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Abstract Number: 1613

The SLE-Associated TLR7 Variant Confers Differential Gene Expression Modulated by Microrna-3148

Yun Deng1, Jian Zhao1, Daisuke Sakurai1, Kenneth M. Kaufman2, Jeffrey C. Edberg3, Robert P. Kimberly4, Diane L. Kamen5, Gary S. Gilkeson6, Chaim O. Jacob7, Robert H. Scofield8, Carl D. Langefeld9, Jennifer A. Kelly10, Marta E. Alarcün-Riquelme on behalf of BIOLUPUS and GENLES networks11, John B. Harley2, Timothy J. Vyse12, Barry I. Freedman13, Patrick M. Gaffney14, Kathy Moser Sivils10, Judith A. James15, Timothy B. Niewold16, Rita M. Cantor17, Weiling Chen1, Bevra H. Hahn18, Elizabeth E. Brown on behalf of PROFILE4 and Betty P. Tsao19, 1Division of Rheumatology, Department of Medicine, David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA, 2Division of Rheumatology and The Center for Autoimmune Genomics & Etiology, Cincinnati Children's Hospital Medical Center; US Department of Veterans Affairs Medical Center, Cincinnati, OH, 3Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 4Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, 5Department of Medicine, Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Charleston, SC, 6Department of Medicine, Division of Rheumatology, Medical University of South Carolina, Charleston, SC, 7Division of Rheumatology, University of Southern California Keck School of Medicine, Los Angeles, CA, 8Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation; Department of Medicine, University of Oklahoma Health Sciences Center; US Department of Veterans Affairs Medical Center, Oklahoma City, OK, 9Center for Public Health Genomics and Department of Biostatistical Sciences, Wake Forest School of Medicine, Winston-Salem, NC, 10Oklahoma Medical Research Foundation, Oklahoma City, OK, 11Centro de Genómica e Investigación Oncológica (GENYO) Pfizer-Universidad de Granada-Junta de Andalucia, Granada, Spain, 12Medical & Molecular Genetics, King's College London, London, United Kingdom, 13Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, 14Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 15Arthritis & Clinical Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, 16Division of Rheumatology and Department of Immunology, Mayo Clinic, Rochester, MN, 17Department of Human Genetics, University of California Los Angeles, Los Angeles, CA, 18Rheumatology, UCLA David Geffen School of Medicine, Los Angeles, CA, 19David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords: polymorphism and systemic lupus erythematosus (SLE)

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Session Information

Title: Genetics and Genomics of Rheumatic Diseases

Session Type: Abstract Submissions (ACR)

Background/Purpose:

We established an X-linked TLR7 3’UTR SNP (rs3853839) as a risk locus for SLE in 9,274 Eastern Asians (Pcombined = 6.5×10-10). Risk-allele carriers have increased TLR7 transcripts and more pronounced IFN signature than non risk-allele carriers. The current study sought replication of SLE-associated SNP(s) in non-Asian ancestries and explored the molecular mechanism underlying the identified genetic variant that affects TLR7 expression.

Methods:

We conducted genotyping and imputation for 67-115 SNPs (varying among different ancestral backgrounds) covering ~80kb of TLR7-TLR8 region in European Americans (EA), African Americans (AA) and Hispanics enriched for the Amerindian-European admixture (HS). Each SNP was assessed for the association with SLE. Haplotype-based conditional testing was conducted to distinguish independent signals from associated SNPs and Mantel-Haenszel testing was used in the trans-ancestral meta-analysis. Association of genotype and TLR7 expression was examined using the RT-PCR, flow cytometry and reporter assays. Pyrosequencing was used to measure allelic variations in TLR7 transcript level.

Results:

Our trans-ancestral fine-mapping confirmed the TLR7 3’UTR SNP rs3853839 as the only variant in TLR7-TLR8 region exhibiting consistent and independent association with SLE (P meta = 1.7×10-10, OR [95%CI] =1.24 [1.18-1.34]) in 13,339 subjects of EA (3,936 cases vs. 3,491 controls), AA (1,679 vs. 1,934) and HS (1,492 vs. 807) ancestries. The risk G allele conferred elevated TLR7 expression in PBMCs from healthy individuals at both mRNA (P = 0.01 in men and 0.02 in women) and protein level (P = 0.009 in men and 0.038 in women). PBMCs from heterozygous women exhibited higher G/C allele ratios in TLR7 transcripts 4 hours after incubation with actinomycin D (inhibitor of transcription initiation) than with vehicle control (P = 0.04), indicating a slower degradation of the G allele-containing transcripts. The non-risk allele, but not risk-allele, was predicted to match microRNA-3148 (miR-3148) at the second base in the binding site. Transcript levels of miR-3148 and TLR7 in PBMCs from 16 SLE patients and 21 normal controls were inversely correlated (R2 = 0.255, P = 0.001), suggesting modulation of TLR7 expression by miR-3148. Overexpression of miR-3148 via transient transfection into HEK 293 cells led to more than 2-fold reduction in luciferase activity driven by the TLR7 3’UTR segment containing the non-risk allele compared to that containing the risk allele (P = 0.002).

Conclusion:

We identified and confirmed a genome-wide significant association between the TLR7 3’UTR SNP and SLE susceptibility in 22,613 subjects of Eastern Asian, European American, African American and Hispanic ancestries (P meta = 6.4×10-19, OR [95%CI] =1.26 [1.20-1.32]). Reduced modulation by miRNA-3148 conferred a slower degradation of the risk allele containing TLR7 transcripts, resulting in elevated levels of gene products and more robust type I IFN signature.


Disclosure:

Y. Deng,
None;

J. Zhao,
None;

D. Sakurai,
None;

K. M. Kaufman,
None;

J. C. Edberg,
None;

R. P. Kimberly,
None;

D. L. Kamen,
None;

G. S. Gilkeson,
None;

C. O. Jacob,
None;

R. H. Scofield,
None;

C. D. Langefeld,
None;

J. A. Kelly,
None;

M. E. Alarcün-Riquelme on behalf of BIOLUPUS and GENLES networks,
None;

J. B. Harley,
None;

T. J. Vyse,
None;

B. I. Freedman,
None;

P. M. Gaffney,
None;

K. Moser Sivils,
None;

J. A. James,
None;

T. B. Niewold,
None;

R. M. Cantor,
None;

W. Chen,
None;

B. H. Hahn,
None;

E. E. Brown on behalf of PROFILE,
None;

B. P. Tsao,
None.

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