Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Association of Variants in the TLR7-TLR8 Region with Systemic Lupus Erythematosus in Non-Asian Populations.

Deng8,  Yun, Zhao8,  Jian, Tan8,  Wenfeng, Kaufman2,  Kenneth M., Brown7,  Elizabeth E., Edberg7,  Jeffrey C., Kamen6,  Diane L.

Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK
University of Southern California, Los Angeles, CA
Wake Forest University Baptist Medical Center, NC
Wake Forest University Health Sciences, NC
Arthritis and Immunology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK; University of Oklahoma Health Sciences Center, Oklahoma City, OK; US Department of Veterans Affairs Medical Center, Oklahoma City, OK
Center for Genomics and Oncological Research, Granada, Spain
Cincinnati Children's Hospital Medical Center and US Department of Veterans Affairs Medical Center, Cincinnati, OH
Imperial College London, Hammersmith Hospital, London, United Kingdom
Medical University of South Carolina, Charleston, SC
University of Alabama, Birmingham, AL
University of California, Los Angeles, CA
University of Chicago, Chicago, IL

Objectives:

Our previous study identified the G allele of an X-linked TLR7 SNP (rs3853839, located at 3'UTR) associated with increased expression levels of TLR7 and SLE susceptibility in 9,274 Eastern Asians (p= 6.5×10-10) that had a stronger male effect. In this study, we sought to further characterize and localize SLE-associated SNPs of TLR7 and its functionally related gene TLR8 (17-kb downstream of rs3853839) in non-Asian populations.

Methods:

A total of 47 SNPs, spanning the ~55kb genomic region of TLR7-TLR8, were genotyped on a customized Illumina array in a collection of case-control samples including European Americans (EA, 3930 cases vs. 3477 controls), African Americans & Gullahs (AA&Gullah, 1674 cases vs. 1915 controls), and Hispanics & Native Americans (Hisp&NA, 1479 cases vs. 800 controls). Additionally, ~400 ancestry informative markers were genotyped to control population stratification and remove genetic outliers for analysis. Association analysis of each SNP was performed using PLINK and conditional analysis was conducted to distinguish independent signals from associated SNPs. We used Q statistic to test the heterogeneity of OR between males and females, and Mantel-Haenszel test to generate a trans-ethnic meta-analysis P value.

Results:

Significant associations of SNPs (P < 0.05) with SLE in each ethnic group were observed at TLR7 region after Bonferroni correction, including 3 SNPs in EA, 1 SNP in AA&Gullah and 1 SNP in Hisp&NA. The following conditional analysis revealed the previously identified TLR7 3'UTR SNP (rs3853839) as the only independent variant across all 3 populations, exhibiting the strongest association (P= 1.5×10-6 in EA, 1.4×10-3 in AA&Gullah and 2.8×10-6 in Hisp&NA, Table 1). Trans-ethnic meta-analysis yielded a P with genome-wide significance (P= 1.05×10-12, OR = 1.26), confirming our previous finding in Eastern Asians. However, unlike the Asian sample where both sexes showed association, the evidence for this SNP conferring risk to SLE was only observed in female non-Asian datasets.

Table 1. Association of rs3853839 with SLE in multiple ethnic groups

    G Allele Frequency  
EthnicityPanelsSexCase/ControlCaseControlPOR (95% CI)
Eastern AsianCombinedM358/15500.890.771.3 × 10-62.33 (1.64–3.30)
  F3976/33900.800.771.2 × 10-71.24 (1.14–1.34)
  All4334/49400.810.776.5 × 10-101.27 (1.17–1.36)
European AmericanReplicationM338/11370.1980.2010.90.99 (0.73–1.34)
  F3592/23400.2030.1653.9 × 10-71.28 (1.17–1.41)
  All3930/34770.2020.1721.5 × 10-61.25 (1.14–1.37)
AA&GulahReplicationM131/5730.2140.1570.11.46 (0.91–2.35)
  F1543/13420.1960.1664.1 × 10-31.22 (1.07–1.40)
  All1674/19150.1960.1651.4 × 1041.23 (1.08–1.41)
Hsp&NAReplicationM114/730.4210.4790.430.79 (0.44–1.43)
  F1365/7270.4460.3666.3 × 10-71.40 (1.23–1.60)
  All1479/8000.4450.3712.8 × 10-61.36 (1.20–1.55)

Conclusion:

We replicated the association between rs3853839 and SLE with genome-wide significance in EA, AA&Gullah, and Hisp&NA populations, showing TLR7 as a common risk locus for SLE in multiple ethnic groups.

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 Variants in the TLR7-TLR8 Region with Systemic Lupus Erythematosus in Non-Asian Populations. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1584
DOI: 10.1002/art.29350

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