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Genetic ancestry plays a role in asthma health disparities. Our aim was to evaluate the impact of ancestry on and identify genetic variants associated with asthma, total serum IgE level, and lung function. A total of 436 Peruvian children (aged 9-19 years) with asthma and 291 without asthma were genotyped by using the Illumina Multi-Ethnic Global Array. Genome-wide proportions of indigenous ancestry populations from continental America (NAT) and European ancestry from the Iberian populations in Spain (IBS) were estimated by using ADMIXTURE. We assessed the relationship between ancestry and the phenotypes and performed a genome-wide association study. The mean ancestry proportions were 84.7% NAT (case patients, 84.2%; controls, 85.4%) and 15.3% IBS (15.8%; 14.6%). With adjustment for asthma, NAT was associated with higher total serum IgE levels (P <.001) and IBS was associated with lower total serum IgE levels (P <.001). NAT was associated with higher FEV 1 percent predicted values (P <.001), whereas IBS was associated with lower FEV 1 values in the controls but not in the case patients. The HLA-DR/DQ region on chromosome 6 (Chr6) was strongly associated with total serum IgE (rs3135348; P = 3.438 × 10–10) and was independent of an association with the haplotype HLA-DQA1 ∼ HLA-DQB1 :04.01∼04.02 (P = 1.55 × 10–05). For lung function, we identified a locus (rs4410198; P = 5.536 × 10–11) mapping to Chr19, near a cluster of zinc finger interacting genes that colocalizes to the long noncoding RNA CTD-2537I9.5. This novel locus was replicated in an independent sample of pediatric case patients with asthma with similar admixture from Brazil (P =.005). This study confirms the role of HLA in atopy, and identifies a novel locus mapping to a long noncoding RNA for lung function that may be specific to children with NAT. [ABSTRACT FROM AUTHOR]

In this review, we summarize recent published work interrogating the relationship between genetic variation or gene expression regulation across the genome and asthma or asthma treatment outcomes. This includes 11 genome-wide association studies of asthma phenotypes that collectively identified 64 novel loci; transcriptome-wide asthma association studies which identified genes involved in virus recognition, bacterial infection, lung tissue remodeling, eosinophilic and neutrophilic inflammation and genes in the chromosome 17q12 asthma susceptibility locus; and three epigenome-wide studies of asthma that had robust sample sizes and replicated findings. We also highlight pharmacogenomic studies of corticosteroids, bronchodilator response to albuterol and zileuton, although finding from these studies may still be preliminary due to their relatively small sample sizes and limited availability of replication cohorts. [ABSTRACT FROM AUTHOR]

Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (single nucleotide polymorphisms) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. To run the first HLA -centric association study with asthma and specific asthma-related phenotypes in a large cohort of African-ancestry individuals. We collected high-density genomics data for the Consortium on Asthma among African-ancestry Populations in the Americas (N = 4993) participants. Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE (tIgE) levels in subjects with and without asthma. Among the 1607 individuals with asthma, 972 had available tIgE levels, with a mean tIgE level of 198.7 IU/mL. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1∗09:01 was associated with increased tIgE levels (P = 8.5 × 10−4; weighted effect size, 0.51 [0.15-0.87]). We identified for the first time an HLA allele associated with tIgE levels in African-ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations. [ABSTRACT FROM AUTHOR]

Minority groups of African descent experience disproportionately greater asthma morbidity compared with other racial groups, suggesting that genetic variation from a common ancestry could influence exacerbation risk. We evaluated clinical trial measures in the context of self-reported race and genetic ancestry to identify risk factors for asthma exacerbations. One thousand eight hundred forty multiethnic subjects from 12 Asthma Clinical Research Network and AsthmaNet trials were analyzed for incident asthma exacerbations with Poisson regression models that included clinical measures, self-reported race (black, non-Hispanic white, and other), and estimates of global genetic African ancestry in a subgroup (n = 760). Twenty-four percent of 1840 subjects self-identified as black. Black and white subjects had common risk factors for exacerbations, including a history of 2 or more exacerbations in the previous year and FEV 1 percent predicted values, whereas chronic sinusitis, allergic rhinitis, and gastroesophageal reflux disease were only associated with increased exacerbation risk in black subjects. In the combined multiethnic cohort, neither race (P =.30) nor percentage of genetic African ancestry as a continuous variable associated with exacerbation risk (adjusted rate ratio [RR], 1.26 [95% CI, 0.94-1.70; P =.13]; RR per 1-SD change [32% ancestry], 0.97 [95% CI, 0.78-1.19; P =.74]). However, in 161 black subjects with genetic data, those with African ancestry greater than the median (≥82%) had a significantly greater risk of exacerbation (RR, 3.06 [95% CI, 1.09-8.6; P =.03]). Black subjects have unique risk factors for asthma exacerbations, of which global African genetic ancestry had the strongest effect. [ABSTRACT FROM AUTHOR]

Regulator of G protein signaling (RGS) 2 terminates bronchoconstrictive Gαq signaling; murine RGS2 knockout demonstrate airway hyperresponsiveness. While RGS2 promoter variants rs2746071 and rs2746072 associate with a clinical mild asthma phenotype, their impact on human airway smooth muscle (HASM) contractility and asthma severity outcomes is unknown. We sought to determine whether reductions in RGS2 expression seen with these 2 RGS2 promoter variants augment HASM contractility and associate with an asthma severity phenotype. We transfected HASM with a range of RGS2 -specific small interfering RNA (siRNA) concentrations and determined RGS2 protein expression by Western blot analysis and intracellular calcium flux induced by histamine (a Gαq-coupled H1 receptor bronchoconstrictive agonist). We conducted regression-based genotype association analyses of RGS2 variants from 611 patients from the National Heart, Lung, and Blood Institute Severe Asthma Research Program 3. RGS2 -specific siRNA caused dose-dependent increases in histamine-stimulated bronchoconstrictive intracellular calcium signaling (2-way ANOVA, P <.0001) with a concomitant decrease in RGS2 protein expression. RGS2 -specific siRNA did not affect Gαq-independent ionomycin-induced intracellular calcium signaling (P =.42). The minor allele frequency of rs2746071 and rs2746072 was 0.46 and 0.28 among African American/non-Hispanic Black patients and was 0.28 and 0.27 among non-Hispanic White patients, among whom these single nucleotide polymorphisms were in stronger linkage disequilibrium (r 2 = 0.97). Among non-Hispanic White patients, risk allele homozygotes for rs2746072 and rs2746071 each had nearly 2-fold greater asthma exacerbation rates relative to alternative genotypes with wild-type alleles (P additive = 2.86 × 10−5/ P recessive = 5.22 × 10−6 and P additive = 3.46 × 10−6/ P recessive = 6.74 × 10−7, respectively) at baseline, which was confirmed by prospective longitudinal exacerbation data. RGS2 promoter variation associates with a molecular and clinical phenotype characterized by enhanced bronchoconstrictive stimulation in vitro and higher asthma exacerbations rates in non-Hispanic White patients. [ABSTRACT FROM AUTHOR]

Pharmacogenetics is being used to develop personalized therapies specific to subjects from different ethnic or racial groups. To date, pharmacogenetic studies have been primarily performed in trial cohorts consisting of non-Hispanic white subjects of European descent. A “bottleneck” or collapse of genetic diversity associated with the first human colonization of Europe during the Upper Paleolithic period, followed by the recent mixing of African, European, and Native American ancestries, has resulted in different ethnic groups with varying degrees of genetic diversity. Differences in genetic ancestry might introduce genetic variation, which has the potential to alter the therapeutic efficacy of commonly used asthma therapies, such as β2-adrenergic receptor agonists (β-agonists). Pharmacogenetic studies of admixed ethnic groups have been limited to small candidate gene association studies, of which the best example is the gene coding for the receptor target of β-agonist therapy, the β2-adrenergic receptor (ADRB2). Large consortium-based sequencing studies are using next-generation whole-genome sequencing to provide a diverse genome map of different admixed populations, which can be used for future pharmacogenetic studies. These studies will include candidate gene studies, genome-wide association studies, and whole-genome admixture-based approaches that account for ancestral genetic structure, complex haplotypes, gene-gene interactions, and rare variants to detect and replicate novel pharmacogenetic loci. [Copyright &y& Elsevier]

The use of β2-adrenergic receptor agonists, or beta agonists, and their potential for an increased risk of asthma-related death were identified in the 1960''s, and appears to have been related to the marketing of specific preparations of short-acting beta agonists (SABA) that are no longer in use today. Subsequent studies have reported a potential for life-threatening or fatal adverse events with the use of long-acting beta agonist (LABA) therapy, but this conclusion must be tempered by the suboptimal design of the studies which form the foundation for these conclusions. Multiple prospective clinical trials and meta-analyses have demonstrated that the combination of a LABA and an ICS confers proven clinical benefits which appear greater than the rare risk for serious or life-threatening adverse events, although all of these studies have inadequate power to be definitive. [Copyright &y& Elsevier]

Loss of bronchoprotection (LOBP) with a regularly used long-acting β 2 -adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β 2 -adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate. We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)–treated patients. We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC 20 value. The mean doubling dose reduction in SPMCh PC 20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P =.62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P =.81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P =.86) and 0.8 for placebo (P =.15; P =.31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P =.43) and 1.02 for placebo (P =.84; P =.44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP. This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA–treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP. [ABSTRACT FROM AUTHOR]

Background: Sputum eosinophil percentages are a strong predictor of airway inflammation and exacerbations and aid asthma management, whereas sputum neutrophil percentages indicate a different severe asthma phenotype that is potentially less responsive to TH2-targeted therapy. Variables, such as blood eosinophil counts, total IgE levels, fraction of exhaled nitric oxide (Feno) levels, or FEV1 percent predicted, might predict airway eosinophil percentages, whereas age, FEV1 percent predicted, or blood neutrophil counts might predict sputum neutrophil percentages. Availability and ease of measurement are useful characteristics, but accuracy in predicting airway eosinophil and neutrophil percentages either individually or combined is not established. Objectives: We sought to determine whether blood eosinophil counts, Feno levels, and IgE levels accurately predict sputum eosinophil percentages and whether age, FEV1 percent predicted, and blood neutrophil counts accurately predict sputum neutrophil percentages. Methods: Subjects in the Wake Forest Severe Asthma Research Program (n = 328) were characterized by blood and sputum cell counts, health care use, lung function, Feno levels, and IgE levels. Multiple analytic techniques were used. Results: Despite significant association with sputum eosinophil percentages, blood eosinophil counts, Feno levels, and total IgE levels did not accurately predict sputum eosinophil percentages, and combinations of these variables did not improve prediction. Age, FEV1 percent predicted, and blood neutrophil counts were similarly unsatisfactory for the prediction of sputum neutrophil percentages. Factor analysis and stepwise selection found Feno levels, IgE levels, and FEV1 percent predicted, but not blood eosinophil counts, correctly predicted 69% of sputum eosinophil percentages of less than 2% or 2% and greater. Likewise, age, asthma duration, and blood neutrophil counts correctly predicted 64% of sputum neutrophil percentages of less than 40% or 40% and greater. A model to predict both sputum eosinophil and neutrophil percentages accurately assigned only 41% of samples. Conclusion: Despite statistically significant associations, Feno levels, IgE levels, blood eosinophil and neutrophil counts, FEV1 percent predicted, and age are poor surrogates, both separately and combined, for accurately predicting sputum eosinophil and neutrophil percentages. [Copyright &y& Elsevier]