PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking

Massarenti, Laura; Enevold, Christian; Damgaard, Dres; Ødum, Niels; Garred, Peter; Frisch, Mørten; Shelef, Miriam A.; Jacobsen, Søren; Nielsen, Claus Henrik

doi:10.3389/fimmu.2021.707690

Cited by 14 publications

(12 citation statements)

References 49 publications

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“…Having previously established that PADI4 SNPs associate with RA in the same cohort [ 30 ], we examined whether SNPs in either PADI2 or PADI4 associated with periodontitis in the non-RA control group. None of the examined SNPs in PADI2 (rs2057094, rs2076616, rs2235912 and rs1005753) or PADI4 (rs74058715, rs11203367, rs1748033 and rs2240335) were significantly associated with periodontitis per se (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…As smoking is also regarded as an important risk factor for ACPA-positive RA in particular [ 12 , 31 ], and PADI SNPs have been suggested to interact with smoking in the pathogenesis of RA [ 30 , 32 ], we examined the associations between SNPs in PADI2 in relation to anti-CCP status and smoking status in the subgroup of patients with self-reported periodontitis.…”

Section: Resultsmentioning

confidence: 99%

“…To our knowledge, no PADI SNPs have been associated with periodontitis. We have recently demonstrated that SNPs in PADI4 contribute to the cumulative risk of anti-CCP-positive RA, particularly in individuals carrying HLA-DR4 [ 30 ]. In the present study, the association of PADI4 and PADI2 SNPs with RA in individuals with self-reported periodontitis was investigated.…”

Section: Introductionmentioning

confidence: 99%

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Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis

Massarenti

Enevold

Damgaard

et al. 2022

IJMS

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Epidemiologic studies have shown associations between periodontitis and rheumatoid arthritis (RA), but a causal relationship has not been established. Citrullination of gingival proteins by human peptidylarginine deiminases (PADs) or PAD from Porphyromonas gingivalis has been proposed to generate autoantigens in anti-CCP-positive RA. This study investigated whether the association between periodontitis and RA is influenced by single nucleotide polymorphisms (SNPs) in the genes encoding PAD2 and PAD4 that catalyze aberrant citrullination in RA and often are overexpressed in inflamed gingival connective tissue in subjects with periodontitis. The study included 137 RA patients and 161 controls with self-reported periodontitis. Periodontitis onset preceded RA onset by 13 years on average and was not associated with any of the SNPs investigated. In subjects with periodontitis, carriage of the minor alleles of rs2057094 and rs2235912 in PADI2 significantly increased the risk of RA (odds ratios 1.42 [p = 0.03] and 1.48 [p = 0.02], respectively), and this effect was driven by the anti-CCP-negative RA patients. The minor alleles of these SNPs only increased risk of anti-CCP-positive RA in individuals with periodontitis and a history of smoking. These data suggest that individuals with periodontitis carrying the minor alleles of SNPs rs2057094, rs2076616 and rs2235912 in PADI2 may be at increased risk of RA.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis

Massarenti

Enevold

Damgaard

et al. 2022

IJMS

Self Cite

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“…In addition, PADs are involved in immune cell processes implicated in autoimmunity, including neutrophil net formation (netosis) ( 62 ) and anti-PAD4 antibodies have been detected in patients with RA and are associated with disease severity ( 63 ). Also intriguing is a recent study reporting an association with PADI4 variants in Caucasian individuals who smoked and carried risk alleles for both HLA-DRB1*04 and PTPN22 ( 64 ). A potential explanation for this synergy is the discovery that PTPN22 interacts with and inhibits PAD activity, but the PTPN22 620W risk variant (rs2476601) disrupts this interaction leading to enhanced citrullination and netosis ( 65 ).…”

Section: Shared Genetic Variants Across Autoimmune Diseasementioning

confidence: 99%

Genetic basis of defects in immune tolerance underlying the development of autoimmunity

Hocking

Buckner²

2022

Front. Immunol.

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Genetic variants associated with susceptibility to autoimmune disease have provided important insight into the mechanisms responsible for the loss of immune tolerance and the subsequent development of autoantibodies, tissue damage, and onset of clinical disease. Here, we review how genetic variants shared across multiple autoimmune diseases have contributed to our understanding of global tolerance failure, focusing on variants in the human leukocyte antigen region, PTPN2 and PTPN22, and their role in antigen presentation and T and B cell homeostasis. Variants unique to a specific autoimmune disease such as those in PADI2 and PADI4 that are associated with rheumatoid arthritis are also discussed, addressing their role in disease-specific immunopathology. Current research continues to focus on determining the functional consequences of autoimmune disease-associated variants but has recently expanded to variants in the non-coding regions of the genome using novel approaches to investigate the impact of these variants on mechanisms regulating gene expression. Lastly, studying genetic risk variants in the setting of autoimmunity has clinical implications, helping predict who will develop autoimmune disease and also identifying potential therapeutic targets.

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“…43–46 ACPA-negative RA is mild, and patients with this disease are more likely to achieve drug-free remission. 47 Unlike ACPA-negative RA, ACPA-positive RA associated with a worse prognosis characterized by the higher rates of erosive damage 43 has different risk factors with most genetic associations 48–50 and environmental risks, such as smoking 51,52 and alcohol abstinence. 53,54…”

Section: Pathophysiology Of Ramentioning

confidence: 99%

Indigenous Nigeria medicinal herbal remedies: A potential source for therapeutic against rheumatoid arthritis

Arunsi

Chioma

Etusim

et al. 2022

Exp Biol Med (Maywood)

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Rheumatoid arthritis (RA) is a debilitating disease associated with locomotion impairment, and conventional therapeutic drugs are not optimal for managing RA. There is an avalanche of medications used for the management of RA. Still, studies have shown that they are associated with severe side effects, including hepatotoxicity, retinopathy, and cardiotoxicity disorders of the central nervous system (CNS), skin, blood, and infections. Complementary and alternative medicine (CAM) is currently gaining attention as a novel panacea for managing debilitating diseases, such as RA. Nigerian folk herbal remedies are replete with a plethora of curative medicine, albeit unvalidated scientifically but with seemingly miraculous provenance. Studies of the identification of bioactive compounds present in these botanicals using advanced spectral analytical techniques have enhanced our understanding of the role of Nigerian herbal remedies in the treatment and management of RA. Interestingly, experimental studies abound that the bioactive compounds present in the extracts of plant botanicals protected animals from the development of RA in different experimental models and reduced the toxicity associated with conventional therapeutics. Validated mechanisms of RA amelioration in human and animal models include suppression of the expression of NF-κB, IL-1β, TNF-α, IL-6, IL-8, IL-17, IL-23, chemokines, TGF-β, RANKL, RANK, iNOS, arginase, COX-2, VEGFA, VEGFR, NFATC1, and TRAP in the synoviocytes. Decreased ROS, NO, MDA, carbonyl groups, and PGE2 in the synovial fluid increased the expression of PPARα/γ; antioxidant and anti-inflammatory molecules also improve RA etiology. In this mini-review, we discuss the global burden of RA, the novel role of plant-based botanicals as potential therapeutics against signaling pathways in RA. Also addressed is the possible repurposing/reprofiling of plant botanicals to increase their therapeutic index among RA patients that patronize traditional healers in Nigeria with a global projection.

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PADI4 Polymorphisms Confer Risk of Anti-CCP-Positive Rheumatoid Arthritis in Synergy With HLA-DRB1*04 and Smoking

Cited by 14 publications

References 49 publications

Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis

Peptidylarginine Deiminase 2 Gene Polymorphisms in Subjects with Periodontitis Predispose to Rheumatoid Arthritis

Genetic basis of defects in immune tolerance underlying the development of autoimmunity

Indigenous Nigeria medicinal herbal remedies: A potential source for therapeutic against rheumatoid arthritis

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