Functional haplotypes of IL-12B are associated with childhood atopic asthma.
BACKGROUND
IL-12 is a heterodimeric proinflammatory cytokine that forms a link between innate and adaptive immunity. Although associations between polymorphisms of IL-12B on chromosome 5q31-33 and asthma have been reported, the genetic influences of the polymorphisms and haplotype of IL-12B are unclear.


OBJECTIVE
To examine whether polymorphisms in IL-12B are associated with childhood atopic asthma in a Japanese population.


METHODS
We identified a total of 13 polymorphisms and characterized the linkage disequilibrium mapping of the gene. Three variants in the promoter and 3' untranslated region were genotyped, and we conducted case-control and case-only association studies between those variants and asthma-related phenotypes (childhood atopic asthma, n = 297; normal controls, n = 555). Haplotype association analysis and functional analysis of these variants were also performed.


RESULTS
3' Untranslated region 10841C > A was significantly associated with the risk of childhood atopic asthma (P = .00062). The -6415 promoter variant, in linkage disequilibrium with the 10841C > A (D' = 0.78 and r2 = 0.61), was also marginally associated with childhood atopic asthma (P = .051). We analyzed the 2-locus haplotype by using these 2 polymorphisms and found a positive association with haplotype CTCTAA-C (-6415 CTCTAA and 10841C; P = .00078). Furthermore, 10841C > A affects the stability of transcripts, and promoter variant -6415GC enhances the transcriptional level of IL-12B.


CONCLUSIONS
Our results imply that functional haplotype CTCTAA-C, which affects the instability of transcripts and the lower transcriptional level of IL-12B, has a protective effect in childhood atopic asthma. On the basis of these findings, the IL-12B gene might be involved in the development of atopic asthma through functional genetic polymorphisms.
Hirota
Tomomitsu
T
Laboratory for Genetics of Allergic Diseases, Single Nucleotide Polymorphism Research Center, Institute of Physical and Chemical Research (RIKEN), Kanagawa, Japan.
Suzuki
Yoichi
Y
Hasegawa
Koichi
K
Obara
Kazuhiko
K
Matsuda
Akira
A
Akahoshi
Mitsuteru
M
Nakashima
Kazuko
K
Cheng
Lei
L
Takahashi
Naomi
N
Shimizu
Makiko
M
Doi
Satoru
S
Fujita
Kimie
K
Enomoto
Tadao
T
Ebisawa
Motohiro
M
Yoshihara
Shigemi
S
Nakamura
Yusuke
Y
Kishi
Fumio
F
Shirakawa
Taro
T
Tamari
Mayumi
M
D020413:3' Untranslated Regions; D000293:Adolescent; D000483:Alleles; D001249:Asthma / Q000235:genetics* / Q000276:immunology*; D001483:Base Sequence; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D004247:DNA / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics*; D007564:Japan; D015810:Linkage Disequilibrium; D008297:Male; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D020871:RNA Stability; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012307:Risk Factors
D020413:3' Untranslated Regions; D012333:RNA, Messenger; D018664:Interleukin-12; D004247:DNA