Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases

Song, Seung Hwan; Kim, Song Soo; Kim, Ji Young; Lee, So Young; Kim, Kwang-Woo; Kwon, In Sun; Kim, Ji Na; Park, Won Hong; Yoo, In Seol; Yoo, Seung‐Min; Kim, Jin Hyun; Kang, Seong Wook; Shim, Seung Cheol

doi:10.1007/s00408-016-9916-x

Cited by 17 publications

(8 citation statements)

References 39 publications

(46 reference statements)

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“…Likewise, each SE allele may differ in their roles in RA-ILD development although their roles in ACPA positive RA development are quite in the same direction. Recently, Song et al explored polymorphisms in PADI4 and HLA-DRB1 in RA patients and found that recessive genotype of padi4_92 was associated with airway abnormalities and that tryptophan at position 9 of HLA-DRB1 amino acid sequence was strongly associated with RA-ILD in Korean patients with an odds ratio (OR) of 22.89 [ 43 ].…”

Section: Lung Involvement In Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

“…HLA-DQB1 ∗ 03:01 and HLA-DQB1 ∗ 06:01 were found as susceptibility alleles for BE in RA [ 41 , 61 ]. A polymorphism in PADI4 (recessive genotype of padi4_92) was reported to associate with the airway abnormalities in RA [ 43 ]. A small study showed that 16% of RA patients with diffuse BE were heterozygous for the delta F508 mutation of the cystic fibrosis transmembrane conductance regulator gene (CFTR) regardless of sweat chloride concentration or nasal potential difference measurements [ 62 ].…”

Section: Lung Involvement In Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

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Lung Involvements in Rheumatic Diseases: Update on the Epidemiology, Pathogenesis, Clinical Features, and Treatment

Lee

Kang

2018

BioMed Research International

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Lung illness encountered in patients with rheumatic diseases bears clinical significance in terms of increased morbidity and mortality as well as potential challenges placed on patient care. Although our understanding of natural history of this important illness is still limited, epidemiologic knowledge has been accumulated during the past decade to provide useful information on the risk factors and prognosis of lung involvements in rheumatic diseases. Moreover, the pathogenesis particularly in the context of genetics has been greatly updated for both the underlying rheumatic disease and associated lung involvement. This review will focus on the current update on the epidemiologic and genetics features and treatment options of the lung involvements associated with four major rheumatic diseases (rheumatoid arthritis, systemic sclerosis, myositis, and systemic lupus erythematosus), with more attention to a specific form of involvement or interstitial lung disease.

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Section: Lung Involvement In Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

Section: Lung Involvement In Rheumatoid Arthritis (Ra)mentioning

confidence: 99%

Lung Involvements in Rheumatic Diseases: Update on the Epidemiology, Pathogenesis, Clinical Features, and Treatment

Lee

Kang

2018

BioMed Research International

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“…The most definite function of PADI4 in human diseases is the close relationship between PADI4 gene polymorphisms and rheumatoid arthritis (RA) risk [45][46][47][48][49]. In addition, high levels of PADI4 protein are expressed in the inflamed synovium of RA patients [50][51][52][53][54][55][56].…”

Section: Padi4 and Rheumatoid Arthritismentioning

confidence: 99%

Role of citrullination modification catalyzed by peptidylarginine deiminase 4 in gene transcriptional regulation

Zhai¹,

Wang²,

Zhao³

et al. 2017

ABBS

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Peptidylarginine deiminase 4 (PADI4), a new histone modification enzyme, which converts both arginine and monomethyl-arginine to citrulline, has gained massive attention in recent years as a potential regulator of gene transcription. Recent studies have shown that arginine residues R2, R8, R17, and R26 in the H3 tail and R3 in the H4 tail can be deiminated by PADI4. This kind of histone post-translational modification has the potential to antagonize histone methylation and coordinate with histone deacetylation to regulate gene transcription. PADI4 also deiminates non-histone proteins, such as p300, NPM1, ING4, RPS2, and DNMT3A. PADI4 has been shown to involve in cell apoptosis and differentiation. Moreover, PADI4 can interact with tumor suppressor p53 and regulate the transcriptional activity of p53. Dysregulation of PADI4 is implicated in a variety of diseases, including rheumatoid arthritis, tumor development, and multiple sclerosis. A wide variety of PADI4 inhibitors have been identified. Further understanding of PADI4 functions may lead to novel diagnostic and therapeutic approaches in these diseases. This review summarizes the recent progress in the study of the regulation mechanism of PADI4 on gene transcription and the major physiological functions of PADI4 in human diseases.

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“…Among the known isoforms of PADIs [ 6 ], PADI2 and PADI4 have been previously associated with RA pathogenesis [ 7 ]. PADI4 polymorphisms leading to higher enzyme levels have been associated with RA susceptibility and HRCT abnormalities in lungs [ 8 ]. PADI4 is mainly expressed in macrophages, neutrophils, and eosinophils and triggers neutrophil extracellular traps (NETs) formation [ 9 ], whereas PADI2 is highly expressed in macrophages [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis

et al. 2017

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BackgroundIncreased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear.MethodsWe evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified.ResultsPADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA-ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs).ConclusionsThese results suggest that the citrullination pathway is upregulated in IPF and in RA-ILD.Electronic supplementary materialThe online version of this article (10.1186/s12931-017-0692-9) contains supplementary material, which is available to authorized users.

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Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases

Abstract: PADI4 polymorphisms and HLA-DRB1 alleles could attribute differently to the development of airway abnormalities and ILD, respectively, in RA.

Cited by 17 publications

References 39 publications

Lung Involvements in Rheumatic Diseases: Update on the Epidemiology, Pathogenesis, Clinical Features, and Treatment

Lung Involvements in Rheumatic Diseases: Update on the Epidemiology, Pathogenesis, Clinical Features, and Treatment

Role of citrullination modification catalyzed by peptidylarginine deiminase 4 in gene transcriptional regulation

Upregulation of citrullination pathway: From Autoimmune to Idiopathic Lung Fibrosis

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