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

被引：84

作者：

Deng, Yun ^{[1
]}

Zhao, Jian ^{[1
]}

Sakurai, Daisuke ^{[1
]}

Kaufman, Kenneth M. ^{[2
,3
,4
]}

Edberg, Jeffrey C. ^{[5
]}

Kimberly, Robert P. ^{[5
]}

Kamen, Diane L. ^{[6
]}

Gilkeson, Gary S. ^{[6
]}

Jacob, Chaim O. ^{[7
]}

Scofield, Hal ^{[8
,9
,10
]}

Langefeld, Carl D. ^{[11
]}

Kelly, Jennifer A. ^{[8
]}

Ramsey-Goldman, Rosalind ^{[12
]}

Petri, Michelle A. ^{[13
]}

Reveille, John D. ^{[14
]}

Vila, Luis M. ^{[15
]}

Alarcon, Graciela S. ^{[5
]}

Vyse, Timothy J. ^{[16
,17
]}

Pons-Estel, Bernardo A. ^{[18
]}

Freedman, Barry I. ^{[19
]}

Gaffney, Patrick M. ^{[8
]}

Sivils, Kathy Moser ^{[8
]}

James, Judith A. ^{[8
,9
]}

Gregersen, Peter K. ^{[20
]}

Anaya, Juan-Manuel ^{[21
]}

Niewold, Timothy B. ^{[22
,23
]}

Merrill, Joan T. ^{[24
]}

Criswell, Lindsey A. ^{[25
]}

Stevens, Anne M. ^{[26
,27
]}

Boackle, Susan A. ^{[28
]}

Cantor, Rita M. ^{[29
]}

Chen, Weiling ^{[1
]}

Grossman, Jeniffer M. ^{[1
]}

Hahn, Bevra H. ^{[1
]}

Harley, John B. ^{[2
,3
,4
]}

Alarcon-Riquelme, Marta E. ^{[8
,30
]}

Brown, Elizabeth E. ^{[5
,31
]}

Tsao, Betty P. ^{[1
]}

机构：

[1] Univ Calif Los Angeles, Div Rheumatol, Los Angeles, CA 90024 USA

[2] Cincinnati Childrens Hosp Med Ctr, Div Rheumatol, Cincinnati, OH USA

[3] Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH USA

[4] US Dept Vet Affairs Med Ctr, Cincinnati, OH USA

[5] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[6] Med Univ S Carolina, Dept Med, Div Rheumatol, Charleston, SC 29425 USA

[7] Univ So Calif, Keck Sch Med, Dept Med, Los Angeles, CA 90033 USA

[8] Oklahoma Med Res Fdn, Arthrit & Clin Immunol Program, Oklahoma City, OK 73104 USA

[9] Univ Oklahoma, Hlth Sci Ctr, Dept Med, Oklahoma City, OK USA

[10] US Dept Vet Affairs Med Ctr, Oklahoma City, OK USA

[11] Wake Forest Univ Hlth Sci, Dept Biostat Sci, Wake Forest, NC USA

[12] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA

[13] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[14] Univ Texas Hlth Sci Ctr Houston, Dept Internal Med, Houston, TX USA

[15] Univ Puerto Rico, Dept Med, San Juan, PR 00936 USA

[16] Kings Coll London, Div Genet, London WC2R 2LS, England

[17] Kings Coll London, Div Mol Med & Immunol, London WC2R 2LS, England

[18] Sanatorio Parque, Dept Med, Rosario, Santa Fe, Argentina

[19] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA

[20] N Shore LIJ Hlth Syst, Robert S Boas Ctr Genom & Human Genet, Feinstein Inst Med Res, Manhasset, NY USA

[21] Univ Rosario, Ctr Autoimmune Dis Res, Bogota, Colombia

[22] Mayo Clin, Div Rheumatol, Rochester, MN USA

[23] Mayo Clin, Dept Immunol, Rochester, MN USA

[24] Oklahoma Med Res Fdn, Clin Pharmacol Program, Oklahoma City, OK 73104 USA

[25] Univ Calif San Francisco, Dept Med, Rosalind Russell Med Res Ctr Arthrit, San Francisco, CA USA

[26] Univ Washington, Dept Pediat, Div Rheumatol, Seattle, WA 98195 USA

[27] Seattle Childrens Res Inst, Ctr Immun & Immunotherapies, Seattle, WA USA

[28] Univ Colorado Denver, Div Rheumatol, Sch Med, Aurora, CO USA

[29] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA USA

[30] Pfizer Univ Granada Junta de Andalucia, Ctr Genom & Invest Oncol GENYO, Granada, Spain

[31] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA

来源：

PLOS GENETICS | 2013年 / 9卷 / 02期

基金：

美国国家卫生研究院; 新加坡国家研究基金会;

关键词：

GENOME-WIDE ASSOCIATION; IMMUNE-RESPONSES; TLR7; SUSCEPTIBILITY; POLYMORPHISMS; AUTOIMMUNITY; POPULATION; ITGAM; WOMEN; LOCI;

D O I：

10.1371/journal.pgen.1003336

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 = 6.5x10(-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 = 7.5x10(-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 (R-2 = 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 = 2.0x10(-19), OR = 1.25 [1.20-1.32]), which confers allelic effect on transcript turnover via differential binding to the epigenetic factor miR-3148.

引用

页数：11

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