PADI4 Haplotypes Contribute to mRNA Expression, the Enzymatic Activity of Peptidyl Arginine Deaminase and Rheumatoid Arthritis Risk in Patients from Western Mexico

Mónica Guadalupe Matuz-Flores, Jesús Alfredo Rosas-Rodríguez, Orlando Tortoledo-Ortiz, Salvador Muñoz-Barrios, Gloria Esther Martínez-Bonilla, Jorge Hernández-Bello, Christian Johana Baños-Hernández, Cesar Pacheco-Tena, Gabriela Athziri Sánchez-Zuno, Beatriz Panduro-Espinoza, José Francisco Muñoz-Valle*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Citrullination is catalyzed by the peptidyl arginine deiminase 4 (PAD4) enzyme, encoded by the PADI4 gene. Increased PAD4 activity promotes the onset and progression of rheumatoid arthritis (RA). This study aimed to evaluate the association of PADI4 haplotypes with RA risk, mRNA expression, and the PAD4 activity in patients with RA from Mexico. Methodology: 100 RA patients and 100 control subjects (CS) were included. Genotyping was performed by PCR-RFLP method, PADI4 mRNA expression was quantified by real-time PCR, the contribution of PADI4 alleles (PADI4_89 G>A, PADI4_90 T>C, and PADI4_92 G>C) to mRNA expression by the ASTQ method, and PAD4 activity by HPLC. Also, the anti-CCP and anti-PADI4 antibodies were quantified by ELISA. Results: The three PADI4 polymorphisms were associated with RA susceptibility (OR = 1.72, p = 0.005; OR = 1.62; p = 0.014; OR = 1.69; p = 0.009; respectively). The 89G, 90T, and 92G alleles have a higher relative contribution to PADI4 mRNA expression from RA patients than 89A, 90C, and 92C alleles in RA patients. Moreover, the GTG/GTG haplotype was associated with RA susceptibility (OR = 2.86; p = 0.024). The GTG haplotype was associated with higher PADI4 mRNA expression (p = 0.04) and higher PAD4 enzymatic activity (p = 0.007) in RA patients. Conclusions: The evaluated polymorphisms contribute to PADI4 mRNA expression and the enzymatic activity of PAD4 in leukocytes. Therefore, the GTG haplotype is a genetic risk factor for RA in western Mexico, and is associated with increased PADI4 mRNA expression and higher PAD4 activity in these patients.

Original languageEnglish
Pages (from-to)4268-4281
Number of pages14
JournalCurrent issues in molecular biology
Volume44
Issue number9
DOIs
StatePublished - Sep 2022

Bibliographical note

Funding Information:
This study was supported by funding of the National Council of Science and Technology (CONACYT Ciencia Básica, Grant No. A1-S-8774 assigned to JFMV), and Universidad de Guadalajara through Fortalecimiento de la Investigación y el Posgrado 2021.

Publisher Copyright:
© 2022 by the authors.

Keywords

  • ACPA
  • PAD4 activity
  • PADI4 expression
  • PADI4 gene
  • Rheumatoid arthritis

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