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Genetic risk score combining six genetic variants associated with the cellular NRF2 expression levels correlates with Type 2 diabetes in the human population

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Abstract

Background

Type 2 diabetes (T2D) is known as an inflammatory disease. NRF2 (Nuclear Factor Erythroid 2 Like2) encodes a transcription factor that binds to antioxidant response elements (AREs) and regulates the expression of genes involved in many antioxidant responses.

Objective

This study aimed to gain insight into individual anti-inflammatory activity to prevent T2D development in humans.

Methods

We performed a genome-wide association study (GWAS) to identify genetic variants influencing NRF2 expression in LCLs (lymphoblastoid cell lines) generated from 74 different individuals. Association analyses between T2D or its related traits and genetic risk score (GRS) calculated by combining genetic variants detected from GWAS for cellular NRF2 expression were performed using data from 8715 subjects. The T2D prediction model using GRS was evaluated by measuring the area under the curve (AUC) of the receiver operating characteristics (ROC) curve.

Results

Our GWAS identified six genetic variants (SNP) showing suggestive evidence of associations with cellular NRF2 expression (P < 10− 6). Logistic regression analysis demonstrated that GRS was associated with an increased risk of T2D (P value = 0.003, OR = 1.13). In addition, linear regression analyses showed positive associations between GRS and fasting glucose (P value = 0.028, β = 0.62), 2-h glucose (P value = 0.0004, β = 1.13) and HbA1C (P value = 0.033, β = 0.03). In the T2D prediction model using GRS, the AUC of the ROC curve was 0.69.

Conclusion

This study highlights genetic variants associated with cellular NRF2 expression and suggests that the GRS of NRF2 expression-associated variants is likely to be a useful indicator of T2D development in the human population.

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Acknowledgements

This study was supported by a National Research Foundation of Korea (NRF) Grant funded by the Ministry of Science and ICT (NRF-2017R1A2B4006508) and Hallym University Research Fund 2017 (HRF-201712-005). The authors appreciate the bioresources that were provided for this study from the National Bank of Korea, the Centers for Disease Control and Prevention, Republic of Korea (4845-301, 4851-302 and 307).

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Author notes

  1. Jae Hun Shin and Kyung-Mi Lee equally contributed to this work.

Authors and Affiliations

  1. Department of Biomedical Science, Hallym University, Chuncheon, 200-702, Gangwon-do, Republic of Korea

    Jae Hun Shin & Yoon Shin Cho

  2. Convergence Research Center for Smart Farm Solution, Korea Institute of Science and Technology, Gangneung, Republic of Korea

    Kyung-Mi Lee, Jimin Shin & Chu Won Nho

  3. Natural Products Research Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea

    Kyung-Mi Lee, Jimin Shin & Chu Won Nho

  4. Department of Ophthalmology, The Catholic University of Korea Incheon St. Mary’s Hospital, Incheon, Republic of Korea

    Kui Dong Kang

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  1. Jae Hun Shin
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  2. Kyung-Mi Lee
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  3. Jimin Shin
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  4. Kui Dong Kang
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  5. Chu Won Nho
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Contributions

Study design: YSC, CWN. Data analysis and interpretation: JHS, K-ML, JS, KDK, CWN, YSC. Manuscript writing and revision: JHS, YSC. Figure production: JHS. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yoon Shin Cho.

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Conflict of interest

Jae Hun Shin, Kyung-Mi Lee, Chu Won Nho, Yoon Shin Cho declare that they have no conflicts of interest.

Ethical approval

This study was approved by the Hallym University Institutional Review Board (HIRB-2017-030).

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Shin, J.H., Lee, KM., Shin, J. et al. Genetic risk score combining six genetic variants associated with the cellular NRF2 expression levels correlates with Type 2 diabetes in the human population. Genes Genom 41, 537–545 (2019). https://doi.org/10.1007/s13258-019-00791-0

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