Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus

Indra Adrianto, Shaofeng Wang, Graham B. Wiley, Christopher J. Lessard, Jennifer A. Kelly, Adam J. Adler, Stuart B. Glenn, Adrienne H. Williams, Julie T. Ziegler, Mary E. Comeau, Miranda C. Marion, Benjamin E. Wakeland, Chaoying Liang, Kenneth M. Kaufman, Joel M. Guthridge, Marta E. Alarcón-Riquelme, Graciela S. Alarcón, Juan Manuel Anaya, Sang Cheol Bae, Jae Hoon Kim & 29 others Young Bin Joo, Susan A. Boackle, Elizabeth E. Brown, Michelle Petri, Rosalind Ramsey-Goldman, John D. Reveille, Luis M. Vilá, Lindsey A. Criswell, Jeffrey C. Edberg, Barry I. Freedman, Gary S. Gilkeson, Chaim O. Jacob, Judith A. James, Diane L. Kamen, Robert P. Kimberly, Javier Martín, Joan T. Merrill, Timothy B. Niewold, Bernardo A. Pons-Estel, R. Hal Scofield, Anne M. Stevens, Betty P. Tsao, Timothy J. Vyse, Carl D. Langefeld, John B. Harley, Edward K. Wakeland, Kathy L. Moser, Courtney G. Montgomery, Patrick M. Gaffney

Research output: Contribution to journalArticle

Abstract

Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. Methods We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. Results We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

Original languageEnglish (US)
Pages (from-to)3695-3705
Number of pages11
JournalArthritis and Rheumatism
Volume64
Issue number11
DOIs
StatePublished - Nov 2012

Fingerprint

Systemic Lupus Erythematosus
Haplotypes
African Americans
Hispanic Americans
Population
Genes
Interferon Type I
Messenger RNA
Proteins
Asian Americans
Genome-Wide Association Study
Human Herpesvirus 4
Genetic Markers
Autoantibodies
Autoimmune Diseases
Reverse Transcription
Immune System
B-Lymphocytes
Western Blotting
Cell Line

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Adrianto, I., Wang, S., Wiley, G. B., Lessard, C. J., Kelly, J. A., Adler, A. J., ... Gaffney, P. M. (2012). Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. Arthritis and Rheumatism, 64(11), 3695-3705. https://doi.org/10.1002/art.34642

Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. / Adrianto, Indra; Wang, Shaofeng; Wiley, Graham B.; Lessard, Christopher J.; Kelly, Jennifer A.; Adler, Adam J.; Glenn, Stuart B.; Williams, Adrienne H.; Ziegler, Julie T.; Comeau, Mary E.; Marion, Miranda C.; Wakeland, Benjamin E.; Liang, Chaoying; Kaufman, Kenneth M.; Guthridge, Joel M.; Alarcón-Riquelme, Marta E.; Alarcón, Graciela S.; Anaya, Juan Manuel; Bae, Sang Cheol; Kim, Jae Hoon; Joo, Young Bin; Boackle, Susan A.; Brown, Elizabeth E.; Petri, Michelle; Ramsey-Goldman, Rosalind; Reveille, John D.; Vilá, Luis M.; Criswell, Lindsey A.; Edberg, Jeffrey C.; Freedman, Barry I.; Gilkeson, Gary S.; Jacob, Chaim O.; James, Judith A.; Kamen, Diane L.; Kimberly, Robert P.; Martín, Javier; Merrill, Joan T.; Niewold, Timothy B.; Pons-Estel, Bernardo A.; Scofield, R. Hal; Stevens, Anne M.; Tsao, Betty P.; Vyse, Timothy J.; Langefeld, Carl D.; Harley, John B.; Wakeland, Edward K.; Moser, Kathy L.; Montgomery, Courtney G.; Gaffney, Patrick M.

In: Arthritis and Rheumatism, Vol. 64, No. 11, 11.2012, p. 3695-3705.

Research output: Contribution to journalArticle

Adrianto, I, Wang, S, 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, M, Ramsey-Goldman, R, Reveille, JD, Vilá, LM, Criswell, LA, Edberg, JC, Freedman, BI, Gilkeson, GS, Jacob, CO, James, JA, Kamen, DL, Kimberly, RP, Martín, 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, 'Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus', Arthritis and Rheumatism, vol. 64, no. 11, pp. 3695-3705. https://doi.org/10.1002/art.34642
Adrianto, Indra ; Wang, Shaofeng ; Wiley, Graham B. ; Lessard, Christopher J. ; Kelly, Jennifer A. ; Adler, Adam J. ; Glenn, Stuart B. ; Williams, Adrienne H. ; Ziegler, Julie T. ; Comeau, Mary E. ; Marion, Miranda C. ; Wakeland, Benjamin E. ; Liang, Chaoying ; Kaufman, Kenneth M. ; Guthridge, Joel M. ; Alarcón-Riquelme, Marta E. ; Alarcón, Graciela S. ; Anaya, Juan Manuel ; Bae, Sang Cheol ; Kim, Jae Hoon ; Joo, Young Bin ; Boackle, Susan A. ; Brown, Elizabeth E. ; Petri, Michelle ; Ramsey-Goldman, Rosalind ; Reveille, John D. ; Vilá, Luis M. ; Criswell, Lindsey A. ; Edberg, Jeffrey C. ; Freedman, Barry I. ; Gilkeson, Gary S. ; Jacob, Chaim O. ; James, Judith A. ; Kamen, Diane L. ; Kimberly, Robert P. ; Martín, Javier ; Merrill, Joan T. ; Niewold, Timothy B. ; Pons-Estel, Bernardo A. ; Scofield, R. Hal ; Stevens, Anne M. ; Tsao, Betty P. ; Vyse, Timothy J. ; Langefeld, Carl D. ; Harley, John B. ; Wakeland, Edward K. ; Moser, Kathy L. ; Montgomery, Courtney G. ; Gaffney, Patrick M. / Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 11. pp. 3695-3705.
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title = "Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus",
abstract = "Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. Methods We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. Results We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.",
author = "Indra Adrianto and Shaofeng Wang and Wiley, {Graham B.} and Lessard, {Christopher J.} and Kelly, {Jennifer A.} and Adler, {Adam J.} and Glenn, {Stuart B.} and Williams, {Adrienne H.} and Ziegler, {Julie T.} and Comeau, {Mary E.} and Marion, {Miranda C.} and Wakeland, {Benjamin E.} and Chaoying Liang and Kaufman, {Kenneth M.} and Guthridge, {Joel M.} and Alarc{\'o}n-Riquelme, {Marta E.} and Alarc{\'o}n, {Graciela S.} and Anaya, {Juan Manuel} and Bae, {Sang Cheol} and Kim, {Jae Hoon} and Joo, {Young Bin} and Boackle, {Susan A.} and Brown, {Elizabeth E.} and Michelle Petri and Rosalind Ramsey-Goldman and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Criswell, {Lindsey A.} and Edberg, {Jeffrey C.} and Freedman, {Barry I.} and Gilkeson, {Gary S.} and Jacob, {Chaim O.} and James, {Judith A.} and Kamen, {Diane L.} and Kimberly, {Robert P.} and Javier Mart{\'i}n and Merrill, {Joan T.} and Niewold, {Timothy B.} and Pons-Estel, {Bernardo A.} and Scofield, {R. Hal} and Stevens, {Anne M.} and Tsao, {Betty P.} and Vyse, {Timothy J.} and Langefeld, {Carl D.} and Harley, {John B.} and Wakeland, {Edward K.} and Moser, {Kathy L.} and Montgomery, {Courtney G.} and Gaffney, {Patrick M.}",
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TY - JOUR

T1 - Association of two independent functional risk haplotypes in TNIP1 with systemic lupus erythematosus

AU - Adrianto, Indra

AU - Wang, Shaofeng

AU - Wiley, Graham B.

AU - Lessard, Christopher J.

AU - Kelly, Jennifer A.

AU - Adler, Adam J.

AU - Glenn, Stuart B.

AU - Williams, Adrienne H.

AU - Ziegler, Julie T.

AU - Comeau, Mary E.

AU - Marion, Miranda C.

AU - Wakeland, Benjamin E.

AU - Liang, Chaoying

AU - Kaufman, Kenneth M.

AU - Guthridge, Joel M.

AU - Alarcón-Riquelme, Marta E.

AU - Alarcón, Graciela S.

AU - Anaya, Juan Manuel

AU - Bae, Sang Cheol

AU - Kim, Jae Hoon

AU - Joo, Young Bin

AU - Boackle, Susan A.

AU - Brown, Elizabeth E.

AU - Petri, Michelle

AU - Ramsey-Goldman, Rosalind

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Criswell, Lindsey A.

AU - Edberg, Jeffrey C.

AU - Freedman, Barry I.

AU - Gilkeson, Gary S.

AU - Jacob, Chaim O.

AU - James, Judith A.

AU - Kamen, Diane L.

AU - Kimberly, Robert P.

AU - Martín, Javier

AU - Merrill, Joan T.

AU - Niewold, Timothy B.

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 - Wakeland, Edward K.

AU - Moser, Kathy L.

AU - Montgomery, Courtney G.

AU - Gaffney, Patrick M.

PY - 2012/11

Y1 - 2012/11

N2 - Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. Methods We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. Results We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

AB - Objective Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody production and altered type I interferon expression. Genetic surveys and genome-wide association studies have identified >30 SLE susceptibility genes. One of these genes, TNIP1, encodes the ABIN1 protein. ABIN1 functions in the immune system by restricting NF-κB signaling. The present study was undertaken to investigate the genetic factors that influence association with SLE in genes that regulate the NF-κB pathway. Methods We analyzed a dense set of genetic markers spanning TNIP1 and TAX1BP1, as well as the TNIP1 homolog TNIP2, in case-control populations of diverse ethnic origins. TNIP1, TNIP2, and TAX1BP1 were fine-mapped in a total of 8,372 SLE cases and 7,492 healthy controls from European-ancestry, African American, Hispanic, East Asian, and African American Gullah populations. Levels of TNIP1 messenger RNA (mRNA) and ABIN1 protein in Epstein-Barr virus-transformed human B cell lines were analyzed by quantitative reverse transcription-polymerase chain reaction and Western blotting, respectively. Results We found significant associations between SLE and genetic variants within TNIP1, but not in TNIP2 or TAX1BP1. After resequencing and imputation, we identified 2 independent risk haplotypes within TNIP1 in individuals of European ancestry that were also present in African American and Hispanic populations. Levels of TNIP1 mRNA and ABIN1 protein were reduced among subjects with these haplotypes, suggesting that they harbor hypomorphic functional variants that influence susceptibility to SLE by restricting ABIN1 expression. Conclusion Our results confirm the association signals between SLE and TNIP1 variants in multiple populations and provide new insight into the mechanism by which TNIP1 variants may contribute to SLE pathogenesis.

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