Asthma susceptibility variants are more strongly associated with clinically similar subgroups.

OBJECTIVE: Genome-wide association studies (GWAS) identified single nucleotide polymorphisms (SNPs) reproducibly associated with asthma. This study evaluated whether GWAS-nominated SNPs are more strongly associated with asthma patients sharing the same clinical characteristics in order to refine the role of recently identified genes.

METHODS: Analyses were performed in unrelated French Canadian subjects (566 cases and 416 controls) with data collected on lung function, blood cell counts, atopy, disease history and medication. Previously defined asthma subgroups were used for analysis: 1) older patients with low atopy and low lung function, 2) high atopy, 3) young non-smoking women and 4) high smoking history. Allele frequencies of 68 GWAS-nominated SNPs were compared between controls and cases or controls and subgroups of cases defined by cluster analysis.

RESULTS: Twelve GWAS-nominated SNPs demonstrated evidence of replication (p value < 0.05) for association with asthma. In phenotypically similar asthma patients, rs10197862, located in IL1RL1/IL18R1, was the most strongly associated SNP with the high atopy subgroup (p = 0.0009). SNPs located at the IL33 and the STARD3/PGAP3 loci were also associated with the high atopy subgroup. Two SNPs, rs1544791 (PDE4D) and rs3806932 (TSLP), were more strongly associated with the high smoking history subgroup than with asthma or any other subgroups. All 10 SNPs that replicated for asthma per se and within subgroups had lower p values in subgroups. Moreover, 12 SNPs were only replicated in a subgroup.

CONCLUSION: This study shows that the majority of GWAS-nominated SNPs are more strongly associated with homogeneous subgroups of asthma than broadly defined asthma.