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BackgroundAlthough inhaled corticosteroid (ICS) medication is considered the cornerstone treatment for patients with persistent asthma, few ICS pharmacogenomic studies have involved nonwhite populations.ObjectiveWe sought to identify genetic predictors of ICS response in multiple population groups with asthma.MethodsThe discovery group comprised African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity (SAPPHIRE) who underwent 6 weeks of monitored ICS therapy (n = 244). A genome-wide scan was performed to identify single nucleotide polymorphism (SNP) variants jointly associated (ie, the combined effect of the SNP and SNP × ICS treatment interaction) with changes in asthma control. Top associations were validated by assessing the joint association with asthma exacerbations in 3 additional groups: African Americans (n = 803 and n = 563) and Latinos (n = 1461). RNA sequencing data from 408 asthmatic patients and 405 control subjects were used to examine whether genotype was associated with gene expression.ResultsOne variant, rs3827907, was significantly associated with ICS-mediated changes in asthma control in the discovery set (P = 7.79 × 10-8) and was jointly associated with asthma exacerbations in 3 validation cohorts (P = .023, P = .029, and P = .041). RNA sequencing analysis found the rs3827907 C-allele to be associated with lower RNASE2 expression (P = 6.10 × 10-4). RNASE2 encodes eosinophil-derived neurotoxin, and the rs3827907 C-allele appeared to particularly influence ICS treatment response in the presence of eosinophilic inflammation (ie, high pretreatment eosinophil-derived neurotoxin levels or blood eosinophil counts).ConclusionWe identified a variant, rs3827907, that appears to influence response to ICS treatment in multiple population groups and likely mediates its effect through eosinophils.

BackgroundAsthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.ObjectiveWe sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.MethodsWe leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups.ResultsWe identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P = 6.8 × 10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P = .002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P = .008). Our findings were replicated in an independent childhood asthma study in Latinos (P = 5.3 × 10-3, combined P = 2.6 × 10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P

BackgroundIgE is a key mediator of allergic inflammation, and its levels are frequently increased in patients with allergic disorders.ObjectiveWe sought to identify genetic variants associated with IgE levels in Latinos.MethodsWe performed a genome-wide association study and admixture mapping of total IgE levels in 3334 Latinos from the Genes-environments & Admixture in Latino Americans (GALA II) study. Replication was evaluated in 454 Latinos, 1564 European Americans, and 3187 African Americans from independent studies.ResultsWe confirmed associations of 6 genes identified by means of previous genome-wide association studies and identified a novel genome-wide significant association of a polymorphism in the zinc finger protein 365 gene (ZNF365) with total IgE levels (rs200076616, P = 2.3 × 10(-8)). We next identified 4 admixture mapping peaks (6p21.32-p22.1, 13p22-31, 14q23.2, and 22q13.1) at which local African, European, and/or Native American ancestry was significantly associated with IgE levels. The most significant peak was 6p21.32-p22.1, where Native American ancestry was associated with lower IgE levels (P = 4.95 × 10(-8)). All but 22q13.1 were replicated in an independent sample of Latinos, and 2 of the peaks were replicated in African Americans (6p21.32-p22.1 and 14q23.2). Fine mapping of 6p21.32-p22.1 identified 6 genome-wide significant single nucleotide polymorphisms in Latinos, 2 of which replicated in European Americans. Another single nucleotide polymorphism was peak-wide significant within 14q23.2 in African Americans (rs1741099, P = 3.7 × 10(-6)) and replicated in non-African American samples (P = .011).ConclusionWe confirmed genetic associations at 6 genes and identified novel associations within ZNF365, HLA-DQA1, and 14q23.2. Our results highlight the importance of studying diverse multiethnic populations to uncover novel loci associated with total IgE levels.

BackgroundIgE is both a marker and mediator of allergic inflammation. Despite reported differences in serum total IgE levels by race-ethnicity, African American and Latino subjects have not been well represented in genetic studies of total IgE.ObjectiveWe sought to identify the genetic predictors of serum total IgE levels.MethodsWe used genome-wide association data from 4292 subjects (2469 African Americans, 1564 European Americans, and 259 Latinos) in the EVE Asthma Genetics Consortium. Tests for association were performed within each cohort by race-ethnic group (ie, African American, Latino, and European American) and asthma status. The resulting P values were meta-analyzed, accounting for sample size and direction of effect. Top single nucleotide polymorphism associations from the meta-analysis were reassessed in 6 additional cohorts comprising 5767 subjects.ResultsWe identified 10 unique regions in which the combined association statistic was associated with total serum IgE levels (P

BackgroundGenome-wide association studies of asthma have implicated many genetic risk factors, with well-replicated associations at approximately 10 loci that account for only a small proportion of the genetic risk.ObjectivesWe aimed to identify additional asthma risk loci by performing an extensive replication study of the results from the EVE Consortium meta-analysis.MethodsWe selected 3186 single nucleotide polymorphisms for replication based on the P values from the EVE Consortium meta-analysis. These single nucleotide polymorphisms were genotyped in ethnically diverse replication samples from 9 different studies, totaling 7202 cases, 6426 controls, and 507 case-parent trios. Association analyses were conducted within each participating study, and the resulting test statistics were combined in a meta-analysis.ResultsTwo novel associations were replicated in European Americans: rs1061477 in the KLK3 gene on chromosome 19 (combined odds ratio = 1.18; 95% CI, 1.10-1.25) and rs9570077 (combined odds ratio =1.20; 95% CI, 1.12-1.29) on chromosome 13q21. We could not replicate any additional associations in the African Americans or Latinos.ConclusionsThis extended replication study identified 2 additional asthma risk loci in populations of European descent. The absence of additional loci for African Americans and Latinos highlights the difficulty in replicating associations in admixed populations.

BackgroundThere are large and persisting disparities in severe asthma exacerbations by race-ethnicity, and African American subjects are among those at greatest risk. It is unclear whether this increased risk solely represents differences in environmental exposures and health care or whether there is a predisposing genetic component.ObjectiveWe sought to assess the relationship between genetic ancestry and severe exacerbations among African American subjects with asthma.MethodsParticipants were part of the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). These subjects were 12 to 56 years of age, received care from a single large health system, and had a physician's diagnosis of asthma. Genetic ancestry was estimated by using a set of validated ancestry informative markers. Severe exacerbations (ie, asthma-related emergency department visits, hospitalizations, and burst oral steroid use) were prospectively identified from health care claims.ResultsWe assessed genetic ancestry in 392 African American subjects with asthma. The average proportion of African ancestry was 76.1%. A significant interaction was identified between ancestry and sex on severe exacerbations, such that the risk was significantly higher with increasing African ancestry among male but not female subjects. The association among male subjects persisted after adjusting for potential confounders (relative rate, 4.30 for every 20% increase in African ancestry; P = .029).ConclusionsAfrican ancestry was significantly and positively associated with severe exacerbations among male African American subjects. These findings suggest that a portion of the risk of asthma exacerbations in this high-risk group is attributable to a genetic risk factor that partitions with ancestry.

A BAFF polymorphism is associated with asthma exacerbations and serum BAFF levels. BAFF expression in vivo increases in natural rhinovirus infection. BAFF may play a role in airway antiviral immunity and impact asthma exacerbation rates.