Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis

Influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study

Ted R. Mikuls, Karen A. Gould, Kimberly K. Bynoté, Fang Yu, Tricia D. LeVan, Geoffrey M. Thiele, Kaleb D. Michaud, James R. O'Dell, Andreas M. Reimold, Roderick Hooker, Liron Caplan, Dannette S. Johnson, Gail Kerr, J. Steuart Richards, Grant W. Cannon, Lindsey A. Criswell, Janelle A. Noble, Louis S. Bridges, Laura Hughes, Peter K. Gregersen

Research output: Contribution to journalArticle

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Abstract

Introduction: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE).Methods: Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction.Results: A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050).Conclusions: This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.

Original languageEnglish (US)
Article numberR213
JournalArthritis Research and Therapy
Volume12
Issue number6
DOIs
StatePublished - Nov 18 2010

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HLA-DRB1 Chains
Glutathione Transferase
Epitopes
Rheumatoid Arthritis
Cross-Sectional Studies
Antibodies
Veterans
Proteins
Registries
Confidence Intervals
Odds Ratio
Autoimmunity
Oxidative Stress
Antioxidants
Genotype

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis : Influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study. / Mikuls, Ted R.; Gould, Karen A.; Bynoté, Kimberly K.; Yu, Fang; LeVan, Tricia D.; Thiele, Geoffrey M.; Michaud, Kaleb D.; O'Dell, James R.; Reimold, Andreas M.; Hooker, Roderick; Caplan, Liron; Johnson, Dannette S.; Kerr, Gail; Richards, J. Steuart; Cannon, Grant W.; Criswell, Lindsey A.; Noble, Janelle A.; Bridges, Louis S.; Hughes, Laura; Gregersen, Peter K.

In: Arthritis Research and Therapy, Vol. 12, No. 6, R213, 18.11.2010.

Research output: Contribution to journalArticle

Mikuls, TR, Gould, KA, Bynoté, KK, Yu, F, LeVan, TD, Thiele, GM, Michaud, KD, O'Dell, JR, Reimold, AM, Hooker, R, Caplan, L, Johnson, DS, Kerr, G, Richards, JS, Cannon, GW, Criswell, LA, Noble, JA, Bridges, LS, Hughes, L & Gregersen, PK 2010, 'Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: Influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study', Arthritis Research and Therapy, vol. 12, no. 6, R213. https://doi.org/10.1186/ar3190
Mikuls, Ted R. ; Gould, Karen A. ; Bynoté, Kimberly K. ; Yu, Fang ; LeVan, Tricia D. ; Thiele, Geoffrey M. ; Michaud, Kaleb D. ; O'Dell, James R. ; Reimold, Andreas M. ; Hooker, Roderick ; Caplan, Liron ; Johnson, Dannette S. ; Kerr, Gail ; Richards, J. Steuart ; Cannon, Grant W. ; Criswell, Lindsey A. ; Noble, Janelle A. ; Bridges, Louis S. ; Hughes, Laura ; Gregersen, Peter K. / Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis : Influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study. In: Arthritis Research and Therapy. 2010 ; Vol. 12, No. 6.
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title = "Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis: Influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study",
abstract = "Introduction: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE).Methods: Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction.Results: A majority of patients in the VARA registry (76{\%}) and SONORA (69{\%}) were positive for ACPA with a similar frequency of GSTM1-null (53{\%} and 52{\%}, respectively) and HLA-DRB1 SE positivity (76{\%} and 71{\%}, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80{\%}) than in SONORA (65{\%}). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95{\%} confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95{\%} CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95{\%} CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95{\%} CI, 0.00 to 0.76; P = 0.050).Conclusions: This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.",
author = "Mikuls, {Ted R.} and Gould, {Karen A.} and Bynot{\'e}, {Kimberly K.} and Fang Yu and LeVan, {Tricia D.} and Thiele, {Geoffrey M.} and Michaud, {Kaleb D.} and O'Dell, {James R.} and Reimold, {Andreas M.} and Roderick Hooker and Liron Caplan and Johnson, {Dannette S.} and Gail Kerr and Richards, {J. Steuart} and Cannon, {Grant W.} and Criswell, {Lindsey A.} and Noble, {Janelle A.} and Bridges, {Louis S.} and Laura Hughes and Gregersen, {Peter K.}",
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TY - JOUR

T1 - Anticitrullinated protein antibody (ACPA) in rheumatoid arthritis

T2 - Influence of an interaction between HLA-DRB1 shared epitope and a deletion polymorphism in glutathione s-transferase in a cross-sectional study

AU - Mikuls, Ted R.

AU - Gould, Karen A.

AU - Bynoté, Kimberly K.

AU - Yu, Fang

AU - LeVan, Tricia D.

AU - Thiele, Geoffrey M.

AU - Michaud, Kaleb D.

AU - O'Dell, James R.

AU - Reimold, Andreas M.

AU - Hooker, Roderick

AU - Caplan, Liron

AU - Johnson, Dannette S.

AU - Kerr, Gail

AU - Richards, J. Steuart

AU - Cannon, Grant W.

AU - Criswell, Lindsey A.

AU - Noble, Janelle A.

AU - Bridges, Louis S.

AU - Hughes, Laura

AU - Gregersen, Peter K.

PY - 2010/11/18

Y1 - 2010/11/18

N2 - Introduction: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE).Methods: Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction.Results: A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050).Conclusions: This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.

AB - Introduction: A deletion polymorphism in glutathione S-transferase Mu-1 (GSTM1-null) has previously been implicated to play a role in rheumatoid arthritis (RA) risk and progression, although no prior investigations have examined its associations with anticitrullinated protein antibody (ACPA) positivity. The purpose of this study was to examine the associations of GSTM1-null with ACPA positivity in RA and to assess for evidence of interaction between GSTM1 and HLA-DRB1 shared epitope (SE).Methods: Associations of GSTM1-null with ACPA positivity were examined separately in two RA cohorts, the Veterans Affairs Rheumatoid Arthritis (VARA) registry (n = 703) and the Study of New-Onset RA (SONORA; n = 610). Interactions were examined by calculating an attributable proportion (AP) due to interaction.Results: A majority of patients in the VARA registry (76%) and SONORA (69%) were positive for ACPA with a similar frequency of GSTM1-null (53% and 52%, respectively) and HLA-DRB1 SE positivity (76% and 71%, respectively). The parameter of patients who had ever smoked was more common in the VARA registry (80%) than in SONORA (65%). GSTM1-null was significantly associated with ACPA positivity in the VARA registry (odds ratio (OR), 1.45; 95% confidence interval (CI), 1.02 to 2.05), but not in SONORA (OR, 1.00; 95% CI, 0.71 to 1.42). There were significant additive interactions between GSTM1 and HLA-DRB1 SE in the VARA registry (AP, 0.49; 95% CI, 0.21 to 0.77; P < 0.001) in ACPA positivity, an interaction replicated in SONORA (AP, 0.38; 95% CI, 0.00 to 0.76; P = 0.050).Conclusions: This study is the first to show that the GSTM1-null genotype, a common genetic variant, exerts significant additive interaction with HLA-DRB1 SE on the risk of ACPA positivity in RA. Since GSTM1 has known antioxidant functions, these data suggest that oxidative stress may be important in the development of RA-specific autoimmunity in genetically susceptible individuals.

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