The IL12B gene is associated with asthma

Abstract

The IL12B gene on chromosome 5q31-33 encodes the p40 subunit of interleukin 12, an immunomodulatory cytokine. To test the hypothesis that the IL12B gene contains polymorphisms associated with asthma, we genotyped six haplotype-tagging polymorphisms in the IL12B gene, both in 708 children enrolled in the Childhood Asthma Management Program (CAMP) and in their parents. Using the family-based association test (FBAT) program and its haplotype (HBAT) and phenotype (PBAT) options, we tested each polymorphism and haplotype for association with asthma and asthma-related phenotypes. We tested positive associations for replication in a case-control study comparing 177 adult moderate-to-severe asthmatics with 177 nonasthmatic controls. In whites in the CAMP cohort, the A allele of the IL12B G4237A polymorphism was undertransmitted to asthmatic children (P=.0008, recessive model), the global test for haplotypes for affection status was positive (P=.009, multiallelic chi (2)), and two polymorphisms were associated with different atopy phenotypes. In addition, we found a strong association between the IL12B_4237 and IL12B_6402 polymorphisms and an asthma-severity phenotype in whites, which we also found in the independent population of white adult asthmatics. IL12B may be an important asthma gene.

Figures

Figure 1

Pairwise linkage disequilibrium (r2) for IL12B SNPs seen at ⩾5% frequency in Europeans in CEPH sample (data from SeattleSNPs, NHLBI Program for Genomic Applications [UW-FHCRC]). SNP numbering is relative to the gene transcription start codon, with mapping to the SNPs we tested, using the SeattleSNPs numbering system.

Figure 2

Box plots of post-bronchodilator FEV1% predicted in the pediatric cohort with mild-to-moderate asthma and of baseline FEV1% predicted in the adult cases with moderate-to-severe asthma, for SNPs IL12B_4237 and IL12B_6402.