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. 2025 Mar 20:16:1499723.
doi: 10.3389/fphar.2025.1499723. eCollection 2025.

The interaction between a leflunomide-response methylation site (cg17330251) and variant (rs705379) on response to leflunomide in patients with rheumatoid arthritis

Feng Zhao  1 , Yulan Chen  1 , Haina Liu  2 , Lei Jin  3 , Xin Feng  4 , Bingbing Dai  5 , Meng Chen  1 , Qiao Wang  1 , Yuxin Yao  1 , Ruobing Liao  1 , Junyi Zhao  1 , Bingjia Qu  1 , Ying Song  1 , Lingyu Fu  1
Affiliations

The interaction between a leflunomide-response methylation site (cg17330251) and variant (rs705379) on response to leflunomide in patients with rheumatoid arthritis

Feng Zhao et al. Front Pharmacol. .

Abstract

Objectives: This research aims to reveal the mechanisms of the effect of the Paraoxonase 1 (PON1) gene on response to leflunomide (LEF) in rheumatoid arthritis (RA) patients, in terms of single nucleotide polymorphism (SNP), DNA methylation levels.

Methods: A total of 240 RA patients enrolled were categorized into the good response group and the non-response group according to the difference in DAS28 scores between baseline and 6 months after LEF administration. The identified LEF-response cytosine-phosphate-guanines (CpGs) island (cg17330251) and its internal SNPs (rs705379, etc.) located at the PON1 promoter were detected by Sanger sequencing and methyl target sequencing.

Results: A total of 12 CpG sites at cg17330251 could be identified in our RA patients. There were significant difference between the responders and non-responders in nine CpG sites: cg17330251_2, cg17330251_3, cg17330251_4, cg17330251_6, cg17330251_7, cg17330251_8, cg17330251_9, cg17330251_10, cg17330251_12, [OR (95CI%) = 0.492 (0.250, 0.969), 0.478 (0.243, 0.940), 0.492 (0.250, 0.969), 0.461 (0.234, 0.907), 0.492 (0.250, 0.969), 0.437 (0.225, 0.849), 0.478 (0.243, 0.941), 0.421 (0.212, 0.836), 0.424 (0.213, 0.843), P < 0.05, respectively]. At all these nine CpG sites, the proportions of low methylation levels in the responders were higher than those in the non-responders (P < 0.05). In a dominant model, there was a significant difference in rs705379 wildtype CC and mutant genotypes (CT + TT) between the responders and non-responders (P < 0.05). The average methylation level of 12 CpG sites was lowest in rs705379-CC (median 0.229, IQR 0.195-0.287), then rs705379-CT (median 0.363, IQR 0.332-0.395), and rs705379-TT (median:0.531, IQR:0.496-0.557). The average methylation levels of 12 CpG sites were significantly negative correlated with ΔDAS28 (r = -0.13, P < 0.05). The Logistic regression indicated that combined effect of rs705379, DNA methylation of the PON1 gene [OR (95CI%) = 1.277 [1.003, 1.626)], systemic inflammation index (SIRI) [OR (95CI%) = 1.079 (1.018, 1.143)] served as protective factors on response to LEF in RA patients.

Conclusion: The RA patients with SNP-rs705379-CC, the low methylation level of PON1-cg17330251 and more SIRI would be susceptible of response to LEF and more suitable to choose LEF treatment.

Keywords: DNA methylation4; PON1; leflunomide; rheumatoid arthritis; single nucleotide polymorphism.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Correlations among rs705379, average methylation levels of cg17330251 of PON1 and ΔDAS28. ***P < 0.001. (A) ΔDAS28 in each genotype at rs705379; (B) Average methylation level of cg17330251 in each genotype at rs705379; (C) Correlation between average methylation level of cg17330251 and ΔDAS28.
FIGURE 2
FIGURE 2
Biological interaction network of PON1. Different colors represent diverse bioinformatics methods.
FIGURE 3
FIGURE 3
GO enrichment analysis of PON1 gene.
See this image and copyright information in PMC

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