IL10 gene polymorphisms are associated with asthma phenotypes in children

Abstract

IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3' UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3' UTR SNP was significantly associated with FEV(1) as a percent of predicted (FEV(1)PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV(1)PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC(20) and FEV(1)PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.

Fig. 1

Position of SNPs within the IL10 gene. The location of the SNPs genotyped in this analysis is shown with numbering according to Table I. Minor allele frequency is shown in parentheses.

Fig. 2

Pair-wise linkage disequilibrium plot for IL10 SNPs of Caucasian CAMP proband's parents. The intensity of shading denotes the R² value.

Fig. 3

Box plot of post-bronchodilator FEV₁ as a percent of predicted for the CAMP children by genotype, with means below the plot. The C allele is the minor allele. There is a 4.5% overall increase in FEV₁PP in an additive genetic model, comparing the CC homozygotes (n=124) to the TT homozygotes (n=130) Heterozygotes TC (n=263).

Fig. 4

Box plot of post-bronchodilator FEV₁ as a percent of predicted for the CAMP children by imputed promoter haplotype. Homozygotes with the GCC promoter haplotype (n=117) had an overall increase in FEV₁PP of 4.5% compared to homozygotes for the ATA haplotype (n=34). Mean post-bronchodilator FEV₁ for GCC haplotyped participants was 105.8% and for ATA haplotyped participants was 101.3%.