The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

Leah C. Kottyan; Erin E. Zoller; Jessica Bene; Xiaoming Lu; Jennifer A. Kelly; Andrew M. Rupert; Christopher J. Lessard; Samuel E. Vaughn; Miranda Marion; Matthew T. Weirauch; Bahram Namjou; Adam Adler; Astrid Rasmussen; Stuart Glenn; Courtney G. Montgomery; Gideon M. Hirschfield; Gang Xie; Catalina Coltescu; Chris Amos; He Li; John A. Ice; Swapan K. Nath; Xavier Mariette; Simon Bowman; Maureen Rischmueller; Sue Lester; Johan G. Brun; Lasse G. Gøransson; Erna Harboe; Roald Omdal; Deborah S. Cunninghame-Graham; Tim Vyse; Corinne Miceli-Richard; Michael T. Brennan; James A. Lessard; Marie Wahren-Herlenius; Marika Kvarnström; Gabor G. Illei; Torsten Witte; Roland Jonsson; Per Eriksson; Gunnel Nordmark; Wan Fai Ng; Juan Manuel Anaya; Nelson L. Rhodus; Barbara M. Segal; Joan T. Merrill; Judith A. James; Joel M. Guthridge; R. Hal Scofield; Marta Alarcon-Riquelme; Sang Cheol Bae; Susan A. Boackle; Lindsey A. Criswell; Gary Gilkeson; Diane L. Kamen; Chaim O. Jacob; Robert Kimberly; Elizabeth Brown; Jeffrey Edberg; Graciela S. Alarcón; John D. Reveille; Luis M. Vilá; Michelle Petri; Rosalind Ramsey-Goldman; Barry I. Freedman; Timothy Niewold; Anne M. Stevens; Betty P. Tsao; Jun Ying; Maureen D. Mayes; Olga Y. Gorlova; Ward Wakeland; Timothy Radstake; Ezequiel Martin; Javier Martin; Katherine Siminovitch; Kathy L. Moser Sivils; Patrick M. Gaffney; Carl D. Langefeld; John B. Harley; Kenneth M. Kaufman

doi:10.1093/hmg/ddu455

The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

Leah C. Kottyan^*, Erin E. Zoller, Jessica Bene, Xiaoming Lu, Jennifer A. Kelly, Andrew M. Rupert, Christopher J. Lessard, Samuel E. Vaughn, Miranda Marion, Matthew T. Weirauch, Bahram Namjou, Adam Adler, Astrid Rasmussen, Stuart Glenn, Courtney G. Montgomery, Gideon M. Hirschfield, Gang Xie, Catalina Coltescu, Chris Amos, He LiJohn A. Ice, Swapan K. Nath, Xavier Mariette, Simon Bowman, Maureen Rischmueller, Sue Lester, Johan G. Brun, Lasse G. Gøransson, Erna Harboe, Roald Omdal, Deborah S. Cunninghame-Graham, Tim Vyse, Corinne Miceli-Richard, Michael T. Brennan, James A. Lessard, Marie Wahren-Herlenius, Marika Kvarnström, Gabor G. Illei, Torsten Witte, Roland Jonsson, Per Eriksson, Gunnel Nordmark, Wan Fai Ng, Juan Manuel Anaya, Nelson L. Rhodus, Barbara M. Segal, Joan T. Merrill, Judith A. James, Joel M. Guthridge, R. Hal Scofield, Marta Alarcon-Riquelme, Sang Cheol Bae, Susan A. Boackle, Lindsey A. Criswell, Gary Gilkeson, Diane L. Kamen, Chaim O. Jacob, Robert Kimberly, Elizabeth Brown, Jeffrey Edberg, Graciela S. Alarcón, John D. Reveille, Luis M. Vilá, Michelle Petri, Rosalind Ramsey-Goldman, Barry I. Freedman, Timothy Niewold, Anne M. Stevens, Betty P. Tsao, Jun Ying, Maureen D. Mayes, Olga Y. Gorlova, Ward Wakeland, Timothy Radstake, Ezequiel Martin, Javier Martin, Katherine Siminovitch, Kathy L. Moser Sivils, Patrick M. Gaffney, Carl D. Langefeld, John B. Harley, Kenneth M. Kaufman

^*Corresponding author for this work

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Abstract

Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-value_meta = 6 × 10^-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-values_EU = 10^-27-10^-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

Original language	English
Pages (from-to)	582-596
Number of pages	15
Journal	Human Molecular Genetics
Volume	24
Issue number	2
DOIs	https://doi.org/10.1093/hmg/ddu455
Publication status	Published - 8 Sept 2014

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Kottyan, L. C., Zoller, E. E., Bene, J., Lu, X., Kelly, J. A., Rupert, A. M., Lessard, C. J., Vaughn, S. E., Marion, M., Weirauch, M. T., Namjou, B., Adler, A., Rasmussen, A., Glenn, S., Montgomery, C. G., Hirschfield, G. M., Xie, G., Coltescu, C., Amos, C., ... Kaufman, K. M. (2014). The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share. Human Molecular Genetics, 24(2), 582-596. https://doi.org/10.1093/hmg/ddu455

@article{a59b7b85626f487f93e250072331704d,

title = "The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share",

abstract = "Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-valuesEU = 10-27-10-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sj{\"o}gren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.",

author = "Kottyan, {Leah C.} and Zoller, {Erin E.} and Jessica Bene and Xiaoming Lu and Kelly, {Jennifer A.} and Rupert, {Andrew M.} and Lessard, {Christopher J.} and Vaughn, {Samuel E.} and Miranda Marion and Weirauch, {Matthew T.} and Bahram Namjou and Adam Adler and Astrid Rasmussen and Stuart Glenn and Montgomery, {Courtney G.} and Hirschfield, {Gideon M.} and Gang Xie and Catalina Coltescu and Chris Amos and He Li and Ice, {John A.} and Nath, {Swapan K.} and Xavier Mariette and Simon Bowman and Maureen Rischmueller and Sue Lester and Brun, {Johan G.} and G{\o}ransson, {Lasse G.} and Erna Harboe and Roald Omdal and Cunninghame-Graham, {Deborah S.} and Tim Vyse and Corinne Miceli-Richard and Brennan, {Michael T.} and Lessard, {James A.} and Marie Wahren-Herlenius and Marika Kvarnstr{\"o}m and Illei, {Gabor G.} and Torsten Witte and Roland Jonsson and Per Eriksson and Gunnel Nordmark and Ng, {Wan Fai} and Anaya, {Juan Manuel} and Rhodus, {Nelson L.} and Segal, {Barbara M.} and Merrill, {Joan T.} and James, {Judith A.} and Guthridge, {Joel M.} and Scofield, {R. Hal} and Marta Alarcon-Riquelme and Bae, {Sang Cheol} and Boackle, {Susan A.} and Criswell, {Lindsey A.} and Gary Gilkeson and Kamen, {Diane L.} and Jacob, {Chaim O.} and Robert Kimberly and Elizabeth Brown and Jeffrey Edberg and Alarc{\'o}n, {Graciela S.} and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Michelle Petri and Rosalind Ramsey-Goldman and Freedman, {Barry I.} and Timothy Niewold and Stevens, {Anne M.} and Tsao, {Betty P.} and Jun Ying and Mayes, {Maureen D.} and Gorlova, {Olga Y.} and Ward Wakeland and Timothy Radstake and Ezequiel Martin and Javier Martin and Katherine Siminovitch and {Moser Sivils}, {Kathy L.} and Gaffney, {Patrick M.} and Langefeld, {Carl D.} and Harley, {John B.} and Kaufman, {Kenneth M.}",

year = "2014",

month = sep,

day = "8",

doi = "10.1093/hmg/ddu455",

language = "English",

volume = "24",

pages = "582--596",

journal = "Human Molecular Genetics",

issn = "0964-6906",

publisher = "Oxford University Press",

number = "2",

}

Kottyan, LC, Zoller, EE, Bene, J, Lu, X, Kelly, JA, Rupert, AM, Lessard, CJ, Vaughn, SE, Marion, M, Weirauch, MT, Namjou, B, Adler, A, Rasmussen, A, Glenn, S, Montgomery, CG, Hirschfield, GM, Xie, G, Coltescu, C, Amos, C, Li, H, Ice, JA, Nath, SK, Mariette, X, Bowman, S, Rischmueller, M, Lester, S, Brun, JG, Gøransson, LG, Harboe, E, Omdal, R, Cunninghame-Graham, DS, Vyse, T, Miceli-Richard, C, Brennan, MT, Lessard, JA, Wahren-Herlenius, M, Kvarnström, M, Illei, GG, Witte, T, Jonsson, R, Eriksson, P, Nordmark, G, Ng, WF, Anaya, JM, Rhodus, NL, Segal, BM, Merrill, JT, James, JA, Guthridge, JM, Scofield, RH, Alarcon-Riquelme, M, Bae, SC, Boackle, SA, Criswell, LA, Gilkeson, G, Kamen, DL, Jacob, CO, Kimberly, R, Brown, E, Edberg, J, Alarcón, GS, Reveille, JD, Vilá, LM, Petri, M, Ramsey-Goldman, R, Freedman, BI, Niewold, T, Stevens, AM, Tsao, BP, Ying, J, Mayes, MD, Gorlova, OY, Wakeland, W, Radstake, T, Martin, E, Martin, J, Siminovitch, K, Moser Sivils, KL, Gaffney, PM, Langefeld, CD, Harley, JB & Kaufman, KM 2014, 'The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share', Human Molecular Genetics, vol. 24, no. 2, pp. 582-596. https://doi.org/10.1093/hmg/ddu455

TY - JOUR

T1 - The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

AU - Kottyan, Leah C.

AU - Zoller, Erin E.

AU - Bene, Jessica

AU - Lu, Xiaoming

AU - Kelly, Jennifer A.

AU - Rupert, Andrew M.

AU - Lessard, Christopher J.

AU - Vaughn, Samuel E.

AU - Marion, Miranda

AU - Weirauch, Matthew T.

AU - Namjou, Bahram

AU - Adler, Adam

AU - Rasmussen, Astrid

AU - Glenn, Stuart

AU - Montgomery, Courtney G.

AU - Hirschfield, Gideon M.

AU - Xie, Gang

AU - Coltescu, Catalina

AU - Amos, Chris

AU - Li, He

AU - Ice, John A.

AU - Nath, Swapan K.

AU - Mariette, Xavier

AU - Bowman, Simon

AU - Rischmueller, Maureen

AU - Lester, Sue

AU - Brun, Johan G.

AU - Gøransson, Lasse G.

AU - Harboe, Erna

AU - Omdal, Roald

AU - Cunninghame-Graham, Deborah S.

AU - Vyse, Tim

AU - Miceli-Richard, Corinne

AU - Brennan, Michael T.

AU - Lessard, James A.

AU - Wahren-Herlenius, Marie

AU - Kvarnström, Marika

AU - Illei, Gabor G.

AU - Witte, Torsten

AU - Jonsson, Roland

AU - Eriksson, Per

AU - Nordmark, Gunnel

AU - Ng, Wan Fai

AU - Anaya, Juan Manuel

AU - Rhodus, Nelson L.

AU - Segal, Barbara M.

AU - Merrill, Joan T.

AU - James, Judith A.

AU - Guthridge, Joel M.

AU - Scofield, R. Hal

AU - Alarcon-Riquelme, Marta

AU - Bae, Sang Cheol

AU - Boackle, Susan A.

AU - Criswell, Lindsey A.

AU - Gilkeson, Gary

AU - Kamen, Diane L.

AU - Jacob, Chaim O.

AU - Kimberly, Robert

AU - Brown, Elizabeth

AU - Edberg, Jeffrey

AU - Alarcón, Graciela S.

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Petri, Michelle

AU - Ramsey-Goldman, Rosalind

AU - Freedman, Barry I.

AU - Niewold, Timothy

AU - Stevens, Anne M.

AU - Tsao, Betty P.

AU - Ying, Jun

AU - Mayes, Maureen D.

AU - Gorlova, Olga Y.

AU - Wakeland, Ward

AU - Radstake, Timothy

AU - Martin, Ezequiel

AU - Martin, Javier

AU - Siminovitch, Katherine

AU - Moser Sivils, Kathy L.

AU - Gaffney, Patrick M.

AU - Langefeld, Carl D.

AU - Harley, John B.

AU - Kaufman, Kenneth M.

PY - 2014/9/8

Y1 - 2014/9/8

N2 - Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-valuesEU = 10-27-10-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

AB - Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10-49; OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3(P-valuesEU = 10-27-10-32, OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credibleset of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögren's syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.

UR - http://www.scopus.com/inward/record.url?scp=84922444783&partnerID=8YFLogxK

U2 - 10.1093/hmg/ddu455

DO - 10.1093/hmg/ddu455

M3 - Article

AN - SCOPUS:84922444783

SN - 0964-6906

VL - 24

SP - 582

EP - 596

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

ER -

The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share

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