Risk‐associated single nucleotide polymorphisms of mitochondrial D‐loop mediate imbalance of cytokines and redox in rheumatoid arthritis

• Published in: International journal of rheumatic diseases Vol. 26; no. 1; pp. 124 - 131
• Main Authors: Zhang, Jingnan, Zhang, Jingjing, Lai, Ruixue, Peng, Chenxing, Guo, Zhanjun, Wang, Cuiju
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2023
• Subjects: Alleles; Arthritis, Rheumatoid - diagnosis; Arthritis, Rheumatoid - genetics; Cytokines; displacement loop; DNA, Mitochondrial - genetics; Fluorescent indicators; Humans; Inflammation; Interferon; Interferon-gamma - genetics; Interferon-gamma - metabolism; Interleukin 6; Mitochondria; Mitochondrial DNA; Nucleotide sequence; Oxidation-Reduction; Oxidative stress; Polymorphism, Single Nucleotide; Reactive Oxygen Species; Replication; Rheumatoid arthritis; Sequence analysis; Serum levels; Single-nucleotide polymorphism; Statistical analysis; Tumor necrosis factor; Tumor necrosis factor-TNF; cytokines; displacement loop; rheumatoid arthritis; mitochondrial DNA; oxidative stress
• ISSN: 1756-1841; 1756-185X; 1756-185X
• DOI: 10.1111/1756-185X.14465

Background We have identified rheumatoid arthritis (RA) risk‐associated single nucleotide polymorphisms (SNPs) in the mitochondrial displacement loop (D‐loop) including the major alleles of nucleotides 195T/C, 16260C/T, and 16519C/T as well as the minor alleles of nucleotides 146T/C and 150C/T previously. Objective We evaluated the potential relationships of these SNPs with status for oxidative stress and inflammation cytokines. Methods The DNA was extracted from blood samples of RA patients, and the SNPs of DNA D‐loop were verified by polymerase chain reaction amplification and sequence analysis. Serum levels of inflammatory cytokines including interferon‐γ (IFN‐γ), interleukin‐2 (IL‐2), IL‐6, IL‐10, and tumor necrosis factor‐α (TNF‐α) were determined by cytometric bead array. Plasma reactive oxygen species (ROS) levels were measured by fluorescent probe technology. Results The RA risk‐related allele 16519C was significantly associated with high IFN‐γ levels (100.576 ± 11.769 vs 64.268 ± 8.199, 95% confidence interval [CI] –66.317 to –6.299, P = 0.018). This allele also associated with ROS at borderline statistics level (619.295 ± 36.687 vs 526.979 ± 25.896, 95% CI –186.145 to –1.513, P = 0.054). The subsequent analysis also showed that the ROS levels were positively correlated with IFN‐γ levels (R = 0.291, P = 0.002). Further analysis showed that RA patients with high C‐reactive protein levels displayed a higher ROS level (P = 0.001). Conclusion Our results imply that the 16519C allele of the mtDNA D‐loop might promote ROS and IFN‐γ levels by altering the replication and transcription of mtDNA, thereby modifying RA development. Remark The potential relationships of RA‐associated SNPs in the mitochondrial D‐loop with status for oxidative stress and inflammation were evaluated. The 16519C allele of the mtDNA D‐loop might promote ROS and IFN‐γ levels by altering the replication and transcription of mtDNA to modify RA development.