Sex-specific association of X-linked Toll-like receptor 7 (TLR7) with male systemic lupus erythematosus.
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.
Shen
Nan
N
Shanghai Renji Hospital, Shanghai JiaoTong University School of Medicine, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, China. nanshensibs@gmail.com
Fu
Qiong
Q
Deng
Yun
Y
Qian
Xiaoxia
X
Zhao
Jian
J
Kaufman
Kenneth M
KM
Wu
Yee Ling
YL
Yu
C Yung
CY
Tang
Yuanjia
Y
Chen
Ji-Yih
JY
Yang
Wanling
W
Wong
Maida
M
Kawasaki
Aya
A
Tsuchiya
Naoyuki
N
Sumida
Takayuki
T
Kawaguchi
Yasushi
Y
Howe
Hwee Siew
HS
Mok
Mo Yin
MY
Bang
So-Young
SY
Liu
Fei-Lan
FL
Chang
Deh-Ming
DM
Takasaki
Yoshinari
Y
Hashimoto
Hiroshi
H
Harley
John B
JB
Guthridge
Joel M
JM
Grossman
Jennifer M
JM
Cantor
Rita M
RM
Song
Yeong Wook
YW
Bae
Sang-Cheol
SC
Chen
Shunle
S
Hahn
Bevra H
BH
Lau
Yu Lung
YL
Tsao
Betty P
BP
D000483:Alleles; D044466:Asian People; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D012737:Sex Factors; D051199:Toll-Like Receptor 7 / Q000235:genetics*
D012333:RNA, Messenger; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7