Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.


Association of a Functional Variant in TLR7 with Systemic Lupus Erythematosus and Rheumatoid Arthritis in Multiple Ancestries.

Deng1,  Yun, Zhao1,  Jian, Tan1,  Wenfeng, Kaufman2,  Kenneth M., Brown3,  Elizabeth E., Edberg4,  Jeffrey C., Kamen5,  Diane L.

David Geffen School of Medicine University of California Los Angeles, Los Angeles, CA
Cincinnati Children's Hospital Medical Center and the US Department of Veterans Affairs Medical Center, Cincinnati, OH
Divisions of Genetics and Molecular Medicine and Immunology, King's College London, London, United Kingdom
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
Oklahoma Medical Research Foundation and Oklahoma University Health Sciences Center, Oklahoma City, OK
Division of Allergy, Immunology and Rheumatology, Chang Gung Memorial Hospital, Taipei, Taiwan
Omaha VA and University of Nebraska, Omaha, NE
Department of Medicine, Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, MA
Marguerite Jones Harbert-Gene V. Ball, MD Professor of Medicine, and Director, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation and US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Department of Medicine and Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL
Department of Medicine, University of Alabama at Birmingham, Birmingham, AL
Medical University of SC, Charleston, SC
Division of Rheumatologyand Immunology, Medical University of South Carolina, Charleston, SC
Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
Arthritis and Clinical Immunology Research Program, Oklahoma Medical Research Foundation, US Department of Veterans Affairs Medical Center and Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK
Department of Biostatistical Sciences, Wake Forest University Health Sciences, Winston-Salem, NC

Background/Purpose:

We have established an X-linked TLR7 3'UTR SNP (rs3853839) as a risk locus for SLE in 9,274 Eastern Asians (OR = 1.27 [1.17–1.36], p= 6.5×10-10). The aim of this study was to seek replication of SLE-associated SNP(s) in 13,275 SLE case-control subjects including European Americans (EA), African Americans (AA), and Hispanics enriched for the Amerindian-European admixture (HS), to assess whether SLE-risk SNP(s) also predispose to RA in 2,877 RA subjects of EA, AA and Asian ancestries, and to explore functional consequences of disease-associated SNP(s).

Methods:

We genotyped 47 SNPs and imputed genotypes for SNPs in the HapMap Phase III and Immunochip. Each SNP was assessed for the association with SLE. Then, identified SLE-risk SNPs were genotyped and assessed for the association with RA. We performed c2 testing to identify disease-associated SNPs, and Mantel-Haenszel testing to generate a trans-ancestral meta-analysis P value. We performed RT-PCR and reporter gene assay to measure gene expression level, pyrosequencing and mRNA stability assay to measure allelic variations in mRNA level and stability.

Results:

The previously identified TLR7 3'UTR SNP (rs3853839) was the only independent variant across all 3 replication populations, exhibiting significant association with SLE below a Bonferroni-corrected P < 4.17×10-3 (Table 1). Trans-ancestral meta-analysis extended our previous finding to 13,275 subjects of EA, AA and HS ancestries (P= 3.1×10-12, OR [95%CI]=1.26 [1.18–1.34]). Additionally, the SLE-risk G allele of rs3853839 was associated with susceptibility of RA in EA and AA populations, but not in Asians (P= 1.5×10-4 in EA, 1.0×10-3 in AA, and 0.67 in Asians). Compared to the C allele, disease-associated G allele conferred elevated expression of TLR7 mRNA in PBMCs from healthy individuals of European ancestry (P= 0.01 and 0.02 for men and women respectively), and enhanced transcriptional activity in transfected HEK 293 cells (P= 0.026). Allelic specific expression confirmed a higher level of G allele-containing TLR7 transcripts in PBMCs from European heterozygote women. PBMCs from heterozygote women exhibited a higher G/C allele ratio in TLR7 transcripts after 4 hours of incubation with actinomycin D (transcriptional inhibitor) than with vehicle control (P= 0.047), suggesting a slower degradation of the G allele-containing transcripts.

Conclusion:

The G allele of TLR7 3'UTR SNP that confers elevated mRNA level through a slower degradation predisposes to SLE and RA in multiple ancestries, highlighting the importance of TLR signaling pathway in the pathogenesis of autoimmune diseases.

To cite this abstract, please use the following information:
Deng, Yun, Zhao, Jian, Tan, Wenfeng, Kaufman, Kenneth M., Brown, Elizabeth E., Edberg, Jeffrey C., et al; Association of a Functional Variant in TLR7 with Systemic Lupus Erythematosus and Rheumatoid Arthritis in Multiple Ancestries. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :634
DOI:

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