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A genome-wide DNA methylation analysis in peripheral blood from patients identifies risk loci associated with Graves’ orbitopathy

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Abstract

Objective

Graves’ orbitopathy (GO) is an inflammatory orbital disease of autoimmune origin with the potential to cause severe functional and psychosocial effects. The pathogenesis has not been fully elucidated. We investigated whether DNA methylation was associated with GO incidence in Chinese patients.

Materials and methods

Six GO patients and six age-matched controls were recruited, and genome-wide DNA methylation patterns were analyzed in their peripheral blood. t tests were performed to determine differential methylated sites in genomic regions and the univariable logistic regression analyses was performed to evaluate their risk with GO incidence. Cluster analysis and principal component analysis (PCA) were performed to determine the effects of the extracted differentially methylated sites.

Results

One hundred and forty-eight differentially methylated sites were identified, including CD14 (fold change = 4.31, p = 0.005), IL17RE (fold change = 2.128, p = 0.005), and DRD4 (fold change = 0.25, p = 0.004), and were supported by cluster and PCA analyses. Univariable logistic regression analyses showed that the methylation patterns at 12 loci were associated with GO incidence. The relative risk per 1% decrease in methylation at ZCCHC6 and GLI3 was 0.15 (95% CI 0.03–0.91; p = 0.039) and 0.65 (95% CI 0.42–0.98; p = 0.042), respectively. Pearson correlation analyses demonstrated that methylation levels at IL17RE were positively associated with Clinical Activity Score (CAS) (r = 0.967, p < 0.05).

Conclusions

Our results demonstrate that differential methylation levels at analyzed sites (genes) may be risk markers of GO. DNA methylation analysis could provide new insights into understanding the disease and provide new treatment strategies for GO in Chinese patients.

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Acknowledgements

This work was supported by the Beijing Municipal Administration of Hospitals Incubating Program (PX2016063) and the Expert Promotion Program of Beijing Health Systems (2015-3-017) to Zhong Xin. We are grateful to the Center for Genetics and Genomic Analysis, Genesky Biotechnologies Inc. (Shanghai, 201203) for their technical support in DNA sequencing.

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Author notes

  1. Z. Xin and L. Hua have contributed equally to this paper.

Authors and Affiliations

  1. Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China

    Z. Xin, T.-T. Shi, X. Tuo, F.-Y. Yang, X. Cao & J.-K. Yang

  2. Department of Mathematics, School of Biomedical Engineering, Capital Medical University, Beijing, China

    L. Hua

  3. Physical Examination Department, Beijing Tongren Hospital, Capital Medical University, Beijing, China

    Y. Li

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  1. Z. Xin
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Correspondence to Z. Xin or J.-K. Yang.

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The authors declare no conflicts of interest.

Ethical approval

The study was conducted with the approval from the Ethics Committee of Beijing Tongren Hospital, Capital Medical University. All procedures performed in the study were in accordance with the 1964 Helsinki declaration and its later amendments.

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Informed written consents were obtained from all individual participants included in this study.

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Xin, Z., Hua, L., Shi, TT. et al. A genome-wide DNA methylation analysis in peripheral blood from patients identifies risk loci associated with Graves’ orbitopathy. J Endocrinol Invest 41, 719–727 (2018). https://doi.org/10.1007/s40618-017-0796-6

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  • DOI: https://doi.org/10.1007/s40618-017-0796-6

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