Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production

Julio E. Molineros, Amit K. Maiti, Celi Sun, Loren L. Looger, Shizhong Han, Xana Kim-Howard, Stuart Glenn, Adam Adler, Jennifer A. Kelly, Timothy B. Niewold, Gary S. Gilkeson, Elizabeth E. Brown, Graciela S. Alarcón, Jeffrey C. Edberg, Michelle Petri, Rosalind Ramsey-Goldman, John D. Reveille, Luis M. Vilá, Barry I. Freedman, Betty P. TsaoLindsey A. Criswell, Chaim O. Jacob, Jason H. Moore, Timothy J. Vyse, Carl L. Langefeld, Joel M. Guthridge, Patrick M. Gaffney, Kathy L. Moser, R. Hal Scofield, Marta E. Alarcón-Riquelme, Scott M. Williams, Joan T. Merrill, Judith A. James, Kenneth M. Kaufman, Robert P. Kimberly, John B. Harley, Swapan K. Nath

Research output: Contribution to journalArticle

63 Citations (Scopus)

Abstract

Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10-14; odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10-7; 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10-8; 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

Original languageEnglish (US)
Article numbere1003222
JournalPLoS Genetics
Volume9
Issue number2
DOIs
StatePublished - Feb 2013

Fingerprint

lupus erythematosus
apoptosis
antibody formation
Systemic Lupus Erythematosus
Autoantibodies
African American
inflammation
African Americans
Apoptosis
Inflammation
ancestry
protein
antibody
allele
DNA
Alleles
Odds Ratio
autoantigens
alleles
nucleic acid

ASJC Scopus subject areas

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

Cite this

Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production. / Molineros, Julio E.; Maiti, Amit K.; Sun, Celi; Looger, Loren L.; Han, Shizhong; Kim-Howard, Xana; Glenn, Stuart; Adler, Adam; Kelly, Jennifer A.; Niewold, Timothy B.; Gilkeson, Gary S.; Brown, Elizabeth E.; Alarcón, Graciela S.; Edberg, Jeffrey C.; Petri, Michelle; Ramsey-Goldman, Rosalind; Reveille, John D.; Vilá, Luis M.; Freedman, Barry I.; Tsao, Betty P.; Criswell, Lindsey A.; Jacob, Chaim O.; Moore, Jason H.; Vyse, Timothy J.; Langefeld, Carl L.; Guthridge, Joel M.; Gaffney, Patrick M.; Moser, Kathy L.; Scofield, R. Hal; Alarcón-Riquelme, Marta E.; Williams, Scott M.; Merrill, Joan T.; James, Judith A.; Kaufman, Kenneth M.; Kimberly, Robert P.; Harley, John B.; Nath, Swapan K.

In: PLoS Genetics, Vol. 9, No. 2, e1003222, 02.2013.

Research output: Contribution to journalArticle

Molineros, JE, Maiti, AK, Sun, C, Looger, LL, Han, S, Kim-Howard, X, Glenn, S, Adler, A, Kelly, JA, Niewold, TB, Gilkeson, GS, Brown, EE, Alarcón, GS, Edberg, JC, Petri, M, Ramsey-Goldman, R, Reveille, JD, Vilá, LM, Freedman, BI, Tsao, BP, Criswell, LA, Jacob, CO, Moore, JH, Vyse, TJ, Langefeld, CL, Guthridge, JM, Gaffney, PM, Moser, KL, Scofield, RH, Alarcón-Riquelme, ME, Williams, SM, Merrill, JT, James, JA, Kaufman, KM, Kimberly, RP, Harley, JB & Nath, SK 2013, 'Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production', PLoS Genetics, vol. 9, no. 2, e1003222. https://doi.org/10.1371/journal.pgen.1003222
Molineros, Julio E. ; Maiti, Amit K. ; Sun, Celi ; Looger, Loren L. ; Han, Shizhong ; Kim-Howard, Xana ; Glenn, Stuart ; Adler, Adam ; Kelly, Jennifer A. ; Niewold, Timothy B. ; Gilkeson, Gary S. ; Brown, Elizabeth E. ; Alarcón, Graciela S. ; Edberg, Jeffrey C. ; Petri, Michelle ; Ramsey-Goldman, Rosalind ; Reveille, John D. ; Vilá, Luis M. ; Freedman, Barry I. ; Tsao, Betty P. ; Criswell, Lindsey A. ; Jacob, Chaim O. ; Moore, Jason H. ; Vyse, Timothy J. ; Langefeld, Carl L. ; Guthridge, Joel M. ; Gaffney, Patrick M. ; Moser, Kathy L. ; Scofield, R. Hal ; Alarcón-Riquelme, Marta E. ; Williams, Scott M. ; Merrill, Joan T. ; James, Judith A. ; Kaufman, Kenneth M. ; Kimberly, Robert P. ; Harley, John B. ; Nath, Swapan K. / Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production. In: PLoS Genetics. 2013 ; Vol. 9, No. 2.
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title = "Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production",
abstract = "Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10-14; odds ratio, 95{\%} confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10-7; 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10-8; 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.",
author = "Molineros, {Julio E.} and Maiti, {Amit K.} and Celi Sun and Looger, {Loren L.} and Shizhong Han and Xana Kim-Howard and Stuart Glenn and Adam Adler and Kelly, {Jennifer A.} and Niewold, {Timothy B.} and Gilkeson, {Gary S.} and Brown, {Elizabeth E.} and Alarc{\'o}n, {Graciela S.} and Edberg, {Jeffrey C.} and Michelle Petri and Rosalind Ramsey-Goldman and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Freedman, {Barry I.} and Tsao, {Betty P.} and Criswell, {Lindsey A.} and Jacob, {Chaim O.} and Moore, {Jason H.} and Vyse, {Timothy J.} and Langefeld, {Carl L.} and Guthridge, {Joel M.} and Gaffney, {Patrick M.} and Moser, {Kathy L.} and Scofield, {R. Hal} and Alarc{\'o}n-Riquelme, {Marta E.} and Williams, {Scott M.} and Merrill, {Joan T.} and James, {Judith A.} and Kaufman, {Kenneth M.} and Kimberly, {Robert P.} and Harley, {John B.} and Nath, {Swapan K.}",
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T1 - Admixture Mapping in Lupus Identifies Multiple Functional Variants within IFIH1 Associated with Apoptosis, Inflammation, and Autoantibody Production

AU - Molineros, Julio E.

AU - Maiti, Amit K.

AU - Sun, Celi

AU - Looger, Loren L.

AU - Han, Shizhong

AU - Kim-Howard, Xana

AU - Glenn, Stuart

AU - Adler, Adam

AU - Kelly, Jennifer A.

AU - Niewold, Timothy B.

AU - Gilkeson, Gary S.

AU - Brown, Elizabeth E.

AU - Alarcón, Graciela S.

AU - Edberg, Jeffrey C.

AU - Petri, Michelle

AU - Ramsey-Goldman, Rosalind

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Freedman, Barry I.

AU - Tsao, Betty P.

AU - Criswell, Lindsey A.

AU - Jacob, Chaim O.

AU - Moore, Jason H.

AU - Vyse, Timothy J.

AU - Langefeld, Carl L.

AU - Guthridge, Joel M.

AU - Gaffney, Patrick M.

AU - Moser, Kathy L.

AU - Scofield, R. Hal

AU - Alarcón-Riquelme, Marta E.

AU - Williams, Scott M.

AU - Merrill, Joan T.

AU - James, Judith A.

AU - Kaufman, Kenneth M.

AU - Kimberly, Robert P.

AU - Harley, John B.

AU - Nath, Swapan K.

PY - 2013/2

Y1 - 2013/2

N2 - Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10-14; odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10-7; 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10-8; 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

AB - Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease with a strong genetic component. African-Americans (AA) are at increased risk of SLE, but the genetic basis of this risk is largely unknown. To identify causal variants in SLE loci in AA, we performed admixture mapping followed by fine mapping in AA and European-Americans (EA). Through genome-wide admixture mapping in AA, we identified a strong SLE susceptibility locus at 2q22-24 (LOD = 6.28), and the admixture signal is associated with the European ancestry (ancestry risk ratio ~1.5). Large-scale genotypic analysis on 19,726 individuals of African and European ancestry revealed three independently associated variants in the IFIH1 gene: an intronic variant, rs13023380 [Pmeta = 5.20×10-14; odds ratio, 95% confidence interval = 0.82 (0.78-0.87)], and two missense variants, rs1990760 (Ala946Thr) [Pmeta = 3.08×10-7; 0.88 (0.84-0.93)] and rs10930046 (Arg460His) [Pdom = 1.16×10-8; 0.70 (0.62-0.79)]. Both missense variants produced dramatic phenotypic changes in apoptosis and inflammation-related gene expression. We experimentally validated function of the intronic SNP by DNA electrophoresis, protein identification, and in vitro protein binding assays. DNA carrying the intronic risk allele rs13023380 showed reduced binding efficiency to a cellular protein complex including nucleolin and lupus autoantigen Ku70/80, and showed reduced transcriptional activity in vivo. Thus, in SLE patients, genetic susceptibility could create a biochemical imbalance that dysregulates nucleolin, Ku70/80, or other nucleic acid regulatory proteins. This could promote antibody hypermutation and auto-antibody generation, further destabilizing the cellular network. Together with molecular modeling, our results establish a distinct role for IFIH1 in apoptosis, inflammation, and autoantibody production, and explain the molecular basis of these three risk alleles for SLE pathogenesis.

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