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Rheumatoid arthritis (RA) is an autoimmune disease mainly characterized by joint inflammation. It presents extra-articular manifestations, with the lungs being one of the affected areas. Among these, damage to the pulmonary interstitium (Interstitial Lung Disease—ILD) has been linked to proteins involved in the inflammatory process and related to extracellular matrix deposition and lung fibrosis establishment. Peptidyl arginine deiminase enzymes (PAD), which carry out protein citrullination, play a role in this context. A genetic association analysis was conducted on genes encoding two PAD isoforms: PAD2 and PAD4. This analysis also included ancestry informative markers and protein level determination in samples from patients with RA, RA-associated ILD, and clinically healthy controls. Significant single nucleotide variants (SNV) and one haplotype were identified as susceptibility factors for RA-ILD development. Elevated levels of PAD4 were found in RA-ILD cases, while PADI2 showed an association with RA susceptibility. This work presents data obtained from previously published research. Population variability has been noticed in genetic association studies. We present data for 14 SNVs that show geographical and genetic variation across the Mexican population, which provides highly informative content and greater intrapopulation genetic diversity. Further investigations in the field should be considered in addition to AIMs. The data presented in this study were analyzed in association with SNV genotypes in PADI2 and PADI4 to assess susceptibility to ILD in RA, as well as with changes in PAD2 and PAD4 protein levels according to carrier genotype, in addition to the use of covariates such as ancestry markers. Dataset: DOI 10.3390/cells12182235 (published manuscript.). The datasets generated for this study can be found in ClinVar accessions SCV001422427–SCV001422434. Dataset License: Attribution 4.0 International (CC BY 4.0) [ABSTRACT FROM AUTHOR]

Protein citrullination is accomplished by a broad enzyme family named Peptidyl Arginine Deiminases (PADs), which makes this post-translational modification in many proteins that perform physiological and pathologic mechanisms in the body. Due to these modifications, citrullination has become a significant topic in the study of pathological processes. It has been related to some chronic and autoimmune diseases, including rheumatoid arthritis (RA), interstitial lung diseases (ILD), multiple sclerosis (MS), and certain types of cancer, among others. Antibody production against different targets, including filaggrin, vimentin, and collagen, results in an immune response if they are citrullinated, which triggers a continuous inflammatory process characteristic of autoimmune and certain chronic diseases. PAD coding genes (PADI1 to PADI4 and PADI6) harbor variations that can be important in these enzymes' folding, activity, function, and half-life. However, few studies have considered these genetic factors in the context of chronic diseases. Exploring PAD pathways and their role in autoimmune and chronic diseases is a major topic in developing new pharmacological targets and valuable biomarkers to improve diagnosis and prevention. The present review addresses and highlights genetic, molecular, biochemical, and physiopathological factors where PAD enzymes perform a major role in autoimmune and chronic diseases. [ABSTRACT FROM AUTHOR]

Around 50% of rheumatoid arthritis (RA) patients show some extra-articular manifestation, with the lung a usually affected organ; in addition, the presence of anti-citrullinated protein antibodies (ACPA) is a common feature, which is caused by protein citrullination modifications, catalyzed by the peptidyl arginine deiminases (PAD) enzymes. We aimed to identify single nucleotide variants (SNV) in PADI2 and PADI4 genes (PAD2 and PAD4 proteins, respectively) associated with susceptibility to interstitial lung disease (ILD) in RA patients and the PAD2 and PAD4 levels. Material and methods: 867 subjects were included: 118 RA-ILD patients, 133 RA patients, and 616 clinically healthy subjects (CHS). Allelic discrimination was performed in eight SNVs using qPCR, four in PADI2 and four in PADI4. The ELISA technique determined PAD2 and PAD4 levels in serum and bronchoalveolar lavage (BAL) samples, and the population structure was evaluated using 14 informative ancestry markers. Results: The rs1005753-GG (OR = 4.9) in PADI2 and rs11203366-AA (OR = 3.08), rs11203367-GG (OR = 2.4) in PADI4 are associated with genetic susceptibility to RA-ILD as well as the ACTC haplotype (OR = 2.64). In addition, the PAD4 protein is increased in RA-ILD individuals harboring the minor allele homozygous genotype in PADI4 SNVs. Moreover, rs1748033 in PADI4, rs2057094, and rs2076615 in PADI2 are associated with RA susceptibility. In conclusion, in RA patients, single nucleotide variants in PADI4 and PADI2 are associated with ILD susceptibility. The rs1748033 in PADI4 and two different SNVs in PADI2 are associated with RA development but not ILD. PAD4 serum levels are increased in RA-ILD patients. [ABSTRACT FROM AUTHOR]