Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

Indra Adrianto, Feng Wen, Amanda Templeton, Graham B. Wiley, Jarrod B. King, Christopher J. Lessard, Jared S. Bates, Yanqing Hu, Jennifer A. Kelly, Kenneth M. Kaufman, Joel M. Guthridge, Marta E. Alarcón-Riquelme, Juan-Manuel Anaya, Sang Cheol Bae, So-Young Bang, Susan A. Boackle, Elizabeth E. Brown, Michelle A. Petri, Caroline J. Gallant, Rosalind Ramsey-GoldmanJohn D. Reveille, Luis M Vila, Lindsey A. Criswell, Jeffrey C. Edberg, Barry I. Freedman, Peter K Gregersen, Gary S. Gilkeson, Chaim O. Jacob, Judith A. James, Diane L. Kamen, Robert P. Kimberly, Javier Martin, Joan T. Merrill, Timothy B. Niewold, So Yeon Park, Bernardo A Pons-Estel, R. Hal Scofield, Anne M. Stevens, Betty P. Tsao, Timothy J. Vyse, Carl D. Langefeld, John B. Harley, Kathy L. Moser, Carol F. Webb, Mary Beth Humphrey, Courtney Gray Montgomery, Patrick M. Gaffney, BIOLUPUS Network

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

Original languageEnglish (US)
Pages (from-to)253-8
Number of pages6
JournalNature Genetics
Volume43
Issue number3
DOIs
StatePublished - Mar 2011

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Systemic Lupus Erythematosus
Haplotypes
Odds Ratio
Nuclear Proteins
Ubiquitin
Autoimmune Diseases
Inflammation
Messenger RNA
Antibodies
Enzymes
Population
Proteins

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Adrianto, I., Wen, F., Templeton, A., Wiley, G. B., King, J. B., Lessard, C. J., ... BIOLUPUS Network (2011). Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nature Genetics, 43(3), 253-8. https://doi.org/10.1038/ng.766
Adrianto, Indra ; Wen, Feng ; Templeton, Amanda ; Wiley, Graham B. ; King, Jarrod B. ; Lessard, Christopher J. ; Bates, Jared S. ; Hu, Yanqing ; Kelly, Jennifer A. ; Kaufman, Kenneth M. ; Guthridge, Joel M. ; Alarcón-Riquelme, Marta E. ; Anaya, Juan-Manuel ; Bae, Sang Cheol ; Bang, So-Young ; Boackle, Susan A. ; Brown, Elizabeth E. ; Petri, Michelle A. ; Gallant, Caroline J. ; Ramsey-Goldman, Rosalind ; Reveille, John D. ; Vila, Luis M ; Criswell, Lindsey A. ; Edberg, Jeffrey C. ; Freedman, Barry I. ; Gregersen, Peter K ; Gilkeson, Gary S. ; Jacob, Chaim O. ; James, Judith A. ; Kamen, Diane L. ; Kimberly, Robert P. ; Martin, Javier ; Merrill, Joan T. ; Niewold, Timothy B. ; Park, So Yeon ; Pons-Estel, Bernardo A ; Scofield, R. Hal ; Stevens, Anne M. ; Tsao, Betty P. ; Vyse, Timothy J. ; Langefeld, Carl D. ; Harley, John B. ; Moser, Kathy L. ; Webb, Carol F. ; Humphrey, Mary Beth ; Montgomery, Courtney Gray ; Gaffney, Patrick M. ; BIOLUPUS Network. / Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. In: Nature Genetics. 2011 ; Vol. 43, No. 3. pp. 253-8.
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abstract = "Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.",
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Adrianto, I, Wen, F, Templeton, A, Wiley, GB, King, JB, Lessard, CJ, Bates, JS, Hu, Y, Kelly, JA, Kaufman, KM, Guthridge, JM, Alarcón-Riquelme, ME, Anaya, J-M, Bae, SC, Bang, S-Y, Boackle, SA, Brown, EE, Petri, MA, Gallant, CJ, Ramsey-Goldman, R, Reveille, JD, Vila, LM, Criswell, LA, Edberg, JC, Freedman, BI, Gregersen, PK, Gilkeson, GS, Jacob, CO, James, JA, Kamen, DL, Kimberly, RP, Martin, J, Merrill, JT, Niewold, TB, Park, SY, Pons-Estel, BA, Scofield, RH, Stevens, AM, Tsao, BP, Vyse, TJ, Langefeld, CD, Harley, JB, Moser, KL, Webb, CF, Humphrey, MB, Montgomery, CG, Gaffney, PM & BIOLUPUS Network 2011, 'Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus', Nature Genetics, vol. 43, no. 3, pp. 253-8. https://doi.org/10.1038/ng.766

Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. / Adrianto, Indra; Wen, Feng; Templeton, Amanda; Wiley, Graham B.; King, Jarrod B.; Lessard, Christopher J.; Bates, Jared S.; Hu, Yanqing; Kelly, Jennifer A.; Kaufman, Kenneth M.; Guthridge, Joel M.; Alarcón-Riquelme, Marta E.; Anaya, Juan-Manuel; Bae, Sang Cheol; Bang, So-Young; Boackle, Susan A.; Brown, Elizabeth E.; Petri, Michelle A.; Gallant, Caroline J.; Ramsey-Goldman, Rosalind; Reveille, John D.; Vila, Luis M; Criswell, Lindsey A.; Edberg, Jeffrey C.; Freedman, Barry I.; Gregersen, Peter K; Gilkeson, Gary S.; Jacob, Chaim O.; James, Judith A.; Kamen, Diane L.; Kimberly, Robert P.; Martin, Javier; Merrill, Joan T.; Niewold, Timothy B.; Park, So Yeon; Pons-Estel, Bernardo A; Scofield, R. Hal; Stevens, Anne M.; Tsao, Betty P.; Vyse, Timothy J.; Langefeld, Carl D.; Harley, John B.; Moser, Kathy L.; Webb, Carol F.; Humphrey, Mary Beth; Montgomery, Courtney Gray; Gaffney, Patrick M.; BIOLUPUS Network.

In: Nature Genetics, Vol. 43, No. 3, 03.2011, p. 253-8.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus

AU - Adrianto, Indra

AU - Wen, Feng

AU - Templeton, Amanda

AU - Wiley, Graham B.

AU - King, Jarrod B.

AU - Lessard, Christopher J.

AU - Bates, Jared S.

AU - Hu, Yanqing

AU - Kelly, Jennifer A.

AU - Kaufman, Kenneth M.

AU - Guthridge, Joel M.

AU - Alarcón-Riquelme, Marta E.

AU - Anaya, Juan-Manuel

AU - Bae, Sang Cheol

AU - Bang, So-Young

AU - Boackle, Susan A.

AU - Brown, Elizabeth E.

AU - Petri, Michelle A.

AU - Gallant, Caroline J.

AU - Ramsey-Goldman, Rosalind

AU - Reveille, John D.

AU - Vila, Luis M

AU - Criswell, Lindsey A.

AU - Edberg, Jeffrey C.

AU - Freedman, Barry I.

AU - Gregersen, Peter K

AU - Gilkeson, Gary S.

AU - Jacob, Chaim O.

AU - James, Judith A.

AU - Kamen, Diane L.

AU - Kimberly, Robert P.

AU - Martin, Javier

AU - Merrill, Joan T.

AU - Niewold, Timothy B.

AU - Park, So Yeon

AU - Pons-Estel, Bernardo A

AU - Scofield, R. Hal

AU - Stevens, Anne M.

AU - Tsao, Betty P.

AU - Vyse, Timothy J.

AU - Langefeld, Carl D.

AU - Harley, John B.

AU - Moser, Kathy L.

AU - Webb, Carol F.

AU - Humphrey, Mary Beth

AU - Montgomery, Courtney Gray

AU - Gaffney, Patrick M.

AU - BIOLUPUS Network

PY - 2011/3

Y1 - 2011/3

N2 - Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

AB - Systemic lupus erythematosus (SLE, MIM152700) is an autoimmune disease characterized by self-reactive antibodies resulting in systemic inflammation and organ failure. TNFAIP3, encoding the ubiquitin-modifying enzyme A20, is an established susceptibility locus for SLE. By fine mapping and genomic re-sequencing in ethnically diverse populations, we fully characterized the TNFAIP3 risk haplotype and identified a TT>A polymorphic dinucleotide (deletion T followed by a T to A transversion) associated with SLE in subjects of European (P = 1.58 × 10(-8), odds ratio = 1.70) and Korean (P = 8.33 × 10(-10), odds ratio = 2.54) ancestry. This variant, located in a region of high conservation and regulatory potential, bound a nuclear protein complex composed of NF-κB subunits with reduced avidity. Further, compared with the non-risk haplotype, the haplotype carrying this variant resulted in reduced TNFAIP3 mRNA and A20 protein expression. These results establish this TT>A variant as the most likely functional polymorphism responsible for the association between TNFAIP3 and SLE.

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SN - 1061-4036

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Adrianto I, Wen F, Templeton A, Wiley GB, King JB, Lessard CJ et al. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus. Nature Genetics. 2011 Mar;43(3):253-8. https://doi.org/10.1038/ng.766