Victor E. Ortega

Effect of rare variants in ADRB2 on risk of severe exacerbations and symptom control during longacting β agonist treatment in a multiethnic asthma population: a genetic study

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 β2-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<0·0001; and African American patients with or without the rare insertion, 3·7 [4·6] 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.

A continuum of admixture in the Western Hemisphere revealed by the African Diaspora genome

The African Diaspora in the Western Hemisphere represents one of the largest forced migrations in history and had a profound impact on genetic diversity in modern populations. To date, the fine-scale population structure of descendants of the African Diaspora remains largely uncharacterized. Here we present genetic variation from deeply sequenced genomes of 642 individuals from North and South American, Caribbean and West African populations, substantially increasing the lexicon of human genomic variation and suggesting much variation remains to be discovered in African-admixed populations in the Americas. We summarize genetic variation in these populations, quantifying the postcolonial sex-biased European gene flow across multiple regions. Moreover, we refine estimates on the burden of deleterious variants carried across populations and how this varies with African ancestry. Our data are an important resource for empowering disease mapping studies in African-admixed individuals and will facilitate gene discovery for diseases disproportionately affecting individuals of African ancestry.

Asthma pharmacogenetics and the development of genetic profiles for personalized medicine

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.

Asthma pharmacogenetics: responding to the call for a personalized approach.

Purpose of reviewAsthma 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 findingsPharmacogenetic 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. SummaryIt 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.

The Effect of Ancestry and Genetic Variation on Lung Function Predictions: What Is “Normal” Lung Function in Diverse Human Populations?

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.

Implications of population structure and ancestry on asthma genetic studies.

Purpose of reviewThe 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 themesThe 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. SummaryThe 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 and the Development of Personalized Approaches for Combination Therapy in Asthma

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.

Predictive genetic profiles for β-agonist therapy in asthma. A future under construction.

The goal of pharmacogenetic research is to determine the effects of genetic variation on the response of a phenotype to a pharmacologic agent. Pharmacogenetics has the potential to identify genetic biomarkers that can be used to stratify individuals for personalized therapies and, thus, place the individual at the center of therapeutic management decisions for precision medicine. Personalized medicine has a potential role in the treatment of asthma as a result of high interindividual variability in therapeutic responsiveness to the different classes of therapy for asthma. Among airways diseases, genetic studies have been successful in the development of personalized therapies for cystic fibrosis in individuals with specific rare coding variants in CFTR, yet no genetic variant has been successfully translated to the treatment of asthma (1). Pharmacogenetic studies addressing inhaled b2-adrenergic receptor agonist (b-agonist) response in asthma are unique among the different classes of pharmacologic therapies used to treat asthma, in that these studies address a controversy dating back to the 1960s. Epidemiologic studies identified an increased risk for asthma-related death during treatment with two less-selective inhaled short-acting b-agonists (SABAs) during mortality epidemics through the 1960s and 1970s, which resolved after the withdrawal of these drugs (2, 3). More recently, two large surveillance studies, including the Salmeterol Multicenter Asthma Research Trial, have shown a small increase in life-threatening asthma exacerbations and death during treatment with the longacting b-agonist (LABA) salmeterol (4). Despite clinical trial and meta-analytical evidence demonstrating the efficacy and safety of LABA when used in combination with an inhaled glucocorticoid, these safety concerns resulted in a boxed warning from the US Food and Drug Administration and a mandatory LABA safety study that is currently enrolling 46,800 patients with asthma (5). Identification of subgroups at risk for adverse responses to b-agonists is critical to understanding the mechanisms that underlie LABA safety and the development of biomarkers for personalized therapies. Genetic studies for b-agonist response in asthma have included biologic candidate genes in the b2-adrenergic receptor and nitric oxide biosynthetic pathways. Most studies have focused on the gene encoding the b2-adrenergic receptor (ADRB2), which has common coding variants, GlyArg and GlnGlu, with functional effects in vitro (6). GlyArg was associated with acute bronchodilation in response to albuterol and long-term response to regular albuterol treatment; however, this locus did not alter responses to LABA therapy in a number of genetic studies, including two genotype-stratified clinical trials (7–10). In a recent study, two rare ADRB2 variants were associated with hospitalization during LABA therapy, suggesting a role for rare variants in determining adverse responses (11). High-throughput whole-genome genotyping has recently provided an opportunity for unbiased genome-wide association studies (GWAS), which have discovered novel pharmacogenetic loci. The first GWAS for acute SABA bronchodilation identified a locus in spermatogenesis-associated serine-rich 2–like gene (SPATS2L) in non-Hispanic whites from six clinical trial cohorts and the National Heart, Lung, and Blood Institute Severe Asthma Research Program. MicroRNA knockdown of SPATS2L in human airway smooth muscle cells resulted in increased expression of the b2-adrenergic receptor (12). Two recent GWAS have identified additional novel loci associated with SABA bronchodilation, one of which used GWAS and admixture mapping to identify rare variants (allele frequency, ,0.05) in solute carrier genes (13, 14). Although some of the common variants identified in these GWAS were replicated in independent cohorts, none met the stringent threshold of genome-wide significance. In this issue of the Journal, Israel and colleagues (pp. 530–537) performed a GWAS of the degree of FEV1 bronchodilation after two or more inhalations of albuterol in 724 non-Hispanic white patients with asthma from the SHARE-Asthma Resource Project, which identified and replicated associations with four loci adjacent to the ankyrin repeat and SOCS (suppressor of cytokine signaling) box– containing 3 gene (ASB3) (15). A meta-analysis of the discovery and replication cohorts identified stronger associations for these single nucleotide polymorphisms (SNPs); thus, this GWAS was the first to report associations reaching genome-wide significance for b-agonist response in asthma. Israel and colleagues also identified plausible relationships between ASB3 and biologic pathways that regulate smooth muscle proliferation and b2-adrenergic receptor signaling, using bioinformatics database analyses to provide supporting biologic evidence for ASB3 as a pharmacogenetic locus. Are the variants identified by Israel and colleagues ideal genetic biomarkers for stratified, personalized treatment in an individual patient with asthma? The data presented are suggestive; however, more information is needed. The four SNPs identified in this GWAS were located approximately 1 million bases away from ASB3 and are likely surrogate-tagging SNPs for another causative variant. More detailed genotyping or DNA sequencing of the genomic region encompassing the regulatory and coding regions containing the SNPs identified in this GWAS and ASB3 will be necessary. In addition, the role of gene variation in ASB3 in the regulation of smooth muscle proliferation and b2-adrenergic receptor-mediated smooth muscle relaxation must be confirmed with in vitro functional studies. Could this novel pharmacogenetic locus for acute SABA bronchodilation alter responses to long-term, regular b-agonist treatment? The GlyArg locus in ADRB2 demonstrated contradictory effects on lung function response during acute bronchodilation versus long-term regular SABA therapy (7, 10). Furthermore, GlyArg genotype was not associated with clinical responsiveness to regular LABA therapy in multiple pharmacogenetic studies (8, 9). Therefore, the ASB3 locus should be evaluated in LABA-treated clinical trial cohorts. An important caveat is that although asthma management guidelines recommend that SABA therapy only be used as a rescue therapy, regular SABA treatment is still used in many areas of the world where asthma controller therapies are not readily available. Thus, the ASB3 locus could identify a subgroup of patients with asthma in whom regular SABA use is effective. It is also important to note that the clinical trial cohorts evaluated in this GWAS were treated EDITORIALS

Income Is an Independent Risk Factor for Worse Asthma Outcomes

Background: Socioeconomic status (SES) is associated with asthma morbidity in observational studies, but the factors underlying this association are uncertain. Objective: We investigated whether 3 SES correlates—low income, low education, and high perceived stress—were independent risk factors for treatment failure and asthma exacerbations in the context of a randomized controlled trial. Methods: The effect of low SES (household income of <

ASSOCIATION OF FREE VITAMIN D3 CONCENTRATIONS AND ASTHMA TREATMENT FAILURES in the VIDA Trial

50,000/y and household educational level of less than a Bachelors degree) and high perceived stress (defined as a score of >20 on a perceived stress scale) on asthma morbidity was analyzed in 381 participants by using Poisson regression models. The primary outcome was treatment failure (defined in the trial protocol as a significant clinical or airflow deterioration), and the secondary outcome was asthma exacerbations requiring systemic corticosteroids. Results: Fifty‐four percent of participants had a low income, 40% had a low educational level, and 17% had high perceived stress levels. Even after adjusting for race and other important confounders, participants with lower income had higher rates of both treatment failures (rate ratio, 1.6; 95% CI, 1.1‐2.3; P = .03) and exacerbations (rate ratio, 1.9; 95% CI, 1.1‐3.3; P = .02). Adherence with inhaled corticosteroids was similarly high for both income categories. Education and perceived stress were not significantly associated with either outcome. Conclusions: In the context of a randomized controlled trial, participants with lower income were more likely to experience adverse asthma outcomes independent of education, perceived stress, race, and medication adherence.