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BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.METHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.RESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 × 10−9 and 2.97 × 10−8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the “atopic march” and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 ×10−6 ≤ p ≤ 3.06 ×10−6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.CONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

Purpose of review The frequency and severity of asthma differ between different racial and ethnic groups. An understanding of the genetic basis for these differences could constitute future genetic biomarker panels for predicting asthma risk and progression in individuals from different ethnic groups. Recent themes The recent mixing of different ancestries during the European colonization of the Americas and the African slave trade has resulted in the complex population structures identified in different ethnic groups. These population structures represent varying degrees of genetic diversity which impacts the allele frequency of individual variants and, thus, how the gene variation is utilized in genetic association studies. In this review, we will discuss the basis for the complex population structures of modern human genomes and the impact of genetic diversity on genetic studies in different ethnic groups. We will also highlight the potential for admixture and rare variant-based genetic studies to identify novel genetic loci for asthma susceptibility and severity. Summary The ability to account for the consequences of genetic diversity in different racial and ethnic groups will be critical in developing genetic profiles for personalized or precision medicine approaches tailored to asthmatic patients from different ethnic groups.

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.

Asthma is a common, chronic disease of the airways that is treated with a combination of different therapies. The combination of LABA and ICS therapy results in a synergistic interaction that is efficacious in improving asthma symptom control; however, genetic variation has the potential to alter therapeutic efficacy. Both agents mediate complex molecular pathways consisting of gene variation that has been investigated with the analysis of candidate genes in the β2-adrenergic receptor and glucocorticoid pathway. These pharmacogenetic studies have been limited to retrospective analyses of clinical trial cohorts and a small number of prospective, genotype-stratified trials. More recently, genome-wide association studies in combination with replication in additional cohorts and in vitro cell-based models have been used to identify novel pathway-related pharmacogenetic variations. This review of the pharmacogenetics of the β2-adrenergic receptor and glucocorticoid pathways highlights the genotypic effects of variation in multiple genes from interacting pathways which may contribute to differential responses to inhaled beta agonists and glucocorticoids. As our understanding of these genetic mechanisms improves, panels of biomarkers may be developed to determine which combination therapies are the most effective with the least risk to an individual asthma patient. Before we can usher in an era of personalized medicine for asthma, it is first important to improve our ability to analyze large volumes of genetic data in large clinical trial cohorts using a combination of study designs, analytical methods, and in vitro functional studies.

Rationale: Despite significant advances in knowledge of the genetic architecture of asthma, specific contributors to the variability in the burden between populations remain uncovered.

Background: Smokers has been clustered into COPD and non-COPD clusters (Li, ATS 2016). Smokers with preserved lung function may have COPD symptoms, exacerbations, and usage of respiratory medicine (Woodruff, NEJM 2016, 374:1811-21). Objectives: We aim to compare clinical characteristics of four clusters mainly composed of smokers with preserved lung function. Methods: Clinical characteristics were compared using the Kruskal-Wallis test and chi-square test. Results: C1 consists of resistant smokers with normal lung function, early emphysema, lower HCU and inhaled steroid (ICS) use, and lower symptom scores. C2 consists of heavy smokers with normal lung function, early emphysema, higher HCU and ICS use, and higher blood neutrophils. C3 has normal lung function, no emphysema, and lower HCU and ICS use. C4 has lower lung function, no emphysema, higher HCU and ICS use, higher “label” of asthma, higher inflammation, and higher symptom scores. Conclusions: Four distinct endophenotypic clusters mainly composed of smokers with preserved lung function have been identified. This study supports heterogeneity of smokers and indicates the distinction between smokers with preserved lung function and COPD is not as simple as measuring spirometry alone .

Introduction: Eosinophils (Eos) in blood or sputum in subjects with COPD are thought to predict exacerbations and therapeutic response. Objective: To determine whether blood Eos in COPD are valid predictors for sputum Eos and exacerbations, we examined and compared blood and sputum Eos in the SPIROMICS cohort for spirometry, clinical measures, quantitated computed tomography (qCT), and exacerbations. Methods: Comprehensive baseline data on SPIROMICS subjects (broad COPD severity range) included demographics, questionnaires, clinical assessments, qCT, blood and sputum collection. Subjects were stratified by mean blood (N=2499, Results: Subjects stratified by blood Eos showed no significant association with disease severity by GOLD Stage compared to sputum Eos (p=0.0006). Baseline FEV1%pred was lower with blood Eos≥200/mL (p=0.006), but differences were small (66% vs Conclusions: Increased blood Eos did not reliably predict sputum Eos, and unlike sputum eosinophils, showed no association with severity or exacerbations in COPD.

Background: PI type Z heterozygotes (Glu 366 Lys in SERPINA1 ) with a prior smoking history have been shown to have greater CT scan-based emphysema compared to PI MM wild types (Sorheim CHEST 2010). There are no studies evaluating the regional effects of rare SERPINA1 variants on CT scan-based emphysema or airtrapping. Aims and Objectives: The effects of rare SERPINA1 variants on regional CT scan emphysema and airtrapping were evaluated in NHLBI SPIROMICS. Methods: 1,715 non-Hispanic Whites(NHW), 392 African Americans, and 98 Hispanics with ≥20 pack-year smoking were genotyped for 24 rare coding variants (allele frequency≤5%). Regression-based models of CT scan emphysema (%lung area≤-950 HFU) and airtrapping (%≤-856 HFU) were performed. Results: In NHW, PI Z was associated with bilateral emphysema (CC=7.8%, CT=12%, TT=24%, p =5.5x10 -8 ) and airtrapping (CC=25%, CT=34%, TT=54%, p =7.1x10 -9 ). PI Z heterozygotes (MZ, N=73), PI Z homozygotes (ZZ, N=9), and PI Z-containing compound heterozygotes (ZS/ZV R , N=7) had greater bilateral emphysema (No Z=7.8%, MZ=12%, ZS/ZV R =13%, ZZ=24%, p=2.0x10 -7 ), and airtrapping (No Z=25%, MZ=33%, ZS/V R =49%, ZZ=54%, p=2.7x10 -8 ) compared to NHW without PI Z (No Z, N=1,499). Lower lung zone emphysema (p=0.008-0.04) and airtrapping (p=0.005-0.02) was lower in No Z compared to MZ. Upper and lower zone disease was lower in No Z versus ZZ (emphysema upper zones p=0.001-0.002, lower zones pp=1.2x10 -9 -1.2x10 -8 ; airtrapping upper zones p=2.5x10 -5 -0.0004, lower zones p=4.0x10 -9 -9.9x10 -9 ). ZS/ZV R had more upper zone airtrapping versus ZZ (p=0.03-0.04). Conclusions: In NHW, PI Z-containing SERPINA1 genotypes have cumulative effects on emphysema and airtrapping in both the upper and lower lung zones.

In the version of this article initially published, the statement "there are no pan-genomes for any other animal or plant species" was incorrect. The statement has been corrected to "there are no reported pan-genomes for any other animal species, to our knowledge." We thank David Edwards for bringing this error to our attention. The error has been corrected in the HTML and PDF versions of the article.

Background Use of vitamin D3 serum concentrations as a biomarker of vitamin D status is questionable because of variation in vitamin D binding protein. Objective To determine associations between free vitamin D3 concentrations and rates of treatment failure and exacerbations in patients with asthma participating in the Vitamin D Add-on Therapy Enhances Corticosteroid Responsiveness in Asthma (VIDA) trial. Methods Free concentrations were directly measured by enzyme-linked immunosorbent assay and stratified into low, medium, and high groups: less than 5 pg/mL (n = 65), 5 to 9 pg/mL (n = 84), and greater than 9 pg/mL (n = 48) after 12 weeks of supplementation with oral vitamin D3 and associated with outcomes. Results Outcomes did not associate with free concentrations: overall treatment failure rates were 0.60 (95% confidence interval [CI] 0.46-0.78), 0.53 (95%CI 0.40- 0.70), and 0.69 (95%CI 0.54-0.90)/person-year (P = .51), respectively; overall exacerbation rates were 0.28 (95%CI 0.17-0.48), 0.15 (95%CI 0.08-0.30) and 0.42 (95%CI 0.27-0.66)/person-year (P = .22). Mean (standard deviation) baseline free concentrations were lower in non-Hispanic blacks and Hispanics compared with non-Hispanic whites: 4.10 (1.33) and 4.38 (1.11) pg/mL vs 5.16 (1.65) pg/ml, (P 25): 5.45 (1.86) vs 4.54 (1.39) (P Conclusion The use of free concentrations was inferior to total concentrations as a biomarker of efficacy of vitamin D3 supplementation in VIDA trial participants. Future studies of vitamin D status in patients with asthma should measure both free and total concentrations to better understand which marker of vitamin D function is most informative.

The use of beta(2)-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.

In August 2006, the Center for Human Genomics of the Wake Forest University School of Medicine in Winston-Salem, NC, hosted the National Institutes of Health-sponsored Roadmap Course entitled Models and Technologies for Defining Phenotype. Twenty-four biomedical and genomic researchers from throughout the world and with varying degrees of experience in the genomics, biological, and biomedical engineering sciences were invited to participate as students in a comprehensive course dedicated to presenting and evaluating current and future approaches that can overcome the problems experienced to date in characterizing the functional consequences of gene variation. A total of 34 senior researchers from four different academic institutions served as course faculty and employed a pedagogical approach that emphasized hands-on workshops, demonstrations, and small group discussions and tasks. Through this report we convey the complex and formidable problems unique to genomics research as we attempt to link the field of genomic research to complex human diseases. Furthermore, we describe the logic and organization of a Roadmap Course designed to teach a diverse group of researchers a multi-disciplinary approach to addressing complex biomedical scenarios in the field of human genomics.

Lung function measures are an invaluable screening test for respiratory health and have been associated with the morbidity and mortality related to different airway disease as well as all-cause mortality. Currently, reference values for spirometric measurements are obtained using equations derived from individual ethnic or racial groups. The rapid expansion of more racially and ethnically diverse populations will challenge current race-based lung function reference equations. Recent international general population studies and ancestry-based genetic studies have found that ancestry and genetic variation are determinants of lung function and have suggested a role for genetic ancestry or gene variants in future lung function reference equations. In this review, we discuss the potential limitations of current lung function reference equations in a global society which is becoming more ethnically, racially, and, thus, genetically diverse. We also focus on how an individual's ancestral background or genetic profile could provide the basis for more accurate, personalized predictions of an individual's baseline lung function.

Asthma GWAS of Puerto Rican individuals finds strongest association within the 17q21 ORMDL3/GSDMB locus http://ow.ly/M23930ayVbG

Small airways function is a potential marker for lung function impairment in α1-antitrypsin deficiency http://ow.ly/qZ5x309idJz

Summary Background Severe adverse life-threatening events associated with longacting β agonist (LABA) use have caused the US Food and Drug Administration (FDA) to review the safety of these drugs, resulting in a boxed warning and a mandatory safety study in 46 800 patients with asthma. Identification of an at-risk, susceptible subpopulation on the basis of predictive biomarkers is crucial for understanding LABA safety. The β 2 -adrenergic receptor gene ( ADRB2 ) contains a common, non-synonymous single nucleotide polymorphism, Gly16Arg, that is unlikely to account for the rare, life-threatening events seen with LABA use. We hypothesise that rare ADRB2 variants modulate therapeutic responses to LABA therapy and contribute to rare, severe adverse events. Methods In this genetic study, ADRB2 was sequenced in 197 African American, 191 non-Hispanic white, and 73 Puerto Rican patients. Sequencing identified six rare variants, which were genotyped in 1165 patients with asthma. The primary hypothesis was that severe asthma exacerbations requiring hospital admission were associated with rare ADRB2 variants in patients receiving LABA therapy. This outcome was assessed overall and by ethnic group. Replication was done in 659 non-Hispanic white patients with asthma. Findings Patients receiving LABA with a rare ADRB2 variant had increased asthma-related hospital admissions (15 [44%] of 34 patients with rare variant vs 121 [22%] of 553 patients with common ADRB2 alleles admitted to hospital in past 12 months; meta-analysis for all ethnic groups, p=0·0003). Specifically, increases in hospital admission rates were recorded in LABA-treated non-Hispanic white patients with the rare Ile 164 allele compared with non-Hispanic white patients with the common allele (odds ratio [OR] 4·48, 95% CI 1·40–13·96, p=0·01) and African American patients with a 25 bp promoter polynucleotide insertion, −376ins, compared with African American patients with the common allele (OR 13·43, 95% CI 2·02–265·42, p=0·006). The subset of non-Hispanic white and African American patients receiving LABAs with these rare variants had increased exacerbations requiring urgent outpatient health-care visits (non-Hispanic white patients with or without the rare Ile 164 allele, 2·6 [SD 3·5] vs 1·1 [2·1] visits, p vs 2·4 [3·4] visits, p=0·01), and more frequently were treated with chronic systemic corticosteroids (OR 4·25, 95% CI 1·38–14·41, p=0·01, and 12·83, 1·96–251·93, p=0·006). Non-Hispanic white patients from the primary and replication cohorts with the rare Ile 164 allele were more than twice as likely as Thr 164 homozygotes to have uncontrolled, persistent symptoms during LABA treatment (p=0·008–0·04). Interpretation The rare ADRB2 variants Ile164 and −376ins are associated with adverse events during LABA therapy and should be evaluated in large clinical trials including the current FDA-mandated safety study. Funding US National Institutes of Health.

Purpose of review Asthma is a chronic, complex disease that is treated with a combination of different therapies. However, interindividual variability in clinical responses to different therapies complicates asthma management. A personalized approach to asthma management could identify appropriate responders to specific agents or those that might be at an increased risk for adverse responses. Recent findings Pharmacogenetic studies of genes from the leukotriene, glucocorticoid, and beta2-adrenergic receptor pathways have improved our understanding of how gene variation determines therapeutic responses to different classes of antiasthma therapies. Such studies have previously been limited to retrospective analyses of candidate genes in the leukotriene, glucocorticoid, and beta2-adrenergic receptor pathways in trial cohorts. However, prospective genotype-stratified trials in asthma have recently been done and recent genome-wide association studies have identified novel pharmacogenetic loci. Summary It will be important to replicate previous genotypic associations in large clinical trial cohorts as future pharmacogenetic studies continue to focus on genome-wide approaches and the study of novel therapeutic pathways. This review of the pharmacogenetics of asthma highlights the contributions of genomics research to the future of personalized medicine in asthma and draws attention to the role of genetic biomarkers in predicting clinical responses to specific therapies.

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 T H 2-targeted therapy. Variables, such as blood eosinophil counts, total IgE levels, fraction of exhaled nitric oxide (Feno) levels, or FEV 1 percent predicted, might predict airway eosinophil percentages, whereas age, FEV 1 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, FEV 1 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, FEV 1 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 FEV 1 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, FEV 1 percent predicted, and age are poor surrogates, both separately and combined, for accurately predicting sputum eosinophil and neutrophil percentages.

Asthma is a complex genetic disease with multiple genetic and environmental determinants contributing to the observed variability in response to common anti-asthma therapies. Asthma pharmacogenetic research has focused on multiple candidate genes including the β2-adrenergic receptor gene (ADRβ2) and its effect on individual responses to beta agonist therapy. At present, knowledge about the effects of ADRβ2 variation on therapeutic responses is evolving and should not alter current Asthma Guideline approaches consisting of the use of short acting beta agonists for as-needed symptom based therapy and the use of a regular long-acting beta agonist in combination with inhaled corticosteroid therapy for optimal control of asthma symptoms in those asthmatics who are not controlled on inhaled corticosteroid alone. This approach is based upon studies showing a consistent pharmacogenetic response to regular use of short acting beta agonists (SABA) and less consistent findings in studies evaluating long acting beta agonist (LABA). While emerging pharmacogenetic studies are provocative and should lead to functional approaches, conflicting data with responses to LABA therapy may be caused by factors that include small sample sizes of study populations and differences in experimental design that may limit the conclusions that may be drawn from these clinical trials at the present time.

Human genetics research will be critical to the development of genetic profiles for personalized or precision medicine in asthma. Genetic profiles will consist of gene variants that predict individual disease susceptibility and risk for progression, predict which pharmacologic therapies will result in a maximal therapeutic benefit, and predict whether a therapy will result in an adverse response and should be avoided in a given individual. Pharmacogenetic studies of the glucocorticoid, leukotriene, and β2-adrenergic receptor pathways have focused on candidate genes within these pathways and, in addition to a small number of genome-wide association studies, have identified genetic loci associated with therapeutic responsiveness. This review summarizes these pharmacogenetic discoveries and the future of genetic profiles for personalized medicine in asthma. The benefit of a personalized, tailored approach to health care delivery is needed in the development of expensive biologic drugs directed at a specific biologic pathway. Prior pharmacogenetic discoveries, in combination with additional variants identified in future studies, will form the basis for future genetic profiles for personalized tailored approaches to maximize therapeutic benefit for an individual asthmatic while minimizing the risk for adverse events.