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Association of Genetic Variations in NRF2, NQO1, HMOX1, and MT with Severity of Coronary Artery Disease and Related Risk Factors

  • Ingkarat Sarutipaiboon
  • Nongnuch Settasatian
  • Nantarat Komanasin
  • Upa Kukongwiriyapan
  • Kittisak Sawanyawisuth
  • Phongsak Intharaphet
  • Vichai Senthong
  • Chatri SettasatianEmail author
Article
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Abstract

NRF2 is a transcription factor which, during oxidative stress, activates transcription of its target antioxidant genes. Polymorphisms in NRF2 and its target antioxidant genes: HMOX-1, NQO1, and MT, have been associated with cardiovascular diseases (CVDs) and diabetes in various ethnic groups, however, with variable results. The aim of this study was to investigate the association of NRF2, HMOX-1, NQO1, and MT gene polymorphisms with CVD risk factors in Thais. The study was conducted in two groups: group with high-risk for coronary artery disease (CAD) and health check-up group. Polymorphisms in NRF2 (rs6721961), NQO1 (rs1800566), MT1A (rs11640851), and HMOX-1 (rs2071746) were genotyped. Expressions of NRF2, HMOX-1, and NQO1 were also determined. In high-risk group, NRF2 rs6721961-TT was associated with CAD [OR (95% CI) 5.07 (1.42–18.10)] and severity of coronary atherosclerosis [Gensini score > 32, OR (95% CI) 4.31 (1.67–11.09)]; rs6721961 GT and TT revealed significant association with lower mRNA expression than GG (p = 0.021). NQO1 rs1800566 also revealed association with CAD, only in female. Combined effect of NQO1-rs1800566, HMOX1-rs2071746, and MT1A-rs11640851 was evaluated on the risks of DM and hypertension. With a combination of risk alleles as genetic risk score (GRS), the highest GRS (score 6) increased risk for hypertension, comparing with GRS 0–2 [OR (95% CI) 1.89 (1.02–3.49)]; group with score 5–6 revealed association with risk of DM [OR (95% CI) 1.481 (1.08–2.04)]. In conclusion, NRF2 rs6721961 associated with CAD and severity of coronary atherosclerosis. NQO1 rs1800566 also associated with CAD, only in female. Combined polymorphisms of three NRF2-regulated genes increased risk of DM and hypertension.

Keywords

Cardiovascular disease (CVD) Diabetes mellitus Nuclear factor (erythroid-derived 2)-like 2 (NRF2) Heme oxygenase-1 (HMOX1) NAD(P)H: quinone oxidoreductase 1 (NQO1) Metallothionein (MT) 

Notes

Acknowledgements

The financial support for this study was from National Research Council of Thailand (NRCT), Ingkarat Sarutipaiboon was supported by a Research Fund for Supporting Lecturer to Admit High Potential Student to Study and Research on His Expert Program Year 2012 (551H208); and Cardiovascular Research Group (CVRG), Khon Kaen University. The Faculty of Associated Medical Sciences, Khon Kaen University had provided all necessary facilities throughout the study.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This study involved human data and protocol was approved by the Khon Kaen University Ethics Committee for Human Research (HE 510414 for the high-risk group and HE 601094 for the health check-up group) based on the Declaration of Helsinki and the ICH Good Clinical Practice Guidelines.

Informed Consent

The high-risk group had voluntarily joined a study and provide written consent forms as well as demographic data and the basic information according to the questionnaire. All consent forms have been reviewed by the Khon Kaen University Ethics Committee for Human Research. For the health check-up group, because the data were obtained from retrospective medical records accompanied with collected left-over samples, formal consent was not required.

Supplementary material

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Supplementary material 1 (DOCX 30 kb)

References

  1. 1.
    Gaziano, T., Reddy, K. S., Paccaud, F., Horton, S., & Chaturvedi, V. (2006). Chapter 33 cardiovascular disease. In D. T. Jamison, J. G. Breman, A. R. Measham, G. Alleyne, M. Claeson, D. B. Evans, et al. (Eds.), Disease control priorities in developing countries (2nd ed., pp. 645–662). Washington: World Bank.Google Scholar
  2. 2.
    Saha, S., Gerdtham, U. G., & Johansson, P. (2010). Economic evaluation of lifestyle interventions for preventing diabetes and cardiovascular diseases. International Journal of Environmental Research and Public Health, 7, 3150–3195.CrossRefGoogle Scholar
  3. 3.
    Al-Mawali, A. (2015). Non-communicable diseases: Shining a light on cardiovascular disease, Oman’s biggest killer. Oman Medical Journal, 30, 227–228.CrossRefGoogle Scholar
  4. 4.
    Jarachvarawat, C. (2009). Risk factors and prevention of coronary artery disease. Journal of Medicine and Health Sciences, 16, 33–41.Google Scholar
  5. 5.
    WHO. (2014). disease and injury country estimates, 2000-2012. Geneva: World Health Organization.Google Scholar
  6. 6.
    Kansanen, E., Kuosmanen, S. M., Leinonen, H., & Levonen, A. L. (2013). The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer. Redox biology, 1, 45–49.CrossRefGoogle Scholar
  7. 7.
    Gu, J., Cheng, Y., Wu, H., Kong, L., Wang, S., Xu, Z., et al. (2017). Metallothionein is downstream of Nrf2 and partially mediates sulforaphane prevention of diabetic cardiomyopathy. Diabetes, 66, 529–542.CrossRefGoogle Scholar
  8. 8.
    Howden, R. (2013). Nrf2 and cardiovascular defense. Oxidative Medicine and Cellular Longevity, 2013, 104308.Google Scholar
  9. 9.
    Collins, A. R., Gupte, A. A., Ji, R., Ramirez, M. R., Minze, L. J., Liu, J. Z., et al. (2012). Myeloid deletion of nuclear factor erythroid 2-related factor 2 increases atherosclerosis and liver injury. Arteriosclerosis, Thrombosis, and Vascular Biology, 32, 2839–2846.CrossRefGoogle Scholar
  10. 10.
    Ruotsalainen, A. K., Inkala, M., Partanen, M. E., Lappalainen, J. P., Kansanen, E., Makinen, P. I., et al. (2013). The absence of macrophage Nrf2 promotes early atherogenesis. Cardiovascular Research, 98, 107–115.CrossRefGoogle Scholar
  11. 11.
    Shimoyama, Y., Mitsuda, Y., Hamajima, N., & Niwa, T. (2014). Polymorphisms of nrf2, an antioxidative gene, are associated with blood pressure in japanese. Nagoya Journal of Medical Science, 76, 113–120.Google Scholar
  12. 12.
    Hartikainen, J. M., Tengstrom, M., Kosma, V. M., Kinnula, V. L., Mannermaa, A., & Soini, Y. (2012). Genetic polymorphisms and protein expression of NRF2 and Sulfiredoxin predict survival outcomes in breast cancer. Cancer Research, 72, 5537–5546.CrossRefGoogle Scholar
  13. 13.
    Suzuki, T., Shibata, T., Takaya, K., Shiraishi, K., Kohno, T., Kunitoh, H., et al. (2013). Regulatory nexus of synthesis and degradation deciphers cellular Nrf2 expression levels. Molecular and Cellular Biology, 33, 2402–2412.CrossRefGoogle Scholar
  14. 14.
    Atia, A., Alrawaiq, N., & Abdullah, A. (2014). A review of NAD(P)H: Quinone oxidoreductase 1 (NQO1); A multifunctional antioxidant enzyme. Journal of Applied Pharmaceutical Science, 4, 118–122.Google Scholar
  15. 15.
    Yu, H., Liu, H., Wang, L. E., & Wei, Q. (2012). A functional NQO1 609C > T polymorphism and risk of gastrointestinal cancers: A meta-analysis. PLoS ONE, 7, e30566.CrossRefGoogle Scholar
  16. 16.
    Han, S. J., Kang, E. S., Kim, H. J., Kim, S. H., Chun, S. W., Ahn, C. W., et al. (2009). The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes. Molecular Genetics and Metabolism, 97, 85–90.CrossRefGoogle Scholar
  17. 17.
    Traver, R. D., Siegel, D., Beall, H. D., Phillips, R. M., Gibson, N. W., Franklin, W. A., et al. (1997). Characterization of a polymorphism in NAD(P)H: Quinone oxidoreductase (DT-diaphorase). British Journal of Cancer, 75, 69–75.CrossRefGoogle Scholar
  18. 18.
    Siegel, D., McGuinness, S. M., Winski, S. L., & Ross, D. (1999). Genotype-phenotype relationships in studies of a polymorphism in NAD(P)H: Quinone oxidoreductase 1. Pharmacogenetics, 9, 113–121.CrossRefGoogle Scholar
  19. 19.
    Traver, R. D., Horikoshi, T., Danenberg, K. D., Stadlbauer, T. H., Danenberg, P. V., Ross, D., et al. (1992). NAD(P)H: Quinone oxidoreductase gene expression in human colon carcinoma cells: Characterization of a mutation which modulates DT-diaphorase activity and mitomycin sensitivity. Cancer Research, 52, 797–802.Google Scholar
  20. 20.
    Gozzelino, R., Jeney, V., & Soares, M. P. (2010). Mechanisms of cell protection by heme oxygenase-1. Annual Review of Pharmacology and Toxicology, 50, 323–354.CrossRefGoogle Scholar
  21. 21.
    Morita, T. (2005). Heme oxygenase and atherosclerosis. Arteriosclerosis, Thrombosis, and Vascular Biology, 25, 1786–1795.CrossRefGoogle Scholar
  22. 22.
    Zbornikova, P., Kralik, L., Lelkova, P., Kalincik, T., Havrdova, E., & Martasek, P. (2012). Microsatellite polymorphism in haem oxygenase 1 gene promoter in multiple sclerosis. Folia Biologica, 58, 69–74.Google Scholar
  23. 23.
    Lee, E. Y., Lee, Y. H., Kim, S. H., Jung, K. S., Kwon, O., Kim, B. S., et al. (2015). Association between heme oxygenase-1 promoter polymorphisms and the development of albuminuria in type 2 diabetes: A case-control study. Medicine, 94, e1825.CrossRefGoogle Scholar
  24. 24.
    Ono, K., Goto, Y., Takagi, S., Baba, S., Tago, N., Nonogi, H., et al. (2004). A promoter variant of the heme oxygenase-1 gene may reduce the incidence of ischemic heart disease in Japanese. Atherosclerosis, 173, 315–319.CrossRefGoogle Scholar
  25. 25.
    Thirumoorthy, N., Shyam, S. A., Manisenthil, K. K., Senthil, K. M., Ganesh, G., & Chatterjee, M. (2011). A review of metallothionein isoforms and their role in pathophysiology. World Journal of Surgical Oncology, 9, 54.CrossRefGoogle Scholar
  26. 26.
    Sabolic, I., Breljak, D., Skarica, M., & Herak-Kramberger, C. M. (2010). Role of metallothionein in cadmium traffic and toxicity in kidneys and other mammalian organs. BioMetals, 23, 897–926.CrossRefGoogle Scholar
  27. 27.
    Yang, L., Li, H., Yu, T., Zhao, H., Cherian, M. G., Cai, L., et al. (2008). Polymorphisms in metallothionein-1 and -2 genes associated with the risk of type 2 diabetes mellitus and its complications. American journal of physiology. Endocrinology and Metabolism, 294, E987–E992.Google Scholar
  28. 28.
    Gensini, G. G. (1983). A more meaningful scoring system for determining the severity of coronary heart disease. American Journal of Cardiology, 51, 606.CrossRefGoogle Scholar
  29. 29.
    Yongsakulchai, P., Settasatian, C., Settasatian, N., Komanasin, N., Kukongwiriyapan, U., Cote, M. L., et al. (2016). Association of combined genetic variations in PPARgamma, PGC-1alpha, and LXRalpha with coronary artery disease and severity in Thai population. Atherosclerosis, 248, 140–148.CrossRefGoogle Scholar
  30. 30.
    American Diabetes Association. (2013). Standards of medical care in diabetes—2013. Diabetes Care, 36(Suppl 1), S11–S66.CrossRefGoogle Scholar
  31. 31.
    Weber, M. A., Schiffrin, E. L., White, W. B., Mann, S., Lindholm, L. H., Kenerson, J. G., et al. (2014). Clinical practice guidelines for the management of hypertension in the community: A statement by the American Society of Hypertension and the International Society of Hypertension. Journal of Clinical Hypertension (Greenwich), 16, 14–26.CrossRefGoogle Scholar
  32. 32.
    WHO. (2000). The Asia-Pacific perspective: Redefining obesity and its treatment (pp. 1–55). Australia Western Pacific Region: World Health Organization.Google Scholar
  33. 33.
    NCEP-ATP III. (2002). Third report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel III) final report. Circulation, 106, 3143–3421.CrossRefGoogle Scholar
  34. 34.
    Shimoyama, Y., Mitsuda, Y., Tsuruta, Y., Hamajima, N., & Niwa, T. (2014). Polymorphism of Nrf2, an antioxidative gene, is associated with blood pressure and cardiovascular mortality in hemodialysis patients. International Journal of Medical Sciences, 11, 726–731.CrossRefGoogle Scholar
  35. 35.
    Ye, J., Coulouris, G., Zaretskaya, I., Cutcutache, I., Rozen, S., & Madden, T. L. (2012). Primer-BLAST: A tool to design target-specific primers for polymerase chain reaction. BMC Bioinformatics, 13, 134.CrossRefGoogle Scholar
  36. 36.
    Giegerich, R., Meyer, F., & Schleiermacher, C. (1996). GeneFisher—Software support for the detection of postulated genes. Proceedings of the 3rd International Conference on Intelligent Systems for Molecular Biology, 4, 68–77.Google Scholar
  37. 37.
    Livak, K. J., & Schmittgen, T. D. (2001). Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods, 25, 402–408.CrossRefGoogle Scholar
  38. 38.
    Lastra, G., Syed, S., Kurukulasuriya, L. R., Manrique, C., & Sowers, J. R. (2014). Type 2 diabetes mellitus and hypertension: An update. Endocrinology and Metabolism Clinics of North America, 43, 103–122.CrossRefGoogle Scholar
  39. 39.
    Ohishi, M. (2018). Hypertension with diabetes mellitus: Physiology and pathology. Hypertension Research, 41, 389–393.CrossRefGoogle Scholar
  40. 40.
    Khan, K. A., Govindarajan, G., Whaley-Connell, A., & Sowers, J. R. (2006). Diabetic hypertension. Heart Failure Clinics, 2, 25–36.CrossRefGoogle Scholar
  41. 41.
    Kunnas, T., Maatta, K., & Nikkari, S. T. (2016). Genetic polymorphisms of transcription factor NRF2 and of its host gene sulfiredoxin (SRXN1) are associated with cerebrovascular disease in a Finnish Cohort, the TAMRISK Study. International Journal of Medical Sciences, 13, 325–329.CrossRefGoogle Scholar
  42. 42.
    Marzec, J. M., Christie, J. D., Reddy, S. P., Jedlicka, A. E., Vuong, H., Lanken, P. N., et al. (2007). Functional polymorphisms in the transcription factor NRF2 in humans increase the risk of acute lung injury. FASEB Journal, 21, 2237–2246.CrossRefGoogle Scholar
  43. 43.
    Cho, H. Y., Marzec, J., & Kleeberger, S. R. (2015). Functional polymorphisms in Nrf2: Implications for human disease. Free Radical Biology & Medicine, 88, 362–372.CrossRefGoogle Scholar
  44. 44.
    Ross, D., Kepa, J. K., Winski, S. L., Beall, H. D., Anwar, A., & Siegel, D. (2000). NAD(P)H: Quinone oxidoreductase 1 (NQO1): Chemoprotection, bioactivation, gene regulation and genetic polymorphisms. Chemico-Biological Interactions, 129, 77–97.CrossRefGoogle Scholar
  45. 45.
    Martin, N. J., Collier, A. C., Bowen, L. D., Pritsos, K. L., Goodrich, G. G., Arger, K., et al. (2009). Polymorphisms in the NQO1, GSTT and GSTM genes are associated with coronary heart disease and biomarkers of oxidative stress. Mutation Research, 674, 93–100.CrossRefGoogle Scholar
  46. 46.
    Boroumand, M., Pourgholi, L., Goodarzynejad, H., Ziaee, S., Hajhosseini-Talasaz, A., Sotoudeh-Anvari, M., et al. (2017). NQO1 C609T polymorphism is associated with coronary artery disease in a gender-dependent manner. Cardiovascular Toxicology, 17, 35–41.CrossRefGoogle Scholar
  47. 47.
    Cheng, Y., Li, J., Martinka, M., & Li, G. (2010). The expression of NAD(P)H: Quinone oxidoreductase 1 is increased along with NF-kappaB p105/p50 in human cutaneous melanomas. Oncology Reports, 23, 973–979.Google Scholar
  48. 48.
    Augustine, L. M., Fisher, C. D., Lickteig, A. J., Aleksunes, L. M., Slitt, A. L., & Cherrington, N. J. (2008). Gender divergent expression of Nqo1 in Sprague Dawley and August Copenhagen x Irish rats. Journal of Biochemical and Molecular Toxicology, 22, 93–100.CrossRefGoogle Scholar
  49. 49.
    Yin, J., Wang, L., Wang, X., Zheng, L., Shi, Y., Shao, A., et al. (2014). NQO1 rs1800566 C > T polymorphism was associated with a decreased risk of esophageal cancer in a Chinese population. Scandinavian Journal of Gastroenterology, 49, 317–322.CrossRefGoogle Scholar
  50. 50.
    Ding, R., Lin, S., & Chen, D. (2012). Association of NQO1 rs1800566 polymorphism and the risk of colorectal cancer: A meta-analysis. International Journal of Colorectal Disease, 27, 885–892.CrossRefGoogle Scholar
  51. 51.
    Wang, G., Zhang, L., & Li, Q. (2006). Genetic polymorphisms of GSTT1, GSTM1, and NQO1 genes and diabetes mellitus risk in Chinese population. Biochemical and Biophysical Research Communications, 341, 310–313.CrossRefGoogle Scholar
  52. 52.
    Joseph, P., & Jaiswal, A. K. (1994). NAD(P)H:quinone oxidoreductase1 (DT diaphorase) specifically prevents the formation of benzo[a]pyrene quinone-DNA adducts generated by cytochrome P4501A1 and P450 reductase. Proceedings of the National Academy of Sciences of the United States, 91, 8413–8417.CrossRefGoogle Scholar
  53. 53.
    Cadenas, E. (1995). Antioxidant and prooxidant functions of DT-diaphorase in quinone metabolism. Biochemical Pharmacology, 49, 127–140.CrossRefGoogle Scholar
  54. 54.
    Ross, D., & Siegel, D. (2017). Functions of NQO1 in cellular protection and CoQ10 metabolism and its potential role as a redox sensitive molecular switch. Frontiers in Physiology, 8, 595.CrossRefGoogle Scholar
  55. 55.
    Ono, K., Mannami, T., & Iwai, N. (2003). Association of a promoter variant of the haeme oxygenase-1 gene with hypertension in women. Journal of Hypertension, 21, 1497–1503.CrossRefGoogle Scholar
  56. 56.
    Lin, R., Fu, W., Zhou, W., Wang, Y., Wang, X., Huang, W., et al. (2011). Association of heme oxygenase-1 gene polymorphisms with essential hypertension and blood pressure in the Chinese Han population. Genetic Testing and Molecular Biomarkers, 15, 23–28.CrossRefGoogle Scholar
  57. 57.
    Solari, V., Piotrowska, A. P., & Puri, P. (2003). Expression of heme oxygenase-1 and endothelial nitric oxide synthase in the lung of newborns with congenital diaphragmatic hernia and persistent pulmonary hypertension. Journal of Pediatric Surgery, 38, 808–813.CrossRefGoogle Scholar
  58. 58.
    Stanford, S. J., Walters, M. J., Hislop, A. A., Haworth, S. G., Evans, T. W., Mann, B. E., et al. (2003). Heme oxygenase is expressed in human pulmonary artery smooth muscle where carbon monoxide has an anti-proliferative role. European Journal of Pharmacology, 473, 135–141.CrossRefGoogle Scholar
  59. 59.
    Stec, D. E., Drummond, H. A., & Vera, T. (2008). Role of carbon monoxide in blood pressure regulation. Hypertension, 51, 597–604.CrossRefGoogle Scholar
  60. 60.
    Schulz, E., Jansen, T., Wenzel, P., Daiber, A., & Munzel, T. (2008). Nitric oxide, tetrahydrobiopterin, oxidative stress, and endothelial dysfunction in hypertension. Antioxidants & Redox Signaling, 10, 1115–1126.CrossRefGoogle Scholar
  61. 61.
    Ceylan-Isik, A. F., Guo, K. K., Carlson, E. C., Privratsky, J. R., Liao, S. J., Cai, L., et al. (2009). Metallothionein abrogates GTP cyclohydrolase I inhibition-induced cardiac contractile and morphological defects: Role of mitochondrial biogenesis. Hypertension, 53, 1023–1031.CrossRefGoogle Scholar
  62. 62.
    Choi, S., Liu, X., & Pan, Z. (2018). Zinc deficiency and cellular oxidative stress: Prognostic implications in cardiovascular diseases. Acta Pharmacologica Sinica, 39, 1120–1132.CrossRefGoogle Scholar
  63. 63.
    Giacconi, R., Bonfigli, A. R., Testa, R., Sirolla, C., Cipriano, C., Marra, M., et al. (2008). +647 A/C and +1245 MT1A polymorphisms in the susceptibility of diabetes mellitus and cardiovascular complications. Molecular Genetics and Metabolism, 94, 98–104.CrossRefGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Ingkarat Sarutipaiboon
    • 1
    • 7
  • Nongnuch Settasatian
    • 2
    • 7
  • Nantarat Komanasin
    • 2
    • 7
  • Upa Kukongwiriyapan
    • 3
    • 7
  • Kittisak Sawanyawisuth
    • 4
  • Phongsak Intharaphet
    • 5
    • 7
  • Vichai Senthong
    • 4
    • 5
    • 7
  • Chatri Settasatian
    • 6
    • 7
    Email author
  1. 1.Biomedical Sciences Program, Graduate SchoolKhon Kaen UniversityKhon KaenThailand
  2. 2.School of Medical Technology, Faculty of Associated Medical SciencesKhon Kaen UniversityKhon KaenThailand
  3. 3.Department of Physiology, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  4. 4.Department of Medicine, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  5. 5.Queen Sirikit Heart Center of the Northeast HospitalKhon Kaen UniversityKhon KaenThailand
  6. 6.Department of Pathology, Faculty of MedicineKhon Kaen UniversityKhon KaenThailand
  7. 7.Cardiovascular Research GroupKhon Kaen UniversityKhon KaenThailand

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