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

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 (1.1...

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Main Authors:	Deng, Yun, Zhao, Jian, Sakurai, Daisuke, Kaufman, Kenneth M., Edberg, Jeffrey C., Kimberly, Robert P., Kamen, Diane L., Gilkeson, Gary S., Jacob, Chaim O., Scofield, R. Hal, Langefeld, Carl D., Kelly, Jennifer A., Ramsey-Goldman, Rosalind, Petri, Michelle A., Reveille, John D., Vilá, Luis M., Alarcón, Graciela S., Vyse, Timothy J., Pons-Estel, Bernardo A., Freedman, Barry I., Gaffney, Patrick M., Sivils, Kathy Moser, James, Judith A., Gregersen, Peter K., Anaya, Juan-Manuel, Niewold, Timothy B., Merrill, Joan T., Criswell, Lindsey A., Stevens, Anne M., Boackle, Susan A., Cantor, Rita M., Chen, Weiling, Grossman, Jeniffer M., Hahn, Bevra H., Harley, John B., Alarcόn-Riquelme, Marta E., Brown, Elizabeth E., Tsao, Betty P.
Format:	Online
Language:	English
Published:	Public Library of Science 2013
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585142/

id	pubmed-3585142
recordtype	oai_dc
spelling	pubmed-35851422013-03-06 MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus Deng, Yun Zhao, Jian Sakurai, Daisuke Kaufman, Kenneth M. Edberg, Jeffrey C. Kimberly, Robert P. Kamen, Diane L. Gilkeson, Gary S. Jacob, Chaim O. Scofield, R. Hal Langefeld, Carl D. Kelly, Jennifer A. Ramsey-Goldman, Rosalind Petri, Michelle A. Reveille, John D. Vilá, Luis M. Alarcón, Graciela S. Vyse, Timothy J. Pons-Estel, Bernardo A. Freedman, Barry I. Gaffney, Patrick M. Sivils, Kathy Moser James, Judith A. Gregersen, Peter K. Anaya, Juan-Manuel Niewold, Timothy B. Merrill, Joan T. Criswell, Lindsey A. Stevens, Anne M. Boackle, Susan A. Cantor, Rita M. Chen, Weiling Grossman, Jeniffer M. Hahn, Bevra H. Harley, John B. Alarcόn-Riquelme, Marta E. Brown, Elizabeth E. Tsao, Betty P. Research Article 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 (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. Public Library of Science 2013-02-28 /pmc/articles/PMC3585142/ /pubmed/23468661 http://dx.doi.org/10.1371/journal.pgen.1003336 Text en © 2013 Deng et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Deng, Yun Zhao, Jian Sakurai, Daisuke Kaufman, Kenneth M. Edberg, Jeffrey C. Kimberly, Robert P. Kamen, Diane L. Gilkeson, Gary S. Jacob, Chaim O. Scofield, R. Hal Langefeld, Carl D. Kelly, Jennifer A. Ramsey-Goldman, Rosalind Petri, Michelle A. Reveille, John D. Vilá, Luis M. Alarcón, Graciela S. Vyse, Timothy J. Pons-Estel, Bernardo A. Freedman, Barry I. Gaffney, Patrick M. Sivils, Kathy Moser James, Judith A. Gregersen, Peter K. Anaya, Juan-Manuel Niewold, Timothy B. Merrill, Joan T. Criswell, Lindsey A. Stevens, Anne M. Boackle, Susan A. Cantor, Rita M. Chen, Weiling Grossman, Jeniffer M. Hahn, Bevra H. Harley, John B. Alarcόn-Riquelme, Marta E. Brown, Elizabeth E. Tsao, Betty P.
spellingShingle	Deng, Yun Zhao, Jian Sakurai, Daisuke Kaufman, Kenneth M. Edberg, Jeffrey C. Kimberly, Robert P. Kamen, Diane L. Gilkeson, Gary S. Jacob, Chaim O. Scofield, R. Hal Langefeld, Carl D. Kelly, Jennifer A. Ramsey-Goldman, Rosalind Petri, Michelle A. Reveille, John D. Vilá, Luis M. Alarcón, Graciela S. Vyse, Timothy J. Pons-Estel, Bernardo A. Freedman, Barry I. Gaffney, Patrick M. Sivils, Kathy Moser James, Judith A. Gregersen, Peter K. Anaya, Juan-Manuel Niewold, Timothy B. Merrill, Joan T. Criswell, Lindsey A. Stevens, Anne M. Boackle, Susan A. Cantor, Rita M. Chen, Weiling Grossman, Jeniffer M. Hahn, Bevra H. Harley, John B. Alarcόn-Riquelme, Marta E. Brown, Elizabeth E. Tsao, Betty P. MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
author_facet	Deng, Yun Zhao, Jian Sakurai, Daisuke Kaufman, Kenneth M. Edberg, Jeffrey C. Kimberly, Robert P. Kamen, Diane L. Gilkeson, Gary S. Jacob, Chaim O. Scofield, R. Hal Langefeld, Carl D. Kelly, Jennifer A. Ramsey-Goldman, Rosalind Petri, Michelle A. Reveille, John D. Vilá, Luis M. Alarcón, Graciela S. Vyse, Timothy J. Pons-Estel, Bernardo A. Freedman, Barry I. Gaffney, Patrick M. Sivils, Kathy Moser James, Judith A. Gregersen, Peter K. Anaya, Juan-Manuel Niewold, Timothy B. Merrill, Joan T. Criswell, Lindsey A. Stevens, Anne M. Boackle, Susan A. Cantor, Rita M. Chen, Weiling Grossman, Jeniffer M. Hahn, Bevra H. Harley, John B. Alarcόn-Riquelme, Marta E. Brown, Elizabeth E. Tsao, Betty P.
author_sort	Deng, Yun
title	MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
title_short	MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
title_full	MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
title_fullStr	MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
title_full_unstemmed	MicroRNA-3148 Modulates Allelic Expression of Toll-Like Receptor 7 Variant Associated with Systemic Lupus Erythematosus
title_sort	microrna-3148 modulates allelic expression of toll-like receptor 7 variant associated with systemic lupus erythematosus
description	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 (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.
publisher	Public Library of Science
publishDate	2013
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585142/
_version_	1611958466012774400

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

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