNT signaling pathway associated with tuberculosis in Chinese population. Sci Rep, 2016, 6: 28530.
13. Castillo EF, Dekonenko A, Arko-Mensah J, et al. Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation. Proc Natl Acad Sci USA, 2012, 109(46): E3168-E3176.
14. Manzanillo PS, Ayres JS, Watson RO, et al. The ubiquitin ligase parkin mediates resistance to intracellular pathogens. Nature, 2013, 501(7468): 512-516.
15. Kumar D, Nath L, Kamal MA, et al. Genome-wide analysis of the host intracellular network that regulates survival of Mycobacterium tuberculosis. Cell, 2010, 140(5): 731-743.
16. Gu X, Gao Y, Mu DG, et al. MiR-23a-5p modulates mycobacterial survival and autophagy during Mycobacterium tuberculosis infection through TLR2/MyD88/NF-κB pathway by targeting TLR2. Exp Cell Res, 2017, 354(2): 71-77.
17. Singh SB, Davis AS, Taylor GA, et al. Human IRGM induces autophagy to eliminate intracellular mycobacteria. Science, 2006, 313(5792): 1438-1441.
18. Etna MP, Sinigaglia A, Grassi A, et al. Mycobacterium tuberculosis-induced miR-155 subverts autophagy by targeting ATG3 in human dendritic cells. PLoS Pathog, 2018, 14(1): e1006790.
19. 中华人民共和国卫生部. 肺结核诊断标准: WS 288—2008, 2008.
20. 胡雪姣. Wnt信号通路相关基因多态性与结核易感性的关联研究及后续功能分析. 成都: 四川大学, 2015.
21. Lam A, Prabhu R, Gross CM, et al. Role of apoptosis and autophagy in tuberculosis. Am J Physiol Lung Cell Mol Physiol, 2017, 313(2): L218-L229.
22. Bradfute SB, Castillo EF, Arko-Mensah JA, et al. Autophagy as an immune effector against tuberculosis. Curr Opin Microbiol, 2013, 16(3): 355-365.
23. Sakowski ET, Koster S, Portal Celhay C, et al. Ubiquilin 1 promotes IFN-γ-Induced xenophagy of Mycobacterium tuberculosis. PLoS Pathog, 2015, 11(7): e1005076.
24. Deretic V, Kimura T, Timmins G, et al. Immunologic manifestations of autophagy. J Clin Invest, 2015, 125(1): 75-84.
25. 全国第五次结核病流行病学抽样调查技术指导组, 全国第五次结核病流行病学抽样调查办公室. 2010年全国第五次结核病流行病学抽样调查报告. 中国防痨杂志, 2012, 34(8): 485-508.
26. Xie H, Li C, Zhang M, et al. Association between IRGM polymorphisms and tuberculosis risk: a meta-analysis. Medicine (Baltimore), 2017, 96(43): e8189.
27. King KY, Lew JD, Ha NP, et al. Polymorphic allele of human IRGM1 is associated with susceptibility to tuberculosis in African Americans. PLoS One, 2011, 6(1): e16317.
28. Che N, Li S, Gao T, et al. Identification of a novel IRGM promoter single nucleotide polymorphism associated with tuberculosis. Clin Chim Acta, 2010, 411(21/22): 1645-1649.
29. Horne DJ, Graustein AD, Shah JA, et al. Human ULK1 variation and susceptibility to Mycobacterium tuberculosis infection. J Infect Dis, 2016, 214(8): 1260-1267.
30. Yao C, Liu BB, Qian XD, et al. Crocin induces autophagic apoptosis in hepatocellular carcinoma by inhibiting Akt/mTOR activity. Onco Targets Ther, 2018, 11: 2017-2028.
31. 李芳, 黄果, 彭平, 等. 自噬相关基因3过表达促进乳腺癌细胞自噬并抑制盐霉素诱导的细胞凋亡. 南方医科大学学报, 2019, 39(2): 162-168.
32. 杜晨阳, 张建军, 王振, 等. miRNA-30a-3p下调Atg3介导的自噬抑制肝癌细胞侵袭和转移. 中华普通外科杂志, 2018, 33(4): 334-337.

West China Medical Journal

Correlation between ATG3 gene polymorphism and susceptibility and symptoms of tuberculosis patients in western China

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