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 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 (SAGE). 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 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 FEV1, 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 (AIMs) 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, β2 adrenergic receptor (β2AR) and ΔFEF25-75, 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 for population stratification confounding in admixed populations.

BACKGROUND:

The effects of in utero tobacco smoke exposure on childhood respiratory health have been investigated, and outcomes have been inconsistent.

OBJECTIVE:

To determine if in utero tobacco smoke exposure is associated with childhood persistent asthma in Mexican, Puerto Rican, and black children.

PATIENTS AND METHODS:

There were 295 Mexican, Puerto Rican, and black asthmatic children, aged 8 to 16 years, who underwent spirometry, and clinical data were collected from the parents during a standardized interview. The effect of in utero tobacco smoke exposure on the development of persistent asthma and related clinical outcomes was evaluated by logistic regression.

RESULTS:

Children with persistent asthma had a higher odds of exposure to in utero tobacco smoke, but not current tobacco smoke, than did children with intermittent asthma (odds ratio [OR]: 3.57; P = .029). Tobacco smoke exposure from parents in the first 2 years of life did not alter this association. Furthermore, there were higher odds of in utero tobacco smoke exposure in children experiencing nocturnal symptoms (OR: 2.77; P = .048), daily asthma symptoms (OR: 2.73; P = .046), and emergency department visits (OR: 3.85; P = .015) within the year.

CONCLUSIONS:

Exposure to tobacco smoke in utero was significantly associated with persistent asthma among Mexican, Puerto Rican, and black children compared with those with intermittent asthma. These results suggest that smoking cessation during pregnancy may lead to a decrease in the incidence of persistent asthma in these populations.

Background

Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma; yet, there is significant variability in treatment response. Dual specificity phosphatase-1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.

Objective

To determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.

Methods

Study participants with asthma were drawn from the following multi-ethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study, the Study of African Americans, Asthma, Genes & Environments (SAGE), and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICS for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in forced expiratory volume at one second (FEV1) and self-reported asthma control.

Results

DUSP1 polymorphisms, rs881152 and rs34507926, localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA participants. This interaction was also seen for rs881152 among SAPPHIRE, but not SAGE participants. Among the group of SAPPHIRE patients prospectively treated with ICS for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV1.

Conclusion

DUSP1 polymorphisms were associated with clinical response to ICS therapy, and therefore, may be useful in the future to identify asthma patients more likely to respond to this controller treatment.

Clinical implications

These findings further our understanding of ICS pharmacogenetics and will hopefully result in improved tailoring of this controller therapy among individuals with asthma and in better disease control.

Capsule summary

We identified genetic variants in DUSP1 which appeared to mediate the clinical response to inhaled corticosteroid (ICS) medication. These findings may eventually assist in identifying individuals with asthma most likely to respond this controller therapy.

Objective

A recent admixture mapping analysis identified interleukin 6 (IL6) and IL6 receptor (IL6R) as candidate genes for inflammatory diseases. In the airways during allergic inflammation, IL6 signaling controls the production of proinflammatory and anti-inflammatory factors. In addition, albuterol, a commonly prescribed asthma therapy, has been shown to influence IL6 gene expression. Therefore, we reasoned that interactions between the IL6 and IL6R genes might be associated with bronchodilator drug responsiveness to albuterol in asthmatic patients.

Methods

Four functional IL6 single nucleotide polymorphisms (SNPs) and a nonsynonymous IL6R SNP were genotyped in 700 Mexican and Puerto Rican asthma families and in 443 African-American asthma cases and controls. Both family-based association tests and linear regression models were used to assess the association between individual SNPs and haplotypes with bronchodilator response. Gene–gene interactions were tested by using multiple linear regression analyses.

Results

No single SNP was consistently associated with drug response in all the three populations. However, on the gene level, we found a consistent IL6 and IL6R pharmacogenetic interaction in the three populations. This pharmacogenetic gene–gene interaction was contextual and dependent upon ancestry (racial background). This interaction resulted in higher drug response to albuterol in Latinos, but lower drug response in African-Americans. Herein, we show that there is an effect modification by ancestry on bronchodilator responsiveness to albuterol.

Conclusion

Genetic variants in the IL6 and IL6R genes act synergistically to modify the bronchodilator drug responsiveness in asthma and this pharmacogenetic interaction is modified by the genetic ancestry.

A highly heritable and reproducible measure of asthma severity is baseline pulmonary function. Pulmonary function is largely determined by airway smooth muscle (ASM) tone and contractility. The large conductance, voltage and calcium-activated potassium (BK) channel negatively regulates smooth muscle tone and contraction in ASM. The modulatory subunit of BK channels, the β1-subunit, is critical for proper activation of BK channels in smooth muscle and has shown sex hormone specific regulation. We hypothesized that KCNMB1 genetic variants in African Americans may underlie differences in bronchial smooth muscle tone and thus pulmonary function, possibly in a sex-specific manner. Through resequencing of the KCNMB1 gene we identified several common variants including a novel African-specific coding polymorphism (C818T, R140W). The C818T SNP and four other KCNMB1 variants were genotyped in two independent groups of African American asthmatics (n = 509) and tested for association with the pulmonary function measure – forced expiratory volume (FEV1) % of predicted value. The 818T allele is associated with a clinically significant decline (−13%) in FEV1 in both cohorts of asthmatics among males but not females (Pcombined = 0.0003). Patch clamp electrophysiology studies of the BK channel expressed with the 140Trp variant of the β1-subunit demonstrated significantly reduced channel openings, predicted by the loss of pulmonary function observed. African American male asthmatics carrying the 818T allele (10% of population) are potentially at risk for greater airway obstruction and increased asthma morbidity. Female asthmatics may be insulated from the deleterious effects of the 818T allele by estrogen-mediated upregulation in BK channel activity.

Rationale: Independent replication of genetic associations in complex diseases, particularly in whole-genome association studies, is critical to confirm the association.

Objectives: A whole-genome association study identified ORMDL3 as a promising candidate gene for asthma in white populations. Here, we attempted to confirm the role of ORMDL3 genetic variants in asthma in three ethnically diverse populations: Mexican, Puerto Rican, and African American.

Methods: We used family-based analyses to test for association between seven candidate single-nucleotide polymorphisms (SNPs) in and around the ORMDL3 gene and asthma and related phenotypes in 701 Puerto Rican and Mexican parent–child trios. We also evaluated these seven SNPs and an additional ORMDL3 SNP in 264 African American subjects with asthma and 176 healthy control subjects.

Measurements and Main Results: We found significant associations between two SNPs within ORMDL3 (rs4378650 and rs12603332) and asthma in Mexicans and African Americans (P = 0.028 and 0.001 for rs4378650 and P = 0.021 and 0.001 for rs12603332, respectively), and a trend toward association in Puerto Ricans (P = 0.076 and 0.080 for SNPs rs4378650 and rs12603332, respectively). These associations became stronger among Mexican and Puerto Rican subjects with asthma with IgE levels greater than 100 IU/ml. We did not find any association between ORMDL3 SNPs and baseline lung function or response to the bronchodilator albuterol.

Conclusions: Our results confirm that the ORMDL3 locus is a risk factor for asthma in ethnically diverse populations. However, inconsistent SNP-level results suggest that further studies will be needed to determine the mechanism by which ORMDL3 predisposes to asthma.

Rationale: Genes in the interleukin (IL)-4/IL-13/IL-4Rα 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-4Rα gene–gene interactions that are associated with asthma in African Americans.

Methods: Eighteen single-nucleotide polymorphisms (SNPs) in IL-4, IL-13, and IL-4Rα 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-4Rα 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-4Rα 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-4Rα (A+4679G) SNPs for baseline lung function among African-American subjects with asthma.

Conclusions: Gene–gene interaction between the IL-13 and IL-4Rα genes may play an important role in asthma among African Americans.