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A common cortactin gene variation confers differential susceptibility to severe asthma.

ABSTRACT: Genomic regions with replicated linkage to asthma-related phenotypes likely harbor multiple susceptibility loci with relatively minor effects on disease susceptibility. The 11q13 chromosomal region has repeatedly been linked to asthma with five genes residing in this region with reported replicated associations. Cortactin, an actin-binding protein encoded by the CTTN gene in 11q13, constitutes a key regulator of cytoskeletal dynamics and contractile cell machinery, events facilitated by interaction with myosin light chain kinase; encoded by MYLK, a gene we recently reported as associated with severe asthma in African Americans. To evaluate potential association of CTTN gene variation with asthma susceptibility, CTTN exons and flanking regions were re-sequenced in 48 non-asthmatic multiethnic samples, leading to selection of nine tagging polymorphisms for case-control association studies in individuals of European and African descent. After ancestry adjustments, an intronic variant (rs3802780) was significantly associated with severe asthma (odds ratio [OR]: 1.71; 95% confidence interval [CI]: 1.20-2.43; p=0.003) in a joint analysis. Further analyses evidenced independent and additive effects of CTTN and MYLK risk variants for severe asthma susceptibility in African Americans (accumulated OR: 2.93, 95% CI: 1.40-6.13, p=0.004). These data suggest that CTTN gene variation may contribute to severe asthma and that the combined effects of CTTN and MYLK risk polymorphisms may further increase susceptibility to severe asthma in African Americans harboring both genetic variants.

SUBMITTER: Ma SF

PROVIDER: S-EPMC3774307 | biostudies-literature | 2008 Dec

REPOSITORIES: biostudies-literature

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A common cortactin gene variation confers differential susceptibility to severe asthma.

Ma Shwu-Fan SF Flores Carlos C Wade Michael S MS Dudek Steven M SM Nicolae Dan L DL Ober Carole C Garcia Joe G N JG

Genetic epidemiology 20081201 8

Genomic regions with replicated linkage to asthma-related phenotypes likely harbor multiple susceptibility loci with relatively minor effects on disease susceptibility. The 11q13 chromosomal region has repeatedly been linked to asthma with five genes residing in this region with reported replicated associations. Cortactin, an actin-binding protein encoded by the CTTN gene in 11q13, constitutes a key regulator of cytoskeletal dynamics and contractile cell machinery, events facilitated by interact ...[more]

PMID: 18521921

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Project description:Background The T helper 2 (Th2) inflammatory pathway, including the Th2-activating cytokine interleukin 33 and its receptor interleukin 1 receptor-like 1 have been strongly implicated in asthma susceptibility (Moffatt MF, et al NEJM 2010). However, the role of Th2 pathway genetic variation in asthma progression and severity is not well understood. Our research group recently developed a clustering algorithm based on comprehensive phenotype information to assign subjects with asthma in the Severe Asthma Research Program (SARP) to 5 primary clusters; 3 of which represent increasing severe allergic asthma (Moore WC, et al AJRCCM, 2010). We hypothesized that common and potentially deleterious rare variation in this pathway would be associated with severe asthma based on SARP cluster designation. Methods To evaluate common variants (minor allele frequency or MAF >5%), 419 SARP non-Hispanic white participants with a cluster assignment were genotyped for 182 single nucleotide polymorphisms (SNPs) in Th2 pathway genes using whole-genome SNP data. Individual SNPs and a cumulative model of significant SNPs were evaluated using contingency tables with a chi-square test for trend and ordinal regression models adjusted for age, sex, and principal components. Rare (MAF <5%) amino acid changes and splice site alterations in this pathway were tested for association with asthma severity outcomes in 20 SARP subjects with whole exome sequence data. Results Individual Th2 pathway variants were associated with overall SARP cluster assignment, and allergic clusters of increasing severity (1, 2, and 4), including GATA3 polymorphism rs1244186 (P = 0.005). In an 18-SNP additive model, an increasing number of Th2 pathway risk genotypes were highly associated with severe allergic asthma (P = 3.9 × 10?6). For example, in cluster 4, the percentage of subjects with at least 9 risk genotypes was 83% compared to 35% in cluster 1. Additionally, there was evidence that subjects with rare variants in this pathway were more likely to report allergy symptoms (P = 0.006), especially in the fall (P = 0.003), compared to subjects with no rare variants. Conclusions Common Th2 pathway variants predict an increased likelihood of severe allergic asthma and rare variants were associated with increased seasonal allergy symptoms.

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A common cortactin gene variation confers differential susceptibility to severe asthma.

Publications

A common cortactin gene variation confers differential susceptibility to severe asthma.

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