A common cortactin gene variation confers differential susceptibility to severe asthma.
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.
Ma
Shwu-Fan
SF
Department of Medicine, University of Chicago, Chicago, Illinois, USA.
Flores
Carlos
C
Wade
Michael S
MS
Dudek
Steven M
SM
Nicolae
Dan L
DL
Ober
Carole
C
Garcia
Joe G N
JG
D001249:Asthma / Q000208:ethnology* / Q000235:genetics*; D044383:Black People; D002135:Calcium-Binding Proteins / Q000235:genetics; D016022:Case-Control Studies; D002880:Chromosomes, Human, Pair 11; D051356:Cortactin / Q000235:genetics*; D003599:Cytoskeleton / Q000378:metabolism; D005006:Ethnicity; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D009219:Myosin-Light-Chain Kinase / Q000235:genetics; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D044465:White People; D001741:Black or African American
D002135:Calcium-Binding Proteins; D051356:Cortactin; C499378:MYLK protein, human; D009219:Myosin-Light-Chain Kinase