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