Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus

Nan Shen(Shanghai Jiao Tong University), Qiong Fu(University of California, Los Angeles), Yun Deng(University of California, Los Angeles), Xiaoxia Qian(Shanghai Jiao Tong University), Jian Zhao(University of California, Los Angeles), Kenneth M. Kaufman(Oklahoma Medical Research Foundation), Yee Ling Wu(Nationwide Children's Hospital), C. Yung Yu(Nationwide Children's Hospital), Yuanjia Tang(Shanghai Jiao Tong University), Ji-Yih Chen(Chang Gung University), Wanling Yang(University of Hong Kong), Maida Wong(University of California, Los Angeles), Aya Kawasaki(University of Tsukuba), Naoyuki Tsuchiya(University of Tsukuba), Takayuki Sumida(University of Tsukuba), Yasushi Kawaguchi(Tokyo Women's Medical University), Hwee Siew Howe(Tan Tock Seng Hospital), Mo Yin Mok(Chinese University of Hong Kong), So‐Young Bang(Hanyang University Seoul Hospital), Fei-Lan Liu(National Defense Medical Center), Deh‐Ming Chang(Tri-Service General Hospital), Yoshinari Takasaki(Juntendo University), Hiroshi Hashimoto(Juntendo University), John B. Harley(Oklahoma Medical Research Foundation), Joel M. Guthridge(Oklahoma Medical Research Foundation), Jennifer M. Grossman(University of California, Los Angeles), Rita M. Cantor(University of California, Los Angeles), Yeong Wook Song(Seoul National University), Sang‐Cheol Bae(Hanyang University Seoul Hospital), Shun‐le Chen(Shanghai Jiao Tong University), Bevra H. Hahn(University of California, Los Angeles), YL Lau(University of Hong Kong), Betty P. Tsao(University of California, Los Angeles)
Proceedings of the National Academy of Sciences
August 23, 2010
10.1073/pnas.1001337107
Cited by 341Open Access
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Abstract

Systemic lupus erythematosus (SLE) is a multisystem, autoimmune disease that predominantly affects women. Previous findings that duplicated Toll-like receptor 7 (Tlr7) promotes lupus-like disease in male BXSB mice prompted us to evaluate TLR7 in human SLE. By using a candidate gene approach, we identified and replicated association of a TLR7 3'UTR SNP, rs3853839 (G/C), with SLE in 9,274 Eastern Asians (P(combined) = 6.5 x 10(-10)), with a stronger effect in male than female subjects [odds ratio, male vs. female = 2.33 (95% CI = 1.64-3.30) vs. 1.24 (95% CI = 1.14-1.34); P = 4.1 x 10(-4)]. G-allele carriers had increased TLR7 transcripts and more pronounced IFN signature than C-allele carriers; heterozygotes had 2.7-fold higher transcripts of G-allele than C-allele. These data established a functional polymorphism in type I IFN pathway gene TLR7 predisposing to SLE, especially in Chinese and Japanese male subjects.

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