Evaluation of candidate genes in a genome-wide association study of childhood asthma in Mexicans

Abstract

Background: More than 200 asthma candidate genes have been examined in human association studies or identified with knockout mouse approaches. However, many have not been systematically replicated in human populations, especially those containing a large number of tagging single nucleotide polymorphisms (SNPs).

Objective: We comprehensively evaluated the association of previously implicated asthma candidate genes with childhood asthma in a Mexico City population.

Methods: From the literature, we identified candidate genes with at least 1 positive report of association with asthma phenotypes in human subjects or implicated in asthma pathogenesis using knockout mouse experiments. We performed a genome-wide association study in 492 asthmatic children aged 5 to 17 years and both parents using the Illumina HumanHap 550v3 BeadChip. Separate candidate gene analyses were performed for 2933 autosomal SNPs in the 237 selected genes by using the log-linear method with a log-additive risk model.

Results: Sixty-one of the 237 genes had at least 1 SNP with a P value of less than .05 for association with asthma. The 9 most significant results were observed for rs2241715 in the gene encoding TGF-beta1 (TGFB1; P = 3.3 x 10(-5)), rs13431828 and rs1041973 in the gene encoding IL-1 receptor-like 1 (IL1RL1; P = 2 x 10(-4) and 3.5 x 10(-4)), 5 SNPs in the gene encoding dipeptidyl-peptidase 10 (DPP10; P = 1.6 x 10(-4) to 4.5 x 10(-4)), and rs17599222 in the gene encoding cytoplasmic FMR1 interacting protein 2 (CYFIP2; P = 4.1 x 10(-4)). False discovery rates were less than 0.1 for all 9 SNPs. Multimarker analysis identified TGFB1, IL1RL1, the gene encoding IL-18 receptor 1 (IL18R1), and DPP10 as the genes most significantly associated with asthma.

Conclusions: This comprehensive analysis of literature-based candidate genes suggests that SNPs in several candidate genes, including TGFB1, IL1RL1, IL18R1, and DPP10, might contribute to childhood asthma susceptibility in a Mexican population.

Figure 1

(a) A summary of associations between 2,933 autosomal SNPs in 237 candidate genes and childhood asthma in a Mexican population. The x axis indicates the genomic position of all SNPs divided by chromosome. The y axis shows the degree of association indicated as -log₁₀P value. (b) Quantile –quantile plot. Distribution of the observed p values for the 2,933 SNPs compared to the p values expected under the null hypothesis of no association. Observed -log₁₀P values are ranked in order on the y axis, and plotted against the corresponding expected -log₁₀P values on the x axis. The red line indicates the null distribution.

Figure 1

(a) A summary of associations between 2,933 autosomal SNPs in 237 candidate genes and childhood asthma in a Mexican population. The x axis indicates the genomic position of all SNPs divided by chromosome. The y axis shows the degree of association indicated as -log₁₀P value. (b) Quantile –quantile plot. Distribution of the observed p values for the 2,933 SNPs compared to the p values expected under the null hypothesis of no association. Observed -log₁₀P values are ranked in order on the y axis, and plotted against the corresponding expected -log₁₀P values on the x axis. The red line indicates the null distribution.