Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients

Judith A. James, Hua Chen, Kendra A. Young, Elizabeth A. Bemis, Jennifer Seifert, Rebecka L. Bourn, Kevin D. Deane, M. Kristen Demoruelle, Marie Feser, James R. O'Dell, Michael H. Weisman, Richard M. Keating, Patrick M. Gaffney, Jennifer A. Kelly, Carl D. Langefeld, John B. Harley, William Robinson, David A. Hafler, Kevin C. O'Connor, Jane BucknerJoel M. Guthridge, Jill M. Norris, V. Michael Holers

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs)of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321)from disease-specific autoantibody-positive (aAb+)systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D)patients; and unaffected aAb+ and autoantibody-negative (aAb–)SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS)were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56%)and FDRs (57·4%), RA patients (32·6%)and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR]2·44)and expanded (OR 3·27)autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE)and organ-specific (T1D)autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

Original languageEnglish (US)
Pages (from-to)76-85
Number of pages10
JournalEBioMedicine
Volume42
DOIs
StatePublished - Apr 2019

Fingerprint

Autoimmunity
Systemic Lupus Erythematosus
Rheumatoid Arthritis
Autoantibodies
Medical problems
Type 1 Diabetes Mellitus
Odds Ratio
Autoimmune Diseases
Cardiolipins
Environmental Exposure
Cross-Sectional Studies

Keywords

  • Autoantibodies
  • Genetic risk
  • Lupus
  • Relatives
  • Rheumatoid arthritis
  • Type I diabetes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

James, J. A., Chen, H., Young, K. A., Bemis, E. A., Seifert, J., Bourn, R. L., ... Holers, V. M. (2019). Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. EBioMedicine, 42, 76-85. https://doi.org/10.1016/j.ebiom.2019.03.063

Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. / James, Judith A.; Chen, Hua; Young, Kendra A.; Bemis, Elizabeth A.; Seifert, Jennifer; Bourn, Rebecka L.; Deane, Kevin D.; Demoruelle, M. Kristen; Feser, Marie; O'Dell, James R.; Weisman, Michael H.; Keating, Richard M.; Gaffney, Patrick M.; Kelly, Jennifer A.; Langefeld, Carl D.; Harley, John B.; Robinson, William; Hafler, David A.; O'Connor, Kevin C.; Buckner, Jane; Guthridge, Joel M.; Norris, Jill M.; Holers, V. Michael.

In: EBioMedicine, Vol. 42, 04.2019, p. 76-85.

Research output: Contribution to journalArticle

James, JA, Chen, H, Young, KA, Bemis, EA, Seifert, J, Bourn, RL, Deane, KD, Demoruelle, MK, Feser, M, O'Dell, JR, Weisman, MH, Keating, RM, Gaffney, PM, Kelly, JA, Langefeld, CD, Harley, JB, Robinson, W, Hafler, DA, O'Connor, KC, Buckner, J, Guthridge, JM, Norris, JM & Holers, VM 2019, 'Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients', EBioMedicine, vol. 42, pp. 76-85. https://doi.org/10.1016/j.ebiom.2019.03.063
James, Judith A. ; Chen, Hua ; Young, Kendra A. ; Bemis, Elizabeth A. ; Seifert, Jennifer ; Bourn, Rebecka L. ; Deane, Kevin D. ; Demoruelle, M. Kristen ; Feser, Marie ; O'Dell, James R. ; Weisman, Michael H. ; Keating, Richard M. ; Gaffney, Patrick M. ; Kelly, Jennifer A. ; Langefeld, Carl D. ; Harley, John B. ; Robinson, William ; Hafler, David A. ; O'Connor, Kevin C. ; Buckner, Jane ; Guthridge, Joel M. ; Norris, Jill M. ; Holers, V. Michael. / Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients. In: EBioMedicine. 2019 ; Vol. 42. pp. 76-85.
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abstract = "Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs)of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321)from disease-specific autoantibody-positive (aAb+)systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D)patients; and unaffected aAb+ and autoantibody-negative (aAb–)SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS)were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56{\%})and FDRs (57·4{\%}), RA patients (32·6{\%})and FDRs (34·8{\%}), and T1D patients (43{\%}). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5{\%} of SLE patients, 16·4{\%} of SLE FDRs, 7·8{\%} of RA patients, 5·3{\%} of RA FDRs, and 10·8{\%} of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR]2·44)and expanded (OR 3·27)autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE)and organ-specific (T1D)autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.",
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author = "James, {Judith A.} and Hua Chen and Young, {Kendra A.} and Bemis, {Elizabeth A.} and Jennifer Seifert and Bourn, {Rebecka L.} and Deane, {Kevin D.} and Demoruelle, {M. Kristen} and Marie Feser and O'Dell, {James R.} and Weisman, {Michael H.} and Keating, {Richard M.} and Gaffney, {Patrick M.} and Kelly, {Jennifer A.} and Langefeld, {Carl D.} and Harley, {John B.} and William Robinson and Hafler, {David A.} and O'Connor, {Kevin C.} and Jane Buckner and Guthridge, {Joel M.} and Norris, {Jill M.} and Holers, {V. Michael}",
year = "2019",
month = "4",
doi = "10.1016/j.ebiom.2019.03.063",
language = "English (US)",
volume = "42",
pages = "76--85",
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TY - JOUR

T1 - Latent autoimmunity across disease-specific boundaries in at-risk first-degree relatives of SLE and RA patients

AU - James, Judith A.

AU - Chen, Hua

AU - Young, Kendra A.

AU - Bemis, Elizabeth A.

AU - Seifert, Jennifer

AU - Bourn, Rebecka L.

AU - Deane, Kevin D.

AU - Demoruelle, M. Kristen

AU - Feser, Marie

AU - O'Dell, James R.

AU - Weisman, Michael H.

AU - Keating, Richard M.

AU - Gaffney, Patrick M.

AU - Kelly, Jennifer A.

AU - Langefeld, Carl D.

AU - Harley, John B.

AU - Robinson, William

AU - Hafler, David A.

AU - O'Connor, Kevin C.

AU - Buckner, Jane

AU - Guthridge, Joel M.

AU - Norris, Jill M.

AU - Holers, V. Michael

PY - 2019/4

Y1 - 2019/4

N2 - Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs)of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321)from disease-specific autoantibody-positive (aAb+)systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D)patients; and unaffected aAb+ and autoantibody-negative (aAb–)SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS)were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56%)and FDRs (57·4%), RA patients (32·6%)and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR]2·44)and expanded (OR 3·27)autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE)and organ-specific (T1D)autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

AB - Background: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs)of patients, who exhibit increased future risk for the same disease. Methods: Samples (n = 1321)from disease-specific autoantibody-positive (aAb+)systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D)patients; and unaffected aAb+ and autoantibody-negative (aAb–)SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS)were calculated. Findings: Alternative autoimmunity occurred in SLE patients (56%)and FDRs (57·4%), RA patients (32·6%)and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR]2·44)and expanded (OR 3·27)autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. Interpretation: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE)and organ-specific (T1D)autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. Fund: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.

KW - Autoantibodies

KW - Genetic risk

KW - Lupus

KW - Relatives

KW - Rheumatoid arthritis

KW - Type I diabetes

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