Mechanisms of asthma and allergic inflammation
Functional haplotypes of IL-12B are associated with childhood atopic asthma

https://doi.org/10.1016/j.jaci.2005.06.010Get rights and content

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.

Conclusion

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.

Section snippets

Study subjects

All subjects with asthma were diagnosed according to the criteria of the National Institutes of Health22 and demonstrated at least 12% improvement in their FEV1 measurement after β2-agonist inhalation. The diagnosis of atopic asthma was based on 1 or more positive skin scratch test responses to seven common aeroallergens in the presence of a positive histamine control and a negative vehicle control. The seven aeroallergens were house dust, Felis domestics dander (Fel d), Canis familiaris

Results

We identified 13 biallelic polymorphisms in IL-12B: 4 in the 5′ flanking region, 1 in the 3′ UTR, and 8 in the intron (Table I and Fig 1). Seven polymorphisms were contained in the public databases available at Web sites. 10841C>A in exon 8 was reported previously as 1188C>A.24 Rare SNPs with minor allele frequencies of 2% were not included in the analysis. Pairwise LD among 8 SNPs with a frequency >0.15 was measured by different parameters, |D′| and r2 (Table II). D′ is inversely biased with

Discussion

We showed here a significant association between asthma susceptibility and an SNP in the 3′ UTR region, 10841C>A, and promoter polymorphism −6415 CTCTAA>GC was also associated with asthma. Furthermore, we found a haplotype that affected the stability of transcripts and enhanced the transcriptional level of IL-12B. Although the functional effects of these 2 polymorphisms were analyzed in this study, the polymorphisms that are in linkage disequilibrium with these 2 variants were not examined.

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    Supported by grants-in-aid from the Ministry of Health, Labor and Welfare; Japan Science and Technology Corp; and the Japanese Millennium project.

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