Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

Yun Deng, Jian Zhao, Daisuke Sakurai, Andrea L. Sestak, Vadim Osadchiy, Carl D. Langefeld, Kenneth M. Kaufman, Jennifer A. Kelly, Judith A. James, Michelle A. Petri, Sang Cheol Bae, Marta E. Alarcón-Riquelme, Graciela S. Alarcón, Juan Manuel Anaya, Lindsey A. Criswell, Barry I. Freedman, Diane L. Kamen, Gary S. Gilkeson, Chaim O. Jacob, Joan T. MerrillPatrick M. Gaffney, Kathy Moser Sivils, Timothy B. Niewold, Rosalind Ramsey-Goldman, John D. Reveille, R. Hal Scofield, Anne M. Stevens, Susan A. Boackle, Luis M. Vilá, I. I Woong Sohn, Seung Lee, Deh Ming Chang, Yeong Wook Song, Timothy J. Vyse, John B. Harley, Elizabeth E. Brown, Jeffrey C. Edberg, Robert P. Kimberly, Rita M. Cantor, Bevra H. Hahn, Jennifer M. Grossman, Betty P. Tsao

Resultado de la investigación: Contribución a RevistaArtículo

7 Citas (Scopus)

Resumen

Objectives Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150a €...kb flanking regions containing NMNAT2 and SMG7 in a 15a €...292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 a '8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 a '3 and 6.8×10 a '8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=a '0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 a '5 and 2.0×10 a '4, respectively). Conclusion We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

Idioma originalEnglish (US)
Páginas (desde-hasta)2007-2013
Número de páginas7
PublicaciónAnnals of the Rheumatic Diseases
Volumen75
N.º11
DOI
EstadoPublished - nov 1 2016

Huella dactilar

Antinuclear Antibodies
Systemic Lupus Erythematosus
Antibody Formation
Messenger RNA
Blood
Blood Cells
Alleles
Nonsense Mediated mRNA Decay
CC Chemokines
Ribonucleoproteins
Autoantigens
Transcription
Luciferases
Chemokines
HEK293 Cells
Genetic Promoter Regions
Quantitative Trait Loci
Genome-Wide Association Study
Linkage Disequilibrium
Small Interfering RNA

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Rheumatology
  • Immunology
  • Biochemistry, Genetics and Molecular Biology(all)

Citar esto

Deng, Y., Zhao, J., Sakurai, D., Sestak, A. L., Osadchiy, V., Langefeld, C. D., ... Tsao, B. P. (2016). Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. Annals of the Rheumatic Diseases, 75(11), 2007-2013. https://doi.org/10.1136/annrheumdis-2015-208441
Deng, Yun ; Zhao, Jian ; Sakurai, Daisuke ; Sestak, Andrea L. ; Osadchiy, Vadim ; Langefeld, Carl D. ; Kaufman, Kenneth M. ; Kelly, Jennifer A. ; James, Judith A. ; Petri, Michelle A. ; Bae, Sang Cheol ; Alarcón-Riquelme, Marta E. ; Alarcón, Graciela S. ; Anaya, Juan Manuel ; Criswell, Lindsey A. ; Freedman, Barry I. ; Kamen, Diane L. ; Gilkeson, Gary S. ; Jacob, Chaim O. ; Merrill, Joan T. ; Gaffney, Patrick M. ; Sivils, Kathy Moser ; Niewold, Timothy B. ; Ramsey-Goldman, Rosalind ; Reveille, John D. ; Scofield, R. Hal ; Stevens, Anne M. ; Boackle, Susan A. ; Vilá, Luis M. ; Sohn, I. I Woong ; Lee, Seung ; Chang, Deh Ming ; Song, Yeong Wook ; Vyse, Timothy J. ; Harley, John B. ; Brown, Elizabeth E. ; Edberg, Jeffrey C. ; Kimberly, Robert P. ; Cantor, Rita M. ; Hahn, Bevra H. ; Grossman, Jennifer M. ; Tsao, Betty P. / Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. En: Annals of the Rheumatic Diseases. 2016 ; Vol. 75, N.º 11. pp. 2007-2013.
@article{8e9f6745e62d423db16f3c7ca20d0f86,
title = "Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production",
abstract = "Objectives Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150a €...kb flanking regions containing NMNAT2 and SMG7 in a 15a €...292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 a '8, OR=1.23 (95{\%} CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 a '3 and 6.8×10 a '8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=a '0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 a '5 and 2.0×10 a '4, respectively). Conclusion We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.",
author = "Yun Deng and Jian Zhao and Daisuke Sakurai and Sestak, {Andrea L.} and Vadim Osadchiy and Langefeld, {Carl D.} and Kaufman, {Kenneth M.} and Kelly, {Jennifer A.} and James, {Judith A.} and Petri, {Michelle A.} and Bae, {Sang Cheol} and Alarc{\'o}n-Riquelme, {Marta E.} and Alarc{\'o}n, {Graciela S.} and Anaya, {Juan Manuel} and Criswell, {Lindsey A.} and Freedman, {Barry I.} and Kamen, {Diane L.} and Gilkeson, {Gary S.} and Jacob, {Chaim O.} and Merrill, {Joan T.} and Gaffney, {Patrick M.} and Sivils, {Kathy Moser} and Niewold, {Timothy B.} and Rosalind Ramsey-Goldman and Reveille, {John D.} and Scofield, {R. Hal} and Stevens, {Anne M.} and Boackle, {Susan A.} and Vil{\'a}, {Luis M.} and Sohn, {I. I Woong} and Seung Lee and Chang, {Deh Ming} and Song, {Yeong Wook} and Vyse, {Timothy J.} and Harley, {John B.} and Brown, {Elizabeth E.} and Edberg, {Jeffrey C.} and Kimberly, {Robert P.} and Cantor, {Rita M.} and Hahn, {Bevra H.} and Grossman, {Jennifer M.} and Tsao, {Betty P.}",
year = "2016",
month = "11",
day = "1",
doi = "10.1136/annrheumdis-2015-208441",
language = "English (US)",
volume = "75",
pages = "2007--2013",
journal = "Annals of the Rheumatic Diseases",
issn = "0003-4967",
publisher = "BMJ Publishing Group",
number = "11",

}

Deng, Y, Zhao, J, Sakurai, D, Sestak, AL, Osadchiy, V, Langefeld, CD, Kaufman, KM, Kelly, JA, James, JA, Petri, MA, Bae, SC, Alarcón-Riquelme, ME, Alarcón, GS, Anaya, JM, Criswell, LA, Freedman, BI, Kamen, DL, Gilkeson, GS, Jacob, CO, Merrill, JT, Gaffney, PM, Sivils, KM, Niewold, TB, Ramsey-Goldman, R, Reveille, JD, Scofield, RH, Stevens, AM, Boackle, SA, Vilá, LM, Sohn, IIW, Lee, S, Chang, DM, Song, YW, Vyse, TJ, Harley, JB, Brown, EE, Edberg, JC, Kimberly, RP, Cantor, RM, Hahn, BH, Grossman, JM & Tsao, BP 2016, 'Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production', Annals of the Rheumatic Diseases, vol. 75, n.º 11, pp. 2007-2013. https://doi.org/10.1136/annrheumdis-2015-208441

Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production. / Deng, Yun; Zhao, Jian; Sakurai, Daisuke; Sestak, Andrea L.; Osadchiy, Vadim; Langefeld, Carl D.; Kaufman, Kenneth M.; Kelly, Jennifer A.; James, Judith A.; Petri, Michelle A.; Bae, Sang Cheol; Alarcón-Riquelme, Marta E.; Alarcón, Graciela S.; Anaya, Juan Manuel; Criswell, Lindsey A.; Freedman, Barry I.; Kamen, Diane L.; Gilkeson, Gary S.; Jacob, Chaim O.; Merrill, Joan T.; Gaffney, Patrick M.; Sivils, Kathy Moser; Niewold, Timothy B.; Ramsey-Goldman, Rosalind; Reveille, John D.; Scofield, R. Hal; Stevens, Anne M.; Boackle, Susan A.; Vilá, Luis M.; Sohn, I. I Woong; Lee, Seung; Chang, Deh Ming; Song, Yeong Wook; Vyse, Timothy J.; Harley, John B.; Brown, Elizabeth E.; Edberg, Jeffrey C.; Kimberly, Robert P.; Cantor, Rita M.; Hahn, Bevra H.; Grossman, Jennifer M.; Tsao, Betty P.

En: Annals of the Rheumatic Diseases, Vol. 75, N.º 11, 01.11.2016, p. 2007-2013.

Resultado de la investigación: Contribución a RevistaArtículo

TY - JOUR

T1 - Decreased SMG7 expression associates with lupus-risk variants and elevated antinuclear antibody production

AU - Deng, Yun

AU - Zhao, Jian

AU - Sakurai, Daisuke

AU - Sestak, Andrea L.

AU - Osadchiy, Vadim

AU - Langefeld, Carl D.

AU - Kaufman, Kenneth M.

AU - Kelly, Jennifer A.

AU - James, Judith A.

AU - Petri, Michelle A.

AU - Bae, Sang Cheol

AU - Alarcón-Riquelme, Marta E.

AU - Alarcón, Graciela S.

AU - Anaya, Juan Manuel

AU - Criswell, Lindsey A.

AU - Freedman, Barry I.

AU - Kamen, Diane L.

AU - Gilkeson, Gary S.

AU - Jacob, Chaim O.

AU - Merrill, Joan T.

AU - Gaffney, Patrick M.

AU - Sivils, Kathy Moser

AU - Niewold, Timothy B.

AU - Ramsey-Goldman, Rosalind

AU - Reveille, John D.

AU - Scofield, R. Hal

AU - Stevens, Anne M.

AU - Boackle, Susan A.

AU - Vilá, Luis M.

AU - Sohn, I. I Woong

AU - Lee, Seung

AU - Chang, Deh Ming

AU - Song, Yeong Wook

AU - Vyse, Timothy J.

AU - Harley, John B.

AU - Brown, Elizabeth E.

AU - Edberg, Jeffrey C.

AU - Kimberly, Robert P.

AU - Cantor, Rita M.

AU - Hahn, Bevra H.

AU - Grossman, Jennifer M.

AU - Tsao, Betty P.

PY - 2016/11/1

Y1 - 2016/11/1

N2 - Objectives Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150a €...kb flanking regions containing NMNAT2 and SMG7 in a 15a €...292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 a '8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 a '3 and 6.8×10 a '8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=a '0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 a '5 and 2.0×10 a '4, respectively). Conclusion We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

AB - Objectives Following up the systemic lupus erythematosus (SLE) genome-wide association studies (GWAS) identification of NMNAT2 at rs2022013, we fine-mapped its 150a €...kb flanking regions containing NMNAT2 and SMG7 in a 15a €...292 case-control multi-ancestry population and tested functions of identified variants. Methods We performed genotyping using custom array, imputation by IMPUTE 2.1.2 and allele specific functions using quantitative real-time PCR and luciferase reporter transfections. SLE peripheral blood mononuclear cells (PBMCs) were cultured with small interfering RNAs to measure antinuclear antibody (ANA) and cyto/chemokine levels in supernatants using ELISA. Results We confirmed association at NMNAT2 in European American (EA) and Amerindian/Hispanic ancestries, and identified independent signal at SMG7 tagged by rs2702178 in EA only (p=2.4×10 a '8, OR=1.23 (95% CI 1.14 to 1.32)). In complete linkage disequilibrium with rs2702178, rs2275675 in the promoter region robustly associated with SMG7 mRNA levels in multiple expression quantitative trait locus (eQTL) datasets. Its risk allele was dose-dependently associated with decreased SMG7 mRNA levels in PBMCs of 86 patients with SLE and 119 controls (p=1.1×10 a '3 and 6.8×10 a '8, respectively) and conferred reduced transcription activity in transfected HEK-293 (human embryonic kidney cell line) and Raji cells (p=0.0035 and 0.0037, respectively). As a critical component in the nonsense-mediated mRNA decay pathway, SMG7 could regulate autoantigens including ribonucleoprotein (RNP) and Smith (Sm). We showed SMG7 mRNA levels in PBMCs correlated inversely with ANA titres of patients with SLE (r=a '0.31, p=0.01), and SMG7 knockdown increased levels of ANA IgG and chemokine (C-C motif) ligand 19 in SLE PBMCs (p=2.0×10 a '5 and 2.0×10 a '4, respectively). Conclusion We confirmed NMNAT2 and identified independent SMG7 association with SLE. The inverse relationship between levels of the risk allele-associated SMG7 mRNAs and ANA suggested the novel contribution of mRNA surveillance pathway to SLE pathogenesis.

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UR - http://www.scopus.com/inward/citedby.url?scp=84956688448&partnerID=8YFLogxK

U2 - 10.1136/annrheumdis-2015-208441

DO - 10.1136/annrheumdis-2015-208441

M3 - Article

C2 - 26783109

AN - SCOPUS:84956688448

VL - 75

SP - 2007

EP - 2013

JO - Annals of the Rheumatic Diseases

JF - Annals of the Rheumatic Diseases

SN - 0003-4967

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