A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus

S. Wang, I. Adrianto, G. B. Wiley, C. J. Lessard, J. A. Kelly, A. J. Adler, S. B. Glenn, A. H. Williams, J. T. Ziegler, M. E. Comeau, M. C. Marion, B. E. Wakeland, C. Liang, K. M. Kaufman, J. M. Guthridge, M. E. Alarcón-Riquelme, G. S. Alarcón, J. M. Anaya, S. C. Bae, J. H. Kim & 29 others Y. B. Joo, S. A. Boackle, E. E. Brown, M. A. Petri, R. Ramsey-Goldman, J. D. Reveille, L. M. Vilá, L. A. Criswell, J. C. Edberg, B. I. Freedman, G. S. Gilkeson, C. O. Jacob, J. A. James, D. L. Kamen, R. P. Kimberly, J. Martin, J. T. Merrill, T. B. Niewold, B. A. Pons-Estel, R. H. Scofield, A. M. Stevens, B. P. Tsao, T. J. Vyse, C. D. Langefeld, J. B. Harley, E. K. Wakeland, K. L. Moser, C. G. Montgomery, P. M. Gaffney

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10-4). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Original languageEnglish (US)
Pages (from-to)380-387
Number of pages8
JournalGenes and Immunity
Volume13
Issue number5
DOIs
StatePublished - Jul 2012
Externally publishedYes

Fingerprint

Systemic Lupus Erythematosus
Haplotypes
Ubiquitin-Conjugating Enzymes
Genome-Wide Association Study
Autoimmunity
Autoantibodies
Autoimmune Diseases
Joints
Cell Proliferation
Inflammation
Kidney
Messenger RNA
Skin
Population
Proteins

Keywords

  • multi-ethnic association study
  • systemic lupus erythematosus
  • UBCH7 expression
  • UBE2L3

ASJC Scopus subject areas

  • Genetics(clinical)
  • Immunology
  • Genetics

Cite this

Wang, S., Adrianto, I., Wiley, G. B., Lessard, C. J., Kelly, J. A., Adler, A. J., ... Gaffney, P. M. (2012). A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes and Immunity, 13(5), 380-387. https://doi.org/10.1038/gene.2012.6

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. / Wang, S.; Adrianto, I.; Wiley, G. B.; Lessard, C. J.; Kelly, J. A.; Adler, A. J.; Glenn, S. B.; Williams, A. H.; Ziegler, J. T.; Comeau, M. E.; Marion, M. C.; Wakeland, B. E.; Liang, C.; Kaufman, K. M.; Guthridge, J. M.; Alarcón-Riquelme, M. E.; Alarcón, G. S.; Anaya, J. M.; Bae, S. C.; Kim, J. H.; Joo, Y. B.; Boackle, S. A.; Brown, E. E.; Petri, M. A.; Ramsey-Goldman, R.; Reveille, J. D.; Vilá, L. M.; Criswell, L. A.; Edberg, J. C.; Freedman, B. I.; Gilkeson, G. S.; Jacob, C. O.; James, J. A.; Kamen, D. L.; Kimberly, R. P.; Martin, J.; Merrill, J. T.; Niewold, T. B.; Pons-Estel, B. A.; Scofield, R. H.; Stevens, A. M.; Tsao, B. P.; Vyse, T. J.; Langefeld, C. D.; Harley, J. B.; Wakeland, E. K.; Moser, K. L.; Montgomery, C. G.; Gaffney, P. M.

In: Genes and Immunity, Vol. 13, No. 5, 07.2012, p. 380-387.

Research output: Contribution to journalArticle

Wang, S, Adrianto, I, Wiley, GB, Lessard, CJ, Kelly, JA, Adler, AJ, Glenn, SB, Williams, AH, Ziegler, JT, Comeau, ME, Marion, MC, Wakeland, BE, Liang, C, Kaufman, KM, Guthridge, JM, Alarcón-Riquelme, ME, Alarcón, GS, Anaya, JM, Bae, SC, Kim, JH, Joo, YB, Boackle, SA, Brown, EE, Petri, MA, Ramsey-Goldman, R, Reveille, JD, Vilá, LM, Criswell, LA, Edberg, JC, Freedman, BI, Gilkeson, GS, Jacob, CO, James, JA, Kamen, DL, Kimberly, RP, Martin, J, Merrill, JT, Niewold, TB, Pons-Estel, BA, Scofield, RH, Stevens, AM, Tsao, BP, Vyse, TJ, Langefeld, CD, Harley, JB, Wakeland, EK, Moser, KL, Montgomery, CG & Gaffney, PM 2012, 'A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus', Genes and Immunity, vol. 13, no. 5, pp. 380-387. https://doi.org/10.1038/gene.2012.6
Wang S, Adrianto I, Wiley GB, Lessard CJ, Kelly JA, Adler AJ et al. A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. Genes and Immunity. 2012 Jul;13(5):380-387. https://doi.org/10.1038/gene.2012.6
Wang, S. ; Adrianto, I. ; Wiley, G. B. ; Lessard, C. J. ; Kelly, J. A. ; Adler, A. J. ; Glenn, S. B. ; Williams, A. H. ; Ziegler, J. T. ; Comeau, M. E. ; Marion, M. C. ; Wakeland, B. E. ; Liang, C. ; Kaufman, K. M. ; Guthridge, J. M. ; Alarcón-Riquelme, M. E. ; Alarcón, G. S. ; Anaya, J. M. ; Bae, S. C. ; Kim, J. H. ; Joo, Y. B. ; Boackle, S. A. ; Brown, E. E. ; Petri, M. A. ; Ramsey-Goldman, R. ; Reveille, J. D. ; Vilá, L. M. ; Criswell, L. A. ; Edberg, J. C. ; Freedman, B. I. ; Gilkeson, G. S. ; Jacob, C. O. ; James, J. A. ; Kamen, D. L. ; Kimberly, R. P. ; Martin, J. ; Merrill, J. T. ; Niewold, T. B. ; Pons-Estel, B. A. ; Scofield, R. H. ; Stevens, A. M. ; Tsao, B. P. ; Vyse, T. J. ; Langefeld, C. D. ; Harley, J. B. ; Wakeland, E. K. ; Moser, K. L. ; Montgomery, C. G. ; Gaffney, P. M. / A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus. In: Genes and Immunity. 2012 ; Vol. 13, No. 5. pp. 380-387.
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abstract = "Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10-4). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.",
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AU - Adrianto, I.

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AU - Kelly, J. A.

AU - Adler, A. J.

AU - Glenn, S. B.

AU - Williams, A. H.

AU - Ziegler, J. T.

AU - Comeau, M. E.

AU - Marion, M. C.

AU - Wakeland, B. E.

AU - Liang, C.

AU - Kaufman, K. M.

AU - Guthridge, J. M.

AU - Alarcón-Riquelme, M. E.

AU - Alarcón, G. S.

AU - Anaya, J. M.

AU - Bae, S. C.

AU - Kim, J. H.

AU - Joo, Y. B.

AU - Boackle, S. A.

AU - Brown, E. E.

AU - Petri, M. A.

AU - Ramsey-Goldman, R.

AU - Reveille, J. D.

AU - Vilá, L. M.

AU - Criswell, L. A.

AU - Edberg, J. C.

AU - Freedman, B. I.

AU - Gilkeson, G. S.

AU - Jacob, C. O.

AU - James, J. A.

AU - Kamen, D. L.

AU - Kimberly, R. P.

AU - Martin, J.

AU - Merrill, J. T.

AU - Niewold, T. B.

AU - Pons-Estel, B. A.

AU - Scofield, R. H.

AU - Stevens, A. M.

AU - Tsao, B. P.

AU - Vyse, T. J.

AU - Langefeld, C. D.

AU - Harley, J. B.

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N2 - Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10-4). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

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KW - systemic lupus erythematosus

KW - UBCH7 expression

KW - UBE2L3

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