DNA methylation change of HIPK3 in Chinese rheumatoid arthritis and its effect on inflammation

Front Immunol. 2023 Jan 10:13:1087279. doi: 10.3389/fimmu.2022.1087279. eCollection 2022.

Abstract

Introduction: Homeodomain-interacting protein kinase 3 (HIPK3) plays an important role in cell proliferation, apoptosis, and inflammation. Over-expression of HIPK3 in immune cells in rheumatoid arthritis (RA) has been reported. In this study, we investigated blood methylation levels and clinical characteristics of RA in a Chinese population.

Methods: A total of 235 patients with RA, 30 with osteoarthritis (OA), and 30 matched healthy controls were recruited. The methylation status of seven CpGs in the differentially methylated region of HIPK3 (cg05501357) was measured using targeted methylation-sequencing technology. The association between methylation haplotypes and the overall methylation status of HIPK3 with clinical characteristics was assessed using generalized linear regression.

Results: All seven CpGs showed hypomethylation status in RA blood compared with OA and normal individuals (overall p= 1.143×10-8 and FDR= 2.799×10-7), which is consistent with the previously reported high expression of HIPK3 in RA immune cells. Among all seven CpGs, 33286785 showed the highest predictive power with an area under the curve (AUC) of 0.829; we received a higher AUC=0.864 when we combined HIPK3 with anti-citrullinated protein antibodies (ACPA -) and rheumatoid factor (RF +) in the prediction model, indicating that when a patient's ACPA is negative, HIPK3 can assist RF as a new clinical index for the diagnosis of RA. We also found that HIPK3 methylation levels were negatively correlated with C-reactive protein (CRP; r= -0.16, p= 0.01). Methylation haplotypes were analyzed, and the full methylation haplotype (FMH; r= 0.16, p= 0.01) and full non-methylation haplotype (FNH; r= 0.18, p= 0.0061) were negatively correlated with CRP.

Conclusion: Circulating blood methylation levels in the protein region of HIPK3 can be utilized as a supportive diagnostic biomarker and CRP level indicator for RA.

Keywords: DNA methylation; HIPK3; inflammation; methylation haplotypes; rheumatoid arthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arthritis, Rheumatoid* / diagnosis
  • Arthritis, Rheumatoid* / genetics
  • DNA Methylation
  • East Asian People
  • Humans
  • Inflammation / genetics
  • Intracellular Signaling Peptides and Proteins / genetics
  • Osteoarthritis*
  • Protein Serine-Threonine Kinases / genetics
  • Rheumatoid Factor

Substances

  • Rheumatoid Factor
  • HIPK3 protein, human
  • Protein Serine-Threonine Kinases
  • Intracellular Signaling Peptides and Proteins

Grants and funding

This work was funded by the National Natural Science Funds of China (82074234 and 82071756), Shanghai Chinese Medicine Development Office, National Administration of Traditional Chinese Medicine, Regional Chinese Medicine (Specialist) Diagnosis and Treatment Center Construction Project-Rheumatology, State Administration of Traditional Chinese Medicine, National TCM Evidence-Based Medicine Research and Construction Project, Basic TCM Evidence-Based Capacity Development Program, Shanghai Municipal Health Commission, and East China Region-based Chinese and Western Medicine Joint Disease Specialist Alliance, Shanghai He Dongyi Famous Chinese Medicine Studio Construction Project (SHGZS-202220); National Key Research and Development Project (2018YFC1705200 and 2018YFC1705203); Shanghai 13th Five-Year Key Specialized College—Department of Osteoarthritis and Arthritis of Integrated Traditional Chinese and Western Medicine (shslczdzk04801); Shanghai Municipal Health Commission (20184Y0103).