Genome-wide association study in Asian populations identifies variants in ETS1 and WDFY4 associated with systemic lupus erythematosus.
Systemic lupus erythematosus is a complex and potentially fatal autoimmune disease, characterized by autoantibody production and multi-organ damage. By a genome-wide association study (320 patients and 1,500 controls) and subsequent replication altogether involving a total of 3,300 Asian SLE patients from Hong Kong, Mainland China, and Thailand, as well as 4,200 ethnically and geographically matched controls, genetic variants in ETS1 and WDFY4 were found to be associated with SLE (ETS1: rs1128334, P = 2.33x10(-11), OR = 1.29; WDFY4: rs7097397, P = 8.15x10(-12), OR = 1.30). ETS1 encodes for a transcription factor known to be involved in a wide range of immune functions, including Th17 cell development and terminal differentiation of B lymphocytes. SNP rs1128334 is located in the 3'-UTR of ETS1, and allelic expression analysis from peripheral blood mononuclear cells showed significantly lower expression level from the risk allele. WDFY4 is a conserved protein with unknown function, but is predominantly expressed in primary and secondary immune tissues, and rs7097397 in WDFY4 changes an arginine residue to glutamine (R1816Q) in this protein. Our study also confirmed association of the HLA locus, STAT4, TNFSF4, BLK, BANK1, IRF5, and TNFAIP3 with SLE in Asians. These new genetic findings may help us to gain a better understanding of the disease and the functions of the genes involved.
Yang
Wanling
W
Department of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
Shen
Nan
N
Ye
Dong-Qing
DQ
Liu
Qiji
Q
Zhang
Yan
Y
Qian
Xiao-Xia
XX
Hirankarn
Nattiya
N
Ying
Dingge
D
Pan
Hai-Feng
HF
Mok
Chi Chiu
CC
Chan
Tak Mao
TM
Wong
Raymond Woon Sing
RW
Lee
Ka Wing
KW
Mok
Mo Yin
MY
Wong
Sik Nin
SN
Leung
Alexander Moon Ho
AM
Li
Xiang-Pei
XP
Avihingsanon
Yingyos
Y
Wong
Chun-Ming
CM
Lee
Tsz Leung
TL
Ho
Marco Hok Kung
MH
Lee
Pamela Pui Wah
PP
Chang
Yuk Kwan
YK
Li
Philip H
PH
Li
Ruo-Jie
RJ
Zhang
Lu
L
Wong
Wilfred Hing Sang
WH
Ng
Irene Oi Lin
IO
Lau
Chak Sing
CS
Sham
Pak Chung
PC
Lau
Yu Lung
YL
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D015810:Linkage Disequilibrium / Q000235:genetics; D008180:Lupus Erythematosus, Systemic / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D025341:Principal Component Analysis; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics*; D015203:Reproducibility of Results; D050797:STAT4 Transcription Factor / Q000235:genetics; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D019061:src-Family Kinases / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C447641:BANK1 protein, human; D004268:DNA-Binding Proteins; C494041:ETS1 protein, human; C431713:IRF5 protein, human; D050835:Interferon Regulatory Factors; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009687:Nuclear Proteins; D050784:Proto-Oncogene Protein c-ets-1; D050797:STAT4 Transcription Factor; C549018:WDFY4 protein, human; C082599:protein-tyrosine kinase p55(blk); D019061:src-Family Kinases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3