Personalized Asthma Therapy in Blacks-the Role of Genetic Ancestry.

It's not about races…Where your blood comes from…I'm not going to spend my life being a color…It don't matter if you're black or white—Michael Jackson, 1991 In recent years, it has become increasingly clear that “one size does not fit all” when it comes to choosing appropriate asthma therapies. Some patients respond to some therapies, whereas other patients respond to other therapies, and some fail to respond at all to any therapy given. Although some of the differential response relates to environmental factors or lack of adherence, in an effort to identify which therapy a given individual responds to, physicians and investigators have attempted to ascertain whether one can use specific features of a given individual to personalize the approach to asthma management. Such features have included phenotypic predictors such as age, race, body mass index, or sex,1Dunn R.M. Lehman E. Chinchilli V.M. Martin R.J. Boushey H.A. Israel E. et al.Impact of age and gender on response to asthma therapy.Am J Respir Crit Care Med. 2015; 192: 551-558Crossref PubMed Scopus (35) Google Scholar whereas endotypic approaches have used specific biomarkers to tailor asthma therapy. For instance, biomarker-based approaches have included utilization of blood biomarkers such as eosinophils to predict responsiveness to inhaled corticosteroids (ICS) or to anti–IL-5, utilization of exhaled nitric oxide to titrate ICS therapy, or novel biomarkers such as periostin and dipeptidyl peptidase 4 as predictors of anti–IL-13 therapy.2Zissler UM, Esser-von Bieren J, Jakwerth CA, Chaker AM, Schmidt-Weber CB. Current and future biomarkers in allergic asthma [published online ahead of print December 15, 2015]. Allergy doi: 10.1111/all.12828.Google Scholar Although these phenotypic and endotypic approaches offer promise to increase the likelihood of response to asthma therapy, the ultimate personalized approach is one that depends on pharmacogenomics, treatment based on one's specific genotype (Fig 1). There have been multiple studies over the last 20 years that have explored genetic determinants of response to therapy, especially ones that have focused on beta-2 receptor polymorphisms and response to beta agonists3Wechsler M.E. Kunselman S.J. Chinchilli V.M. Bleecker E. Boushey H.A. Calhoun W.J. et al.Effect of beta2-adrenergic receptor polymorphism on response to long acting beta2 agonist in asthma (LARGE trial): a genotype-stratified, randomized, placebo-controlled, crossover trial.Lancet. 2009; 374: 1754-1764Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar as well as other retrospective analyses assessing response to different asthma medications based on polymorphisms of genes in the leukotriene and corticosteroid pathways. None of these has assessed the role of genetic ancestry in terms of response to therapy. More importantly, none of these has really resulted in changes in therapeutic approach, possibly because of the lack of replication of data in a prospective manner, or because of the notion that a substantial proportion of lack of response is environmentally mediated. Nonetheless, it is important to keep searching for novel predictors of response because substantial cost and risk of adverse effects are manifest with therapeutic interventions that are not effective in controlling disease. In this issue of the Journal, Wells et al4Wells K.E. Cajigal S. Peterson E.L. Ahmedani B.K. Kumar R. Lanfear D.E. et al.Assessing differences in inhaled corticosteroid response by self reported race-ethnicity and genetic ancestry among individuals with asthma.J Allergy Clin Immunol. 2016; 137: 1364-1369Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar attempt to assess the utility of 2 novel predictors of response to asthma therapy as they explore whether self-reported ethnicity and genetic ancestry can predict ICS responsiveness in blacks with asthma. Although ICS remain the cornerstone of asthma therapy, many patients with asthma, especially those with noneosinophilic asthma, fail to demonstrate a benefit with their use. Indeed, blacks with asthma, both adults and children, bear a disproportionate burden of disease when compared with whites in the United States: they have a higher prevalence of disease, a higher hospitalization rate, and greater morbidity and mortality.5Akinbami L.J. Moorman J.E. Bailey C. Zahran H.S. King M. Johnson C.A. et al.Trends in asthma prevalence, health care use, and mortality in the United States, 2001-2010.NCHS Data Brief. 2012; : 1-8PubMed Google Scholar, 6Akinbami L.J. Moorman J.E. Simon A.E. Schoendorf K.C. Trends in racial disparities for asthma outcomes among children 0 to 17 years, 2001-2010.J Allergy Clin Immunol. 2014; 134: 547-553Abstract Full Text Full Text PDF PubMed Scopus (196) Google Scholar Is this just because of their genetic ancestry? There are multiple factors that are thought to contribute to the greater disease severity seen in this population. Behavioral and socioeconomic factors, including adherence and access to health care providers and medications, are clearly a significant component.7Thakur N. Oh S.S. Nguyen E.A. Martin M. Roth L.A. Galanter J. et al.Socioeconomic status and childhood asthma in urban minority youths. The GALA II and SAGE II studies.Am J Respir Crit Care Med. 2013; 188: 1202-1209Crossref PubMed Scopus (81) Google Scholar However, even when controlling for socioeconomic status, there continue to be significant race-related differences in asthma morbidity and mortality.8McDaniel M. Paxson C. Waldfogel J. Racial disparities in childhood asthma in the United States: evidence from the National Health Interview Survey, 1997 to 2003.Pediatrics. 2006; 117: e868-e877Crossref PubMed Scopus (129) Google Scholar It is thus natural to question, as these authors did, whether African ancestry, in and of itself, is a major determinant of these discrepancies. The authors build upon and confirm previously published data9Gould W. Peterson E.L. Karungi G. Zoratti A. Gaggin J. Toma G. et al.Factors predicting inhaled corticosteroid responsiveness in African American patients with asthma.J Allergy Clin Immunol. 2010; 126: 1131-1138Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar by increasing their sample size and including a group of patients with European ancestry. They studied 339 participants in the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity and explored predictors of response to ICS over 6 weeks in a nonrandomized, open-label, prospective trial. Baseline Asthma Control Test score, percent of predicted FEV1, degree of bronchodilator response, and ICS adherence were significantly associated with ICS response. Although the finding that inhaled steroids improve lung function has been long reported, even in this population, the demonstration that blacks respond similarly to ICS as European Americans is both novel and important because one possible explanation for the increased black morbidity has been that blacks respond less well to these medications. Indeed, a previous analysis of the National Institute of Health's Asthma Clinical Research Network's cohort had demonstrated that blacks treated with ICS had more asthma treatment failures than whites who were treated similarly with ICS.10Wechsler M.E. Castro M. Lehman E. Chinchilli V. Rand Sutherland E. Denlinger L. et al.the NHLBI Asthma Clinical Research NetworkImpact of race on asthma treatment failures in the Asthma Clinical Research Network.Am J Respir Crit Care Med. 2011; 184: 1247-1253Crossref PubMed Scopus (72) Google Scholar However, in that retrospective study, almost all the differences in response to ICS were attributed to concomitant use of long-acting beta-agonists. Perhaps it is only a subset of blacks who are poor responders to ICS? Although ICS have been shown to be the preferred step-up asthma therapy in blacks with eczema,11Malka J. Mauger D.T. Covar R. Rabinovitch N. Lemanske Jr., R.F. Spahn J.D. et al.Eczema and race as combined determinants for differential response to step-up asthma therapy.J Allergy Clin Immunol. 2014; 134: 483-485Abstract Full Text Full Text PDF PubMed Scopus (24) Google Scholar for example, clearly we need novel specific phenotypic or physiologic characteristics that can identify those most likely to respond to these and other therapies. The most fascinating aspect of this study, however, is that neither self-reported race-ethnicity among all participants nor proportion of African ancestry among black participants was associated with differential ICS responsiveness. This suggests that there is not a significant contribution of black genetic ethnicity to the differential response. It also suggests that studying genetic ancestry does not offer substantially more than using the less precise “self-identified” race. Although blacks remain a vulnerable patient population who suffer significant morbidity and mortality from asthma, this study suggests that we cannot blame ICS because blacks responded as well as whites. Nor can we blame degree of African genetic ethnicity. There must be other factors in this population that play a more important role in causing these differences, and we still need to identify what is at the root of these differences. Although the authors' findings were similar after restricting the cohort to individuals with an Asthma Control Test score of less than 20 or FEV1 of less than 70%, one of the weaknesses of the study is that this is a relatively mild population of patients with asthma who were previously not on ICS. It may be more pertinent to study steroid responsiveness in patients with more severe disease on different steroid doses because those with severe asthma account for a significant degree of health care burden in this population. Furthermore, this was a relatively short treatment duration of ICS. Importantly, this study does not tell us whether the response to long-acting beta-agonists, anticholinergics, leukotriene receptor antagonists, or newer biologics such as omalizumab or mepolizumab is substantially influenced by genetic ancestry or race. Although ICS therapy has long been recognized as a key asthma controller therapy among all patients with asthma regardless of race or ethnicity, guidance on whether these other therapies have differential responses across racial or ethnic groups would be useful in guiding therapy in those with more severe asthma who are not controlled by these commonly prescribed controller medications. This study poses the important question of whether self-reported race or genetic ancestry predicts responsiveness to asthma therapies, and paves the way for a better understanding of personalized asthma management. In general, blacks are understudied in clinical trials and thus we have little information about whether they respond the same or differently to standard therapies. Clearly, more investigation needs to be done in this patient population so that we can understand what leads to the important clinical differences that exist. Although we will continue to need more robust cohorts to inform us about what impact racial differences and genetic ancestry may have on the response to different therapies or in those with more severe asthma, based on this analysis, it appears that Michael Jackson was correct, when he opined 25 years ago, that when it comes to ICS, “it don't matter if you're black or white.” Assessing differences in inhaled corticosteroid response by self-reported race-ethnicity and genetic ancestry among asthmatic subjectsJournal of Allergy and Clinical ImmunologyVol. 137Issue 5PreviewInhaled corticosteroids (ICSs) are the preferred treatment for achieving asthma control. However, little is known regarding the factors contributing to treatment response and whether treatment response differs by population group. Full-Text PDF