Identification of two new loci at IL23R and RAB32 that influence susceptibility to leprosy.
We performed a genome-wide association study with 706 individuals with leprosy and 5,581 control individuals and replicated the top 24 SNPs in three independent replication samples, including a total of 3,301 individuals with leprosy and 5,299 control individuals from China. Two loci not previously associated with the disease were identified with genome-wide significance: rs2275606 (combined P = 3.94 × 10(-14), OR = 1.30) on 6q24.3 and rs3762318 (combined P = 3.27 × 10(-11), OR = 0.69) on 1p31.3. These associations implicate IL23R and RAB32 as new susceptibility genes for leprosy. Furthermore, we identified evidence of interaction between the NOD2 and RIPK2 loci, which is consistent with the biological association of the proteins encoded by these genes (NOD2-RIPK2 complex) in activating the NF-κB pathway as a part of the host defense response to infection. Our findings have expanded the biological functions of IL23R by uncovering its involvement in infectious disease susceptibility and suggest a potential involvement of autophagocytosis in leprosy pathogenesis. The IL23R association supports previous observations of the marked overlap of susceptibility genes for leprosy and Crohn's disease, implying common pathogenesis mechanisms.
Shandong Provincial Institute of Dermatology and Venereology, Provincial Academy of Medical Science, Jinan, China. zhangfuren@hotmail.com
Furen
F
Zhang
Hong
H
Liu
Shumin
S
Chen
Huiqi
H
Low
Liangdan
L
Sun
Yong
Y
Cui
Tongsheng
T
Chu
Yi
Y
Li
Xi'an
X
Fu
Yongxiang
Y
Yu
Gongqi
G
Yu
Benqing
B
Shi
Hongqing
H
Tian
Dianchang
D
Liu
Xiulu
X
Yu
Jinghui
J
Li
Nan
N
Lu
Fangfang
F
Bao
Chunying
C
Yuan
Jian
J
Liu
Huaxu
H
Liu
Lin
L
Zhang
Yonghu
Y
Sun
Mingfei
M
Chen
Qing
Q
Yang
Haitao
H
Yang
Rongde
R
Yang
Lianhua
L
Zhang
Qiang
Q
Wang
Hong
H
Liu
Fuguang
F
Zuo
Haizhen
H
Zhang
Chiea Chuen
CC
Khor
Martin L
ML
Hibberd
Sen
S
Yang
Jianjun
J
Liu
Xuejun
X
Zhang
D000368:Aged; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007918:Leprosy / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D025341:Principal Component Analysis; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2 / Q000235:genetics; D018123:Receptors, Interleukin / Q000235:genetics*; D020691:rab GTP-Binding Proteins / Q000235:genetics*
C515500:IL23R protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D018123:Receptors, Interleukin; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; C466094:Rab32 protein, human; D020691:rab GTP-Binding Proteins