Sequencing the locus in African Americans implicates rare noncoding variants in asthma susceptibility


Common genetic variations in the IL4 gene have been associated with asthma and atopy in European and Asian populations, but not in African Americans.


Because populations of African descent have increased levels of genetic variation compared to other populations, particularly with respect to low frequency or rare variants, we hypothesized that rare variants in the IL4 gene contribute to the development of asthma in African Americans.


To test this hypothesis, we sequenced the IL4 locus in 72 African Americans with asthma and 70 African American non-asthmatic controls to identify novel and rare polymorphisms in the IL4 gene that may be contributing to asthma susceptibility.


We report an excess of private non-coding SNPs in the subjects with asthma compared to non-asthmatic control subjects (P=0.031). Tajima’s D is significantly more negative in cases (−0.375) compared to controls (−0.073) (P=0.04), reflecting an excess of rare variants in the cases.


Our findings indicate that SNPs at the IL4 locus that are potentially exclusive to African Americans are associated with susceptibility to asthma. Only three of the 26 private SNPs (i.e., SNPs present only in the cases or only in the controls) are tagged by single SNPs on one of the common genotyping platforms used in genome-wide association studies. We also find that most of the private SNPs cannot be reliably imputed, highlighting the importance of sequencing to identify genetic variants contributing to common diseases in African Americans.