Sequencing the IL4 locus in African Americans implicates rare noncoding variants in asthma susceptibility

• Published in: Journal of allergy and clinical immunology Vol. 124; no. 6; pp. 1204 - 1209.e9
• Main Authors: Haller, Gabe, Torgerson, Dara G., Ober, Carole, Thompson, Emma E.
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.12.2009; Elsevier; Elsevier Limited
• Subjects: Accuracy; African Americans; Allergy and Immunology; Asthma; Asthma - genetics; Asthma - immunology; Biological and medical sciences; Black or African American - genetics; Chromosomes; Chronic obstructive pulmonary disease, asthma; Deoxyribonucleic acid; Disease; DNA; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Frequency - genetics; Gene Frequency - immunology; Gene polymorphism; Genes; Genetic diversity; Genetic Predisposition to Disease; Genotype; Genotyping; Humans; Hypotheses; IgE; IL4; Immunopathology; Interleukin 4; Interleukin-4 - genetics; Interleukin-4 - immunology; Introns - genetics; Linkage Disequilibrium - genetics; Medical sciences; Pneumology; Polymorphism, Single Nucleotide - genetics; Polymorphism, Single Nucleotide - immunology; Population; private alleles; Rare variants; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Single-nucleotide polymorphism; Studies; IL4; MAF; SNP; private alleles; IgE; Rare variants; African Americans; asthma; Single nucleotide polymorphism; Minor allele frequency; Genetic variability; Non coding sequence; Interleukin 4; Immunology; Bronchus disease; Genetics; Obstructive pulmonary disease; Locus; Sequencing; Human; Lung disease; Immunopathology; Nucleotide sequence; Respiratory disease; Cytokine; Genotype; Asthma; Variant; Allele; Sensitivity; African American
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2009.09.013

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 with 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 controls without asthma to identify novel and rare polymorphisms in the IL4 gene that may be contributing to asthma susceptibility. We report an excess of private noncoding single nucleotide polymorphisms (SNPs) in the subjects with asthma compared with control subjects without asthma ( P = .031). Tajima's D is significantly more negative in subjects with asthma (–0.375) than controls (–0.073; P = .04), reflecting an excess of rare variants in the subjects with asthma. Our findings indicate that SNPs at the IL4 locus that are potentially exclusive to African Americans are associated with susceptibility to asthma. Only 3 of the 26 private SNPs (ie, SNPs present only in the subjects with asthma 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.