Novel risk loci for rheumatoid arthritis in Han Chinese and congruence with risk variants in Europeans.
OBJECTIVE
To investigate differences in genetic risk factors for rheumatoid arthritis (RA) in Han Chinese as compared with Europeans.


METHODS
A genome-wide association study was conducted in China with 952 patients and 943 controls, and 32 variants were followed up in 2,132 patients and 2,553 controls. A transpopulation meta-analysis with results from a large European RA study was also performed to compare the genetic architecture across the 2 ethnic remote populations.


RESULTS
Three non-major histocompatibility complex (non-MHC) loci were identified at the genome-wide significance level, the effect sizes of which were larger in anti-citrullinated protein antibody (ACPA)-positive patients than in ACPA-negative patients. These included 2 novel variants, rs12617656, located in an intron of DPP4 (odds ratio [OR] 1.56, P = 1.6 × 10(-21) ), and rs12379034, located in the coding region of CDK5RAP2 (OR 1.49, P = 1.1 × 10(-16) ), as well as a variant at the known CCR6 locus, rs1854853 (OR 0.71, P = 6.5 × 10(-15) ). The analysis of ACPA-positive patients versus ACPA-negative patients revealed that rs12617656 at the DPP4 locus showed a strong interaction effect with ACPAs (P = 5.3 × 10(-18) ), and such an interaction was also observed for rs7748270 at the MHC locus (P = 5.9 × 10(-8) ). The transpopulation meta-analysis showed genome-wide overlap and enrichment in association signals across the 2 populations, as confirmed by prediction analysis.


CONCLUSIONS
This study has expanded the list of alleles that confer risk of RA, provided new insight into the pathogenesis of RA, and added empirical evidence to the emerging polygenic nature of complex trait variation driven by common genetic variants.
Shanghai Changzheng Hospital and Second Military Medical University, Shanghai, China.
Lei
L
Jiang
Jian
J
Yin
Lingying
L
Ye
Jian
J
Yang
Gibran
G
Hemani
Ai-Jun
AJ
Liu
Hejian
H
Zou
Dongyi
D
He
Lingyun
L
Sun
Xiaofeng
X
Zeng
Zhanguo
Z
Li
Yi
Y
Zheng
Yiping
Y
Lin
Yi
Y
Liu
Yongfei
Y
Fang
Jianhua
J
Xu
Yinong
Y
Li
Shengming
S
Dai
Jianlong
J
Guan
Lindi
L
Jiang
Qianghua
Q
Wei
Yi
Y
Wang
Yang
Y
Li
Cibo
C
Huang
Xiaoxia
X
Zuo
Yu
Y
Liu
Xin
X
Wu
Libin
L
Zhang
Ling
L
Zhou
Qing
Q
Zhang
Ting
T
Li
Ling
L
Chen
Zhen
Z
Xu
Xiaoping
X
Yang
Feng
F
Qian
Weilin
W
Xie
Wei
W
Liu
Qian
Q
Guo
Shaolan
S
Huang
Jing
J
Zhao
Mengmeng
M
Li
Yanhua
Y
Jin
Jie
J
Gao
Ying
Y
Lv
Yiwen
Y
Wang
Li
L
Lin
Aihua
A
Guo
Patrick
P
Danoy
Dana
D
Willner
Catherine
C
Cremin
Johanna
J
Hadler
Fengchun
F
Zhang
Yan
Y
Zhao
Mengtao
M
Li
Tao
T
Yue
Xiaolei
X
Fan
Jianping
J
Guo
Rong
R
Mu
Jingyi
J
Li
Chao
C
Wu
Ming
M
Zeng
Jiucun
J
Wang
Shilin
S
Li
Li
L
Jin
Binbin
B
Wang
Jing
J
Wang
Xu
X
Ma
Liangdan
L
Sun
Xuejun
X
Zhang
Matthew A
MA
Brown
Peter M
PM
Visscher
Ding-Feng
DF
Su
Huji
H
Xu
D000328:Adult; D000483:Alleles; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000208:ethnology* / Q000235:genetics*; D044466:Asian People / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins; D002681:China / Q000453:epidemiology; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics*; D005060:Europe / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease / Q000208:ethnology / Q000235:genetics; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054399:Receptors, CCR6 / Q000235:genetics*; D012307:Risk Factors; D044465:White People / Q000235:genetics*
C106311:CCR6 protein, human; C405929:CDK5RAP2 protein, human; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D054399:Receptors, CCR6; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4