Ethnicity-specific gene-gene interaction between IL-13 and IL-4Ralpha among African Americans with asthma.

RATIONALE: Genes in the interleukin (IL)-4/IL-13/IL-4Ralpha pathway have been shown to be associated with asthma and related phenotypes in some populations, but not in others. Furthermore, interaction between these genes has been shown to affect asthma in white and Chinese populations. OBJECTIVES: To determine whether there are IL-4/IL-13 and IL-4Ralpha gene-gene interactions that are associated with asthma in African Americans. METHODS: Eighteen single-nucleotide polymorphisms (SNPs) in IL-4, IL-13, and IL-4Ralpha genes were genotyped in 264 African Americans with asthma and 176 healthy control subjects. We tested the SNPs for genetic associations and gene-gene interactions with asthma, baseline lung function, bronchodilator drug response, and total serum IgE levels. MEASUREMENTS AND MAIN RESULTS: We identified 94 SNPs in IL-4, IL-13, and IL-4Ralpha genes by directly sequencing these genes in 24 African-American subjects with asthma. Seventeen SNPs were analyzed for association with asthma and related phenotypes. We found no evidence of association in the IL-4 gene. One SNP in the IL-13 gene (A-646G, rs2069743) and two SNPs in the IL-4Ralpha gene (A+4679G, rs1805010, and C+22656T, rs1805015) showed association with lung function (both baseline and post-bronchodilator). Although the association between individual SNPs and asthma-related phenotypes differed from previous studies performed in white and Chinese populations, significant gene-gene interaction was found between the IL-13 (A-646G) and IL-4Ralpha (A+4679G) SNPs for baseline lung function among African-American subjects with asthma. CONCLUSIONS: Gene-gene interaction between the IL-13 and IL-4Ralpha genes may play an important role in asthma among African Americans.

The PTGDR gene is not associated with asthma in 3 ethnically diverse populations.

BACKGROUND: The prostanoid DP receptor (PTGDR) gene on chromosome 14q22.1 has been identified as an asthma susceptibility gene. A haplotype with decreased transcription factor binding and transcription efficiency was associated with decreased asthma susceptibility in African American and white subjects. The significance of PTGDR gene variants in asthma has yet to be determined in Latinos, the largest US minority population, nor has the association been replicated in other populations. OBJECTIVE: To determine the role of PTGDR gene variants in asthma susceptibility and asthma-related traits among the Mexican, Puerto Rican, and African American populations. METHODS: We determined whether single nucleotide polymorphisms (SNPs) and haplotypes in PTGDR were associated with asthma and asthma-related traits by family-based and cross-sectional cohort analyses in 336 Puerto Rican and 273 Mexican asthmatic trios and by case-control analysis among African American subjects with asthma and healthy controls (n = 352). RESULTS: We identified 13 SNPs in the PTGDR gene, and 6 were further analyzed. There was no significant association between PTGDR variants and asthma by family-based or case-control analyses. SNPs -441C and -197C and haplotype TTT showed marginal association with asthma-related traits in Mexican subjects. SNP -441 genotype TT (P = .05) and haplotype TTT (P = .02) were associated with increased IgE levels in African Americans. CONCLUSION: We conclude that the PTGDR gene is not a significant risk factor for asthma among Puerto Ricans, Mexicans, or African Americans. CLINICAL IMPLICATIONS: Asthma candidate genes provide insights to pathophysiology and potentially new therapeutic targets, although the PTGDR gene was not found to be a significant risk factor for asthma in 3 populations.

Beta 2-adrenergic receptor polymorphisms: pharmacogenetic response to bronchodilator among African American asthmatics.

Beta2-adrenergic receptor (beta2AR) gene polymorphisms have been reported to be associated with various asthma-related traits in different racial/ethnic populations. However, it is unknown whether beta2AR genetic variants are associated with asthma in African Americans. In this study, we have examined whether there is association between beta2AR genetic variants and asthma in African Americans. We have recruited 264 African American asthmatic subjects and 176 matched healthy controls participating in the Study of African Americans, Asthma, Genes and Environments (SAGE). We genotyped seven known and recently identified beta2AR SNP variants, then tested genotype and haplotype association of asthma-related traits with the beta2AR SNPs in our African American cohort with adjustment of confounding effect due to admixture background and environmental risk factors. We found a significant association of the SNP -47 (Arg-19Cys) polymorphism with DeltaFEF(25-75), a measure of bronchodilator drug responsiveness, in African American asthmatics after correction for multiple testing (P = 0.001). We did not observe association of the SNP +46 (Arg16Gly) variant with asthma disease diagnosis and asthma-related phenotypes. In contrast to previous results between the Arg16Gly variant and traits related to bronchodilator responsiveness, our results indicate that the Arg-19Cys polymorphism in beta upstream peptide may play an important role in bronchodilator drug responsiveness in African American subjects. Our findings highlight the importance of investigating genetic risk factors for asthma in different populations.

Admixture-matched case-control study: a practical approach for genetic association studies in admixed populations.

Case-control genetic association studies in admixed populations are known to be susceptible to genetic confounding due to population stratification. The transmission/disequilibrium test (TDT) approach can avoid this problem. However, the TDT is expensive and impractical for late-onset diseases. Case-control study designs, in which, cases and controls are matched by admixture, can be an appealing and a suitable alternative for genetic association studies in admixed populations. In this study, we applied this matching strategy when recruiting our African American participants in the Study of African American, Asthma, Genes and Environments. Group admixture in this cohort consists of 83% African ancestry and 17% European ancestry, which was consistent with reports from other studies. By carrying out several complementary analyses, our results show that there is a substructure in the cohort, but that the admixture distributions are almost identical in cases and controls, and also in cases only. We performed association tests for asthma-related traits with ancestry, and only found that FEV(1), a measure for baseline pulmonary function, was associated with ancestry after adjusting for socio-economic and environmental risk factors (P=0.01). We did not observe an excess of type I error rate in our association tests for ancestry informative markers and asthma-related phenotypes when ancestry was not adjusted in the analyses. Furthermore, using the association tests between genetic variants in a known asthma candidate gene, beta(2) adrenergic receptor (beta(2)AR) and DeltaFEF(25-75), an asthma-related phenotype, as an example, we demonstrated population stratification was not a confounder in our genetic association. Our present work demonstrates that admixture-matched case-control strategies can efficiently control population stratification confounding in admixed populations.