MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus

Yun Deng; Jian Zhao; Daisuke Sakurai; Kenneth M. Kaufman; Jeffrey C. Edberg; Robert P. Kimberly; Diane L. Kamen; Gary S. Gilkeson; Chaim O. Jacob; R. Hal Scofield; Carl D. Langefeld; Jennifer A. Kelly; Rosalind Ramsey-Goldman; Michelle A. Petri; John D. Reveille; Luis M. Vilá; Graciela S. Alarcón; Timothy J. Vyse; Bernardo A. Pons-Estel; Barry I. Freedman; Patrick M. Gaffney; Kathy Moser Sivils; Judith A. James; Peter K. Gregersen; Juan Manuel Anaya; Timothy B. Niewold; Joan T. Merrill; Lindsey A. Criswell; Anne M. Stevens; Susan A. Boackle; Rita M. Cantor; Weiling Chen; Jeniffer M. Grossman; Bevra H. Hahn; John B. Harley; Marta E. Alarcn-Riquelme; Elizabeth E. Brown; Betty P. Tsao

doi:10.1371/journal.pgen.1003336

MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus

Yun Deng, Jian Zhao, Daisuke Sakurai, Kenneth M. Kaufman, Jeffrey C. Edberg, Robert P. Kimberly, Diane L. Kamen, Gary S. Gilkeson, Chaim O. Jacob, R. Hal Scofield, Carl D. Langefeld, Jennifer A. Kelly, Rosalind Ramsey-Goldman, Michelle A. Petri, John D. Reveille, Luis M. Vilá, Graciela S. Alarcón, Timothy J. Vyse, Bernardo A. Pons-Estel, Barry I. FreedmanPatrick M. Gaffney, Kathy Moser Sivils, Judith A. James, Peter K. Gregersen, Juan Manuel Anaya, Timothy B. Niewold, Joan T. Merrill, Lindsey A. Criswell, Anne M. Stevens, Susan A. Boackle, Rita M. Cantor, Weiling Chen, Jeniffer M. Grossman, Bevra H. Hahn, John B. Harley, Marta E. Alarcn-Riquelme, Elizabeth E. Brown, Betty P. Tsao

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Abstract

We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10^-10, odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (P_meta = 7.5×10^-11, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R² = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (P_meta = 2.0×10^-19, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.

Original language	English (US)
Article number	e1003336
Journal	PLoS Genetics
Volume	9
Issue number	2
DOIs	https://doi.org/10.1371/journal.pgen.1003336
State	Published - Feb 2013

All Science Journal Classification (ASJC) codes

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

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Deng, Y., Zhao, J., Sakurai, D., Kaufman, K. M., Edberg, J. C., Kimberly, R. P., Kamen, D. L., Gilkeson, G. S., Jacob, C. O., Scofield, R. H., Langefeld, C. D., Kelly, J. A., Ramsey-Goldman, R., Petri, M. A., Reveille, J. D., Vilá, L. M., Alarcón, G. S., Vyse, T. J., Pons-Estel, B. A., ... Tsao, B. P. (2013). MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus. PLoS Genetics, 9(2), Article e1003336. https://doi.org/10.1371/journal.pgen.1003336

@article{18de9c11f7d64249bcdd232d9d31d9d7,

title = "MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus",

abstract = "We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10-10, odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10-11, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10-19, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.",

author = "Yun Deng and Jian Zhao and Daisuke Sakurai and Kaufman, {Kenneth M.} and Edberg, {Jeffrey C.} and Kimberly, {Robert P.} and Kamen, {Diane L.} and Gilkeson, {Gary S.} and Jacob, {Chaim O.} and Scofield, {R. Hal} and Langefeld, {Carl D.} and Kelly, {Jennifer A.} and Rosalind Ramsey-Goldman and Petri, {Michelle A.} and Reveille, {John D.} and Vil{\'a}, {Luis M.} and Alarc{\'o}n, {Graciela S.} and Vyse, {Timothy J.} and Pons-Estel, {Bernardo A.} and Freedman, {Barry I.} and Gaffney, {Patrick M.} and Sivils, {Kathy Moser} and James, {Judith A.} and Gregersen, {Peter K.} and Anaya, {Juan Manuel} and Niewold, {Timothy B.} and Merrill, {Joan T.} and Criswell, {Lindsey A.} and Stevens, {Anne M.} and Boackle, {Susan A.} and Cantor, {Rita M.} and Weiling Chen and Grossman, {Jeniffer M.} and Hahn, {Bevra H.} and Harley, {John B.} and Alarcn-Riquelme, {Marta E.} and Brown, {Elizabeth E.} and Tsao, {Betty P.}",

year = "2013",

month = feb,

doi = "10.1371/journal.pgen.1003336",

language = "English (US)",

volume = "9",

journal = "PLoS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "2",

}

Deng, Y, Zhao, J, Sakurai, D, Kaufman, KM, Edberg, JC, Kimberly, RP, Kamen, DL, Gilkeson, GS, Jacob, CO, Scofield, RH, Langefeld, CD, Kelly, JA, Ramsey-Goldman, R, Petri, MA, Reveille, JD, Vilá, LM, Alarcón, GS, Vyse, TJ, Pons-Estel, BA, Freedman, BI, Gaffney, PM, Sivils, KM, James, JA, Gregersen, PK, Anaya, JM, Niewold, TB, Merrill, JT, Criswell, LA, Stevens, AM, Boackle, SA, Cantor, RM, Chen, W, Grossman, JM, Hahn, BH, Harley, JB, Alarcn-Riquelme, ME, Brown, EE & Tsao, BP 2013, 'MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus', PLoS Genetics, vol. 9, no. 2, e1003336. https://doi.org/10.1371/journal.pgen.1003336

TY - JOUR

T1 - MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus

AU - Deng, Yun

AU - Zhao, Jian

AU - Sakurai, Daisuke

AU - Kaufman, Kenneth M.

AU - Edberg, Jeffrey C.

AU - Kimberly, Robert P.

AU - Kamen, Diane L.

AU - Gilkeson, Gary S.

AU - Jacob, Chaim O.

AU - Scofield, R. Hal

AU - Langefeld, Carl D.

AU - Kelly, Jennifer A.

AU - Ramsey-Goldman, Rosalind

AU - Petri, Michelle A.

AU - Reveille, John D.

AU - Vilá, Luis M.

AU - Alarcón, Graciela S.

AU - Vyse, Timothy J.

AU - Pons-Estel, Bernardo A.

AU - Freedman, Barry I.

AU - Gaffney, Patrick M.

AU - Sivils, Kathy Moser

AU - James, Judith A.

AU - Gregersen, Peter K.

AU - Anaya, Juan Manuel

AU - Niewold, Timothy B.

AU - Merrill, Joan T.

AU - Criswell, Lindsey A.

AU - Stevens, Anne M.

AU - Boackle, Susan A.

AU - Cantor, Rita M.

AU - Chen, Weiling

AU - Grossman, Jeniffer M.

AU - Hahn, Bevra H.

AU - Harley, John B.

AU - Alarcn-Riquelme, Marta E.

AU - Brown, Elizabeth E.

AU - Tsao, Betty P.

PY - 2013/2

Y1 - 2013/2

N2 - We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10-10, odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10-11, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10-19, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.

AB - We previously reported that the G allele of rs3853839 at 3′untranslated region (UTR) of Toll-like receptor 7 (TLR7) was associated with elevated transcript expression and increased risk for systemic lupus erythematosus (SLE) in 9,274 Eastern Asians [P = 6.5×10-10, odds ratio (OR) (95%CI) = 1.27 (1.17-1.36)]. Here, we conducted trans-ancestral fine-mapping in 13,339 subjects including European Americans, African Americans, and Amerindian/Hispanics and confirmed rs3853839 as the only variant within the TLR7-TLR8 region exhibiting consistent and independent association with SLE (Pmeta = 7.5×10-11, OR = 1.24 [1.18-1.34]). The risk G allele was associated with significantly increased levels of TLR7 mRNA and protein in peripheral blood mononuclear cells (PBMCs) and elevated luciferase activity of reporter gene in transfected cells. TLR7 3′UTR sequence bearing the non-risk C allele of rs3853839 matches a predicted binding site of microRNA-3148 (miR-3148), suggesting that this microRNA may regulate TLR7 expression. Indeed, miR-3148 levels were inversely correlated with TLR7 transcript levels in PBMCs from SLE patients and controls (R2 = 0.255, P = 0.001). Overexpression of miR-3148 in HEK-293 cells led to significant dose-dependent decrease in luciferase activity for construct driven by TLR7 3′UTR segment bearing the C allele (P = 0.0003). Compared with the G-allele construct, the C-allele construct showed greater than two-fold reduction of luciferase activity in the presence of miR-3148. Reduced modulation by miR-3148 conferred slower degradation of the risk G-allele containing TLR7 transcripts, resulting in elevated levels of gene products. These data establish rs3853839 of TLR7 as a shared risk variant of SLE in 22,613 subjects of Asian, EA, AA, and Amerindian/Hispanic ancestries (Pmeta = 2.0×10-19, OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.

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MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus

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