Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

Harinder Manku, Carl D. Langefeld, Sandra G. Guerra, Talat H. Malik, Marta Alarcon-Riquelme, Juan Manuel Anaya, Sang Cheol Bae, Susan A. Boackle, Elizabeth E. Brown, Lindsey A. Criswell, Barry I. Freedman, Patrick M. Gaffney, Peter A. Gregersen, Joel M. Guthridge, Sang Hoon Han, John B. Harley, Chaim O. Jacob, Judith A. James, Diane L. Kamen, Kenneth M. KaufmanJennifer A. Kelly, Javier Martin, Joan T. Merrill, Kathy L. Moser, Timothy B. Niewold, So Yeon Park, Bernardo A. Pons-Estel, Amr H. Sawalha, R. Hal Scofield, Nan Shen, Anne M. Stevens, Celi Sun, Gary S. Gilkeson, Jeff C. Edberg, Robert P. Kimberly, Swapan K. Nath, Betty P. Tsao, Tim J. Vyse

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.

Original languageEnglish (US)
Article numbere1003554
JournalPLoS Genetics
Volume9
Issue number7
DOIs
StatePublished - Jul 2013

Fingerprint

African American
African Americans
Haplotypes
haplotypes
allele
loci
Alleles
antibody formation
alleles
Autoantibodies
Genetic Recombination
recombination
Lymphopenia
autoimmune diseases
Linkage Disequilibrium
ethnicity
linkage disequilibrium
nationalities and ethnic groups
atherosclerosis
stroke

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Manku, H., Langefeld, C. D., Guerra, S. G., Malik, T. H., Alarcon-Riquelme, M., Anaya, J. M., ... Vyse, T. J. (2013). Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4. PLoS Genetics, 9(7), [e1003554]. https://doi.org/10.1371/journal.pgen.1003554

Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4. / Manku, Harinder; Langefeld, Carl D.; Guerra, Sandra G.; Malik, Talat H.; Alarcon-Riquelme, Marta; Anaya, Juan Manuel; Bae, Sang Cheol; Boackle, Susan A.; Brown, Elizabeth E.; Criswell, Lindsey A.; Freedman, Barry I.; Gaffney, Patrick M.; Gregersen, Peter A.; Guthridge, Joel M.; Han, Sang Hoon; Harley, John B.; Jacob, Chaim O.; James, Judith A.; Kamen, Diane L.; Kaufman, Kenneth M.; Kelly, Jennifer A.; Martin, Javier; Merrill, Joan T.; Moser, Kathy L.; Niewold, Timothy B.; Park, So Yeon; Pons-Estel, Bernardo A.; Sawalha, Amr H.; Scofield, R. Hal; Shen, Nan; Stevens, Anne M.; Sun, Celi; Gilkeson, Gary S.; Edberg, Jeff C.; Kimberly, Robert P.; Nath, Swapan K.; Tsao, Betty P.; Vyse, Tim J.

In: PLoS Genetics, Vol. 9, No. 7, e1003554, 07.2013.

Research output: Contribution to journalArticle

Manku, H, Langefeld, CD, Guerra, SG, Malik, TH, Alarcon-Riquelme, M, Anaya, JM, Bae, SC, Boackle, SA, Brown, EE, Criswell, LA, Freedman, BI, Gaffney, PM, Gregersen, PA, Guthridge, JM, Han, SH, Harley, JB, Jacob, CO, James, JA, Kamen, DL, Kaufman, KM, Kelly, JA, Martin, J, Merrill, JT, Moser, KL, Niewold, TB, Park, SY, Pons-Estel, BA, Sawalha, AH, Scofield, RH, Shen, N, Stevens, AM, Sun, C, Gilkeson, GS, Edberg, JC, Kimberly, RP, Nath, SK, Tsao, BP & Vyse, TJ 2013, 'Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4', PLoS Genetics, vol. 9, no. 7, e1003554. https://doi.org/10.1371/journal.pgen.1003554
Manku H, Langefeld CD, Guerra SG, Malik TH, Alarcon-Riquelme M, Anaya JM et al. Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4. PLoS Genetics. 2013 Jul;9(7). e1003554. https://doi.org/10.1371/journal.pgen.1003554
Manku, Harinder ; Langefeld, Carl D. ; Guerra, Sandra G. ; Malik, Talat H. ; Alarcon-Riquelme, Marta ; Anaya, Juan Manuel ; Bae, Sang Cheol ; Boackle, Susan A. ; Brown, Elizabeth E. ; Criswell, Lindsey A. ; Freedman, Barry I. ; Gaffney, Patrick M. ; Gregersen, Peter A. ; Guthridge, Joel M. ; Han, Sang Hoon ; Harley, John B. ; Jacob, Chaim O. ; James, Judith A. ; Kamen, Diane L. ; Kaufman, Kenneth M. ; Kelly, Jennifer A. ; Martin, Javier ; Merrill, Joan T. ; Moser, Kathy L. ; Niewold, Timothy B. ; Park, So Yeon ; Pons-Estel, Bernardo A. ; Sawalha, Amr H. ; Scofield, R. Hal ; Shen, Nan ; Stevens, Anne M. ; Sun, Celi ; Gilkeson, Gary S. ; Edberg, Jeff C. ; Kimberly, Robert P. ; Nath, Swapan K. ; Tsao, Betty P. ; Vyse, Tim J. / Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4. In: PLoS Genetics. 2013 ; Vol. 9, No. 7.
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abstract = "We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.",
author = "Harinder Manku and Langefeld, {Carl D.} and Guerra, {Sandra G.} and Malik, {Talat H.} and Marta Alarcon-Riquelme and Anaya, {Juan Manuel} and Bae, {Sang Cheol} and Boackle, {Susan A.} and Brown, {Elizabeth E.} and Criswell, {Lindsey A.} and Freedman, {Barry I.} and Gaffney, {Patrick M.} and Gregersen, {Peter A.} and Guthridge, {Joel M.} and Han, {Sang Hoon} and Harley, {John B.} and Jacob, {Chaim O.} and James, {Judith A.} and Kamen, {Diane L.} and Kaufman, {Kenneth M.} and Kelly, {Jennifer A.} and Javier Martin and Merrill, {Joan T.} and Moser, {Kathy L.} and Niewold, {Timothy B.} and Park, {So Yeon} and Pons-Estel, {Bernardo A.} and Sawalha, {Amr H.} and Scofield, {R. Hal} and Nan Shen and Stevens, {Anne M.} and Celi Sun and Gilkeson, {Gary S.} and Edberg, {Jeff C.} and Kimberly, {Robert P.} and Nath, {Swapan K.} and Tsao, {Betty P.} and Vyse, {Tim J.}",
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T1 - Trans-Ancestral Studies Fine Map the SLE-Susceptibility Locus TNFSF4

AU - Manku, Harinder

AU - Langefeld, Carl D.

AU - Guerra, Sandra G.

AU - Malik, Talat H.

AU - Alarcon-Riquelme, Marta

AU - Anaya, Juan Manuel

AU - Bae, Sang Cheol

AU - Boackle, Susan A.

AU - Brown, Elizabeth E.

AU - Criswell, Lindsey A.

AU - Freedman, Barry I.

AU - Gaffney, Patrick M.

AU - Gregersen, Peter A.

AU - Guthridge, Joel M.

AU - Han, Sang Hoon

AU - Harley, John B.

AU - Jacob, Chaim O.

AU - James, Judith A.

AU - Kamen, Diane L.

AU - Kaufman, Kenneth M.

AU - Kelly, Jennifer A.

AU - Martin, Javier

AU - Merrill, Joan T.

AU - Moser, Kathy L.

AU - Niewold, Timothy B.

AU - Park, So Yeon

AU - Pons-Estel, Bernardo A.

AU - Sawalha, Amr H.

AU - Scofield, R. Hal

AU - Shen, Nan

AU - Stevens, Anne M.

AU - Sun, Celi

AU - Gilkeson, Gary S.

AU - Edberg, Jeff C.

AU - Kimberly, Robert P.

AU - Nath, Swapan K.

AU - Tsao, Betty P.

AU - Vyse, Tim J.

PY - 2013/7

Y1 - 2013/7

N2 - We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.

AB - We previously established an 80 kb haplotype upstream of TNFSF4 as a susceptibility locus in the autoimmune disease SLE. SLE-associated alleles at this locus are associated with inflammatory disorders, including atherosclerosis and ischaemic stroke. In Europeans, the TNFSF4 causal variants have remained elusive due to strong linkage disequilibrium exhibited by alleles spanning the region. Using a trans-ancestral approach to fine-map the locus, utilising 17,900 SLE and control subjects including Amerindian/Hispanics (1348 cases, 717 controls), African-Americans (AA) (1529, 2048) and better powered cohorts of Europeans and East Asians, we find strong association of risk alleles in all ethnicities; the AA association replicates in African-American Gullah (152,122). The best evidence of association comes from two adjacent markers: rs2205960-T (P = 1.71×10-34, OR = 1.43[1.26-1.60]) and rs1234317-T (P = 1.16×10-28, OR = 1.38[1.24-1.54]). Inference of fine-scale recombination rates for all populations tested finds the 80 kb risk and non-risk haplotypes in all except African-Americans. In this population the decay of recombination equates to an 11 kb risk haplotype, anchored in the 5′ region proximal to TNFSF4 and tagged by rs2205960-T after 1000 Genomes phase 1 (v3) imputation. Conditional regression analyses delineate the 5′ risk signal to rs2205960-T and the independent non-risk signal to rs1234314-C. Our case-only and SLE-control cohorts demonstrate robust association of rs2205960-T with autoantibody production. The rs2205960-T is predicted to form part of a decameric motif which binds NF-κBp65 with increased affinity compared to rs2205960-G. ChIP-seq data also indicate NF-κB interaction with the DNA sequence at this position in LCL cells. Our research suggests association of rs2205960-T with SLE across multiple groups and an independent non-risk signal at rs1234314-C. rs2205960-T is associated with autoantibody production and lymphopenia. Our data confirm a global signal at TNFSF4 and a role for the expressed product at multiple stages of lymphocyte dysregulation during SLE pathogenesis. We confirm the validity of trans-ancestral mapping in a complex trait.

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