Background/Purpose

Rheumatoid arthritis (RA) causes a myriad of pulmonary complications, including bronchiolitis and bronchiectasis, pleuritis, and interstitial lung disease (ILD). Recently, several studies have shown the association of rheumatoid arthritis-related lung disease (RA-LD) with the high titers of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) which are the most specific serologic marker for RA. Single nucleotide polymorphisms (SNPs) in a citrullinating (or deiminating) enzyme, peptidyl arginine deiminase type IV (PADI4) have been reproducibly associated with RA susceptibility in several populations.

The aim of the present study is to investigate if the SNPs in PADI4 gene are associated with RA-LD.

Methods

A total of 103 consecutive RA patients, who satisfied the 1987 American College of Rheumatology classification criteria, were genotyped for two nonsynonymous (padi4_89 and padi4_92) and one synonymous (padi4_104) SNPs in PADI4. RA-LD was diagnosed using high-resolution computed tomography of the chest. The following data were collected from medical records: Age, sex, disease duration, smoking history, use of disease-modifying anti-rheumatic drugs (DMARDs), RF, and ACPA. We used the t-test for continuous variables and the chi-square or Fisher’s exact test for categorical variables. Multivariate logistic regression analysis was performed to assess the relationship between the SNPs in the PADI4 gene and RA-LD.

Results

Of the 103 RA patients, 8 (7.8%) had interstitial lung disease (ILD) and 33 (32.0%) had small airway disease (AD). High titers of ACPA (≥80 U/mL; p=0.022) and RF (≥ULN×3; p=0.008) were significantly associated with susceptibility to RA-LD (Table 1). SNPs and genotypes in exon-3 (padi4_92) of PADI4 showed significant association with susceptibility to RA-LD (p=0.013, p=0.004, respectively) (Table 2)(Table 3). No statistically significant differences were seen between RA patients with LD and those without LD with respect to sex, smoking history, anti-Ro antibody, and use of DMARDs.

Conclusion

Our results suggest that SNPs and genotypes in exon-3 (padi4_92) of PADI4 are associated with susceptibility to RA-LD. Further studies are warranted to clarify the mechanisms by which SNPs in the PADI4 gene affect the development of RA-LD.

Table 1 Clinical characteristics of RA patients with or without lung disease Characteristics RA-no LD (n = 69) RA-LD (n = 34) p-value      Age (yrs)†      51.77±9.25      58.50±8.26    0.001      Female      62 (89.9)      30 (88.2)    1.000      RA duration (yrs)†      10.49±7.84      7.11±7.14    0.037      Smoking history      6 (9.1)      1 (3.1)    0.421      Positive ACPA      53 (77.9)      30 (88.2)    0.208      ACPA titer (U/mL)†    204.51±201.33    300.74±201.07    0.025      High-titier ACPA      (≥80 U/mL)      40 (59.7)      28 (82.4)    0.022      Positive RF      53 (76.8)      30 (88.2)    0.168      RF titer (IU/mL)†      58.36±70.37      89.35±87.51    0.056      High-titer RF      (≥ULN×3)      20 (20.9)      19 (55.9)    0.008      Positive anti-Ro Ab      12 (18.8)      4 (11.8)    0.567      anti-Ro titer      0.71±1.39      0.53±1.27    0.520      Use of DMARDs       Biologic agents      17 (24.6)      11 (32.4)    0.408       Methotrexate      66 (95.7)      27 (79.4)    0.14       Leflunomide      7 (10.1)      4 (11.8)    1.000       Hydroxychloroquine      37 (53.6)      17 (50.0)    0.729       Sulfasalazine      5 (7.2)      2 (5.9)    1.000 Values are the number (%), †; (mean±SD). RA-LD group encompasses the interstitial lung disease (ILD) and small airway disease (AD). RA-no LD group includes RA patients without ILD or small AD. Smoking history is defined as positive for current or former smokers. In biologic agents, anti-tumor necrosis factor-α inhibitors (such as Etanercept, Adalimumab, and Golimumab), Abatacept, and Tocilizumab were included. Significance was determined by means of the independent t-test for continuous variables and the chi-square or Fisher’s exact test for categorical variables. RA, rheumatoid arthritis; ACPA, anti-citrullinated protein antibodies; RF, rheumatoid factor

Table 2 Association of the alleles of PADI4SNPs with RA-LD susceptibility SNP Allele RA-no LD RA-LD OR (95% CI)    p-value    padi4_89    A    0.52    0.61    1    0.418    G      0.48      0.39      0.749    (0.372-1.508)    padi4_92    C    0.18    0.41    1    0.004    G      0.82      0.59      0.319 (0.147-0.692)    padi4_104    C    0.61    0.67    1    0.809    T      0.39      0.33      0.914    (0.441-1.896) Values are frequency. Age, sex-adjusted odds ratios (ORs) and p values for carriers of minor susceptibility alleles versus noncarriers were calculated by multivariate logistic regression. SNP, single nucleotide polymorphism; RA, rheumatoid arthritis; 95% CI, 95% confidence interval.

Table 3 Association of PADI4SNP genotypes with RA-LD susceptibility SNP Genotype RA-no LD RA-LD OR (95% CI)    p-value    padi4_89    AA    0.25    0.39    1    0.087    AG/GG      0.75      0.61      0.429    (0.162-1.132)      padi4_92    CC    0.14    0.39    1    0.004    CG/GG      0.86      0.61      0.195    (0.065-0.589)      padi4_104    CC    0.32    0.46    1    0.081    CT/TT      0.68      0.54      0.429    (0.166-1.110)   Values are frequency. Age, sex-adjusted odds ratios (ORs) and Pvalues for carriers of minor susceptibility alleles versus noncarriers were calculated by multivariate logistic regression. SNP, single nucleotide polymorphism; RA, rheumatoid arthritis; 95% CI, 95% confidence interval.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/association-of-single-nucleotide-polymorphisms-of-padi4-gene-with-susceptibility-to-rheumatoid-arthritis-related-lung-disease/