Genetic variants of <i>HKDC-1</i> associated with first-line anti-tuberculosis drug-induced liver injury in tuberculosis patients in western China_West China Medical Journal

Authors：

WANG Dengchao , SONG Jiajia , BAI Hao , LIU Tangyuheng , JIAO Lin , WU Tao , WU Lijuan , ZHANG Jingwei ,  YING Binwu

Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

YING Binwu, Email: binwuying@126.com

Keywords：

Anti-tuberculosis drug-induced liver injury; HKDC-1 gene; Single nucleotide polymorphism

DOI：

10.7507/1002-0179.201907076

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Objective To explore the relationship between hexokinase domain-containing protein 1 (HKDC-1) single nucleotide polymorphism (SNP) and first-line anti-tuberculosis drug-induced liver injury (ATDILI) in tuberculosis patients in western China.Methods From November 2016 to April 2018, 746 tuberculosis patients treated in West China Hospital of Sichuan University were collected and divided into ATDILI group and non-ATDILI group according to the liver function indicators. DNA was extracted by QIAamp® DNA Blood Mini Kit (Qiagen, Germany). Seven SNPs of the HKDC-1 gene were genotyped by high-throughput genotyping technique and the differences between the two groups were compared.Results There were 118 ATDILI and 628 non-ATDILI cases enrolled in this study. In clinical symptoms, the differences in incidences of fever and weight loss between the two groups were statistically significant (P=0.004, 0.024). The C allele at rs906219 was associated with low susceptibility to ATDILI [odds ratio (OR)=0.737, 95% confidence interval (CI) (0.556, 0.957), P=0.033], and the additive model and dominant model showed that CC/CA genotype had a lower risk of ATDILI than AA genotype [CC vs. AA: OR=0.563, 95%CI (0.325, 0.976), P=0.039; CC+CA vs. AA: OR=0.533, 95%CI (0.348, 0.817), P=0.004].Conclusion The SNP of rs906219 in HKDC-1 is correlated with ATDILI occurrence in tuberculosis patients in western China, which provides clues for personalized anti-tuberculosis treatment.

Citation： WANG Dengchao, SONG Jiajia, BAI Hao, LIU Tangyuheng, JIAO Lin, WU Tao, WU Lijuan, ZHANG Jingwei, YING Binwu. Genetic variants of HKDC-1 associated with first-line anti-tuberculosis drug-induced liver injury in tuberculosis patients in western China. West China Medical Journal, 2019, 34(8): 878-884. doi: 10.7507/1002-0179.201907076 Copy

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3.	Wang Y, Xiang X, Wu SQ, et al. Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population. Infect Genet Evol, 2017, 51: 198-202.
4.	Wang P, Pradhan K, Zhong XB, et al. Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B, 2016, 6(5): 384-392.
5.	Chen R, Wang J, Zhang Y, et al. Key factors of susceptibility to anti-tuberculosis drug-induced hepatotoxicity. Arch Toxicol, 2015, 89(6): 883-897.
6.	Wattanapokayakit S, Mushiroda T, Yanai H, et al. NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients. Int J Tuberc Lung Dis, 2016, 20(10): 1364-1369.
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10.	Irwin DM, David M, Tan H, et al. Molecular evolution of the vertebrate hexokinase gene family: identification of a conserved fifth vertebrate hexokinase gene. Comp Biochem Physiol Part D Genomics Proteomics, 2008, 3(1): 96-107.
11.	Pusec CM, De Jesus A, Khan MW, et al. Hepatic HKDC1 expression contributes to liver metabolism. Endocrinology, 2019, 160(2): 313-330.
12.	Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA, 2006, 103(8): 2653-2658.
13.	Theurey P, Rieusset J. Mitochondria-associated membranes response to nutrient availability and role in metabolic diseases. Trends Endocrinol Metab, 2017, 28(1): 32-45.
14.	Tweed CD, Wills GH, Crook AM, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. BMC Med, 2018, 16(1): 46-46.
15.	Guo C, Ludvik AE, Arlotto ME, et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun, 2015, 6: 60-69.
16.	Gosmain Y, Lefai E, Ryser S, et al. Sterol regulatory element-binding protein-1 mediates the effect of insulin on hexokinase II gene expression in human muscle cells. Diabetes, 2004, 53: 321-329.
17.	Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell, 1999, 98: 115-124.
18.	Khan MW, Ding X, Cotler SJ, et al. Studies on the tissue localization of HKDC1, a putative novel fifth hexokinase, in humans. J Histochem Cytochem, 2018, 66: 385-392.
19.	Maldonado EN. VDAC-tubulin, an anti-warburg pro-oxidant switch. Front Oncol, 2017, 7: 4-15.
20.	Chen X, Lv Y, Sun Y, et al. PGC1β regulates breast tumor growth and metastasis by SREBP1-mediated HKDC1 expression. Front Oncol, 2019, 9: 290-303.
21.	Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol, 2008, 22(4): 335-353.
22.	Karbowski M, Kurono C, Wozniak M, et al. Free radical-induced megamitochondria formation and apoptosis. Free Radic Biol Med, 1999, 26: 396-409.

1. World Health Organization. Global tuberculosis report 2018. (2018-09-18) [2019-06-10]. http://www.who.int/tb/publications/global_report/en/.
2. Sharma SK, Rohit S, Pawan S, et al. Safety of 3 different reintroduction regimens of antituberculosis drugs after development of antituberculosis treatment-induced hepatotoxicity. Clin Infect Dis, 2010, 50(6): 833-839.
3. Wang Y, Xiang X, Wu SQ, et al. Association of CYP2B6 gene polymorphisms and anti-tuberculosis drug-induced hepatotoxicity in a Chinese population. Infect Genet Evol, 2017, 51: 198-202.
4. Wang P, Pradhan K, Zhong XB, et al. Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B, 2016, 6(5): 384-392.
5. Chen R, Wang J, Zhang Y, et al. Key factors of susceptibility to anti-tuberculosis drug-induced hepatotoxicity. Arch Toxicol, 2015, 89(6): 883-897.
6. Wattanapokayakit S, Mushiroda T, Yanai H, et al. NAT2 slow acetylator associated with anti-tuberculosis drug-induced liver injury in Thai patients. Int J Tuberc Lung Dis, 2016, 20(10): 1364-1369.
7. Metushi IG, Sanders C, Lee WM, et al. Detection of anti-isoniazid and anti-cytochrome P450 antibodies in patients with isoniazid-induced liver failure. Hepatology, 2014, 59(3): 1084-1093.
8. Lee KK, Fujimoto K, Zhang C, et al. Isoniazid-induced cell death is precipitated by underlying mitochondrial complex I dysfunction in mouse hepatocytes. Free Radic Biol Med, 2013, 65: 584-594.
9. Tafazoli S, Mashregi M, O’Brien PJ. Role of hydrazine in isoniazid-induced hepatotoxicity in a hepatocyte inflammation model. Toxicol Appl Pharmacol, 2008, 229(1): 94-101.
10. Irwin DM, David M, Tan H, et al. Molecular evolution of the vertebrate hexokinase gene family: identification of a conserved fifth vertebrate hexokinase gene. Comp Biochem Physiol Part D Genomics Proteomics, 2008, 3(1): 96-107.
11. Pusec CM, De Jesus A, Khan MW, et al. Hepatic HKDC1 expression contributes to liver metabolism. Endocrinology, 2019, 160(2): 313-330.
12. Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA, 2006, 103(8): 2653-2658.
13. Theurey P, Rieusset J. Mitochondria-associated membranes response to nutrient availability and role in metabolic diseases. Trends Endocrinol Metab, 2017, 28(1): 32-45.
14. Tweed CD, Wills GH, Crook AM, et al. Liver toxicity associated with tuberculosis chemotherapy in the REMoxTB study. BMC Med, 2018, 16(1): 46-46.
15. Guo C, Ludvik AE, Arlotto ME, et al. Coordinated regulatory variation associated with gestational hyperglycaemia regulates expression of the novel hexokinase HKDC1. Nat Commun, 2015, 6: 60-69.
16. Gosmain Y, Lefai E, Ryser S, et al. Sterol regulatory element-binding protein-1 mediates the effect of insulin on hexokinase II gene expression in human muscle cells. Diabetes, 2004, 53: 321-329.
17. Wu Z, Puigserver P, Andersson U, et al. Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1. Cell, 1999, 98: 115-124.
18. Khan MW, Ding X, Cotler SJ, et al. Studies on the tissue localization of HKDC1, a putative novel fifth hexokinase, in humans. J Histochem Cytochem, 2018, 66: 385-392.
19. Maldonado EN. VDAC-tubulin, an anti-warburg pro-oxidant switch. Front Oncol, 2017, 7: 4-15.
20. Chen X, Lv Y, Sun Y, et al. PGC1β regulates breast tumor growth and metastasis by SREBP1-mediated HKDC1 expression. Front Oncol, 2019, 9: 290-303.
21. Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol, 2008, 22(4): 335-353.
22. Karbowski M, Kurono C, Wozniak M, et al. Free radical-induced megamitochondria formation and apoptosis. Free Radic Biol Med, 1999, 26: 396-409.

West China Medical Journal

Genetic variants of HKDC-1 associated with first-line anti-tuberculosis drug-induced liver injury in tuberculosis patients in western China

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