Genomewide association study of leprosy.
BACKGROUND
The narrow host range of Mycobacterium leprae and the fact that it is refractory to growth in culture has limited research on and the biologic understanding of leprosy. Host genetic factors are thought to influence susceptibility to infection as well as disease progression.


METHODS
We performed a two-stage genomewide association study by genotyping 706 patients and 1225 controls using the Human610-Quad BeadChip (Illumina). We then tested three independent replication sets for an association between the presence of leprosy and 93 single-nucleotide polymorphisms (SNPs) that were most strongly associated with the disease in the genomewide association study. Together, these replication sets comprised 3254 patients and 5955 controls. We also carried out tests of heterogeneity of the associations (or lack thereof) between these 93 SNPs and disease, stratified according to clinical subtype (multibacillary vs. paucibacillary).


RESULTS
We observed a significant association (P<1.00x10(-10)) between SNPs in the genes CCDC122, C13orf31, NOD2, TNFSF15, HLA-DR, and RIPK2 and a trend toward an association (P=5.10x10(-5)) with a SNP in LRRK2. The associations between the SNPs in C13orf31, LRRK2, NOD2, and RIPK2 and multibacillary leprosy were stronger than the associations between these SNPs and paucibacillary leprosy.


CONCLUSIONS
Variants of genes in the NOD2-mediated signaling pathway (which regulates the innate immune response) are associated with susceptibility to infection with M. leprae.
Zhang
Fu-Ren
FR
Shandong Provincial Institute of Dermatology and Venereology, Shandong Academy of Medical Science, Jinan, Shandong, China. zhangfuren@hotmail.com
Huang
Wei
W
Chen
Shu-Min
SM
Sun
Liang-Dan
LD
Liu
Hong
H
Li
Yi
Y
Cui
Yong
Y
Yan
Xiao-Xiao
XX
Yang
Hai-Tao
HT
Yang
Rong-De
RD
Chu
Tong-Sheng
TS
Zhang
Chi
C
Zhang
Lin
L
Han
Jian-Wen
JW
Yu
Gong-Qi
GQ
Quan
Cheng
C
Yu
Yong-Xiang
YX
Zhang
Zheng
Z
Shi
Ben-Qing
BQ
Zhang
Lian-Hua
LH
Cheng
Hui
H
Wang
Chang-Yuan
CY
Lin
Yan
Y
Zheng
Hou-Feng
HF
Fu
Xi-An
XA
Zuo
Xian-Bo
XB
Wang
Qiang
Q
Long
Heng
H
Sun
Yi-Ping
YP
Cheng
Yi-Lin
YL
Tian
Hong-Qing
HQ
Zhou
Fu-Sheng
FS
Liu
Hua-Xu
HX
Lu
Wen-Sheng
WS
He
Su-Min
SM
Du
Wen-Li
WL
Shen
Min
M
Jin
Qi-Yi
QY
Wang
Ying
Y
Low
Hui-Qi
HQ
Erwin
Tantoso
T
Yang
Ning-Han
NH
Li
Jin-Yong
JY
Zhao
Xin
X
Jiao
Yue-Lin
YL
Mao
Li-Guo
LG
Yin
Gang
G
Jiang
Zhen-Xia
ZX
Wang
Xiao-Dong
XD
Yu
Jing-Ping
JP
Hu
Zong-Hou
ZH
Gong
Cui-Hua
CH
Liu
Yu-Qiang
YQ
Liu
Rui-Yu
RY
Wang
De-Min
DM
Wei
Dong
D
Liu
Jin-Xian
JX
Cao
Wei-Kun
WK
Cao
Hong-Zhong
HZ
Li
Yong-Ping
YP
Yan
Wei-Guo
WG
Wei
Shi-Yu
SY
Wang
Kui-Jun
KJ
Hibberd
Martin L
ML
Yang
Sen
S
Zhang
Xue-Jun
XJ
Liu
Jian-Jun
JJ
D000368:Aged; D016022:Case-Control Studies; D005260:Female; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D056006:Leprosy, Multibacillary / Q000235:genetics*; D056005:Leprosy, Paucibacillary / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009166:Mycobacterium leprae; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D015398:Signal Transduction
C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein