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Asthma in Puerto Ricans: Lessons from a high-risk population

2016; Elsevier BV; Volume: 138; Issue: 6 Linguagem: Inglês

10.1016/j.jaci.2016.08.047

1097-6825

Sylvia Szentpetery, Erick Forno, Glorisa Canino, Juan C. Celedón,

Health disparities and outcomes

Per the 2014 Census, there were 8.6 million Puerto Ricans in the United States, including 5.1 million residents of the continental United States and 3.5 million residents of the island of Puerto Rico (a US territory). In the United States Puerto Ricans report the largest proportion of families at less than the poverty level (24%).1Available at: http://centropr.hunter.cuny.edu/research/datacenter/puerto-ricans-us-earn-less-money-and-pay-more-housing. Accessed June 14, 2016.Google Scholar Puerto Ricans are disproportionately affected by asthma. In the United States the prevalence of asthma is higher in Puerto Ricans (16.1%) than in non-Hispanic blacks (11.2%), non-Hispanic whites (7.7%), or Mexicans (5.4%).2Akinbami 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 Moreover, morbidity and mortality from asthma are higher in Puerto Ricans than in other racial or ethnic groups.3Rosser F.J. Forno E. Cooper P.J. Celedon J.C. Asthma in Hispanics. An 8-year update.Am J Respir Crit Care Med. 2014; 189: 1316-1327Crossref PubMed Scopus (96) Google Scholar Studying Puerto Ricans or other high-risk groups is not only important for public health but might also yield new insights into asthma pathogenesis. A growing body of evidence supports a multifactorial cause of asthma in Puerto Ricans, with yet-to-be identified interactions between heredity and environmental risk factors. Puerto Ricans can be of any race, but most have variable proportions of European, West African, and Native American ancestry. Recent work with ancestry-informative genetic markers shows that, on average, Puerto Ricans are 60% to 70% European, 18% to 25% African, and 12% to 15% Native American.4Brehm J.M. Acosta-Perez E. Klei L. Roeder K. Barmada M.M. Boutaoui N. et al.African ancestry and lung function in Puerto Rican children.J Allergy Clin Immunol. 2012; 129: 1484-1490.e6Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 5Pino-Yanes M. Thakur N. Gignoux C.R. Galanter J.M. Roth L.A. Eng C. et al.Genetic ancestry influences asthma susceptibility and lung function among Latinos.J Allergy Clin Immunol. 2015; 135: 228-235Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Among Hispanic children (including Puerto Ricans), African ancestry is inversely associated with lung function (FEV1 and forced vital capacity) but positively associated with asthma, whereas Native American ancestry is positively associated with lung function but inversely associated with asthma.4Brehm J.M. Acosta-Perez E. Klei L. Roeder K. Barmada M.M. Boutaoui N. et al.African ancestry and lung function in Puerto Rican children.J Allergy Clin Immunol. 2012; 129: 1484-1490.e6Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 5Pino-Yanes M. Thakur N. Gignoux C.R. Galanter J.M. Roth L.A. Eng C. et al.Genetic ancestry influences asthma susceptibility and lung function among Latinos.J Allergy Clin Immunol. 2015; 135: 228-235Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar Thus extrapolating reference values for lung function from other Hispanic subgroups (eg, Mexican Americans) to Puerto Ricans might lead to erroneous conclusions. This could be ameliorated if reference values were developed for Puerto Ricans, preferably having ancestry data (from genetic markers) incorporated into equations to calculate such values. To date, it is unknown whether ancestral effects on asthma or lung function in Puerto Ricans are explained by allelic variants or environmental factors correlated with racial ancestry. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that increase susceptibility to asthma across racial/ethnic groups ("cosmopolitan"), including Puerto Ricans. Asthma susceptibility loci replicated in Puerto Ricans include the chromosome 17q21 locus and IL33, with other loci replicated in Hispanic cohorts that include but are not limited to Puerto Ricans (ie, thymic stromal lymphopoietin [TSLP]).3Rosser F.J. Forno E. Cooper P.J. Celedon J.C. Asthma in Hispanics. An 8-year update.Am J Respir Crit Care Med. 2014; 189: 1316-1327Crossref PubMed Scopus (96) Google Scholar, 6Galanter J.M. Torgerson D. Gignoux C.R. Sen S. Roth L.A. Via M. et al.Cosmopolitan and ethnic-specific replication of genetic risk factors for asthma in 2 Latino populations.J Allergy Clin Immunol. 2011; 128: 37-43.e12Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar Although some susceptibility variants for asthma can exclusively affect Puerto Ricans ("ethnic specific"), no such variant has been identified confidently. Few studies have examined gene-environment interactions or epigenetic mechanisms for asthma in Puerto Ricans.3Rosser F.J. Forno E. Cooper P.J. Celedon J.C. Asthma in Hispanics. An 8-year update.Am J Respir Crit Care Med. 2014; 189: 1316-1327Crossref PubMed Scopus (96) Google Scholar Published evidence supports the following environmental or behavioral risk factors for asthma or asthma morbidity (eg, severe exacerbations) in Puerto Ricans: cigarette smoking and second-hand smoke (SHS), prematurity, allergens, air pollution, diet, vitamin D insufficiency, obesity, exposure to violence, chronic psychosocial stress, inadequate access to health care, low health literacy, and poor adherence to prescribed treatment (ie, because of concerns about side effects or medication costs).3Rosser F.J. Forno E. Cooper P.J. Celedon J.C. Asthma in Hispanics. An 8-year update.Am J Respir Crit Care Med. 2014; 189: 1316-1327Crossref PubMed Scopus (96) Google Scholar, 7Castro-Rodriguez J.A. Forno E. Rodriguez-Martinez C.E. Celedon J.C. Risk and protective factors for childhood asthma: what is the evidence?.J Allergy Clin Immunol Pract. 2016; ([Epub ahead of print])Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar Although some of these risk factors affect members of other racial or ethnic groups, their frequency and co-occurrence are particularly high in Puerto Ricans. For example, Puerto Rican women are more likely to be heavy smokers and to deliver prematurely than women in other ethnic groups, thus exposing their term and premature children to SHS.3Rosser F.J. Forno E. Cooper P.J. Celedon J.C. Asthma in Hispanics. An 8-year update.Am J Respir Crit Care Med. 2014; 189: 1316-1327Crossref PubMed Scopus (96) Google Scholar Compared with non-Hispanic white children, Puerto Rican children are also more likely to be exposed to cockroach allergen and community violence, to engage in poor dietary habits and be obese, and to have limited access to high-quality health care, further increasing their risk of asthma and asthma morbidity.3Rosser F.J. Forno E. Cooper P.J. Celedon J.C. Asthma in Hispanics. An 8-year update.Am J Respir Crit Care Med. 2014; 189: 1316-1327Crossref PubMed Scopus (96) Google Scholar Chronic stress might be particularly relevant to asthma in Puerto Ricans, who are often exposed to violence and other stressors. Indeed, recent findings implicate parental stress, physical or sexual abuse, and violence in the cause of childhood asthma in Puerto Ricans,8Rosenberg S.L. Miller G.E. Brehm J.M. Celedon J.C. Stress and asthma: novel insights on genetic, epigenetic, and immunologic mechanisms.J Allergy Clin Immunol. 2014; 134: 1009-1015Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar partly through genetic and epigenetic mechanisms. In a study of Puerto Rican school-aged children, exposure to violence was associated with methylation of the promoter of ADCYAP1R1, which was in turn associated with asthma. Moreover, an ADCYAP1R1 SNP was associated with asthma in Puerto Rican children.9Chen W. Boutaoui N. Brehm J.M. Han Y.Y. Schmitz C. Cressley A. et al.ADCYAP1R1 and asthma in Puerto Rican children.Am J Respir Crit Care Med. 2013; 187: 584-588Crossref PubMed Scopus (72) Google Scholar Chronic stress has also been associated with reduced expression of the gene for the β2-adrenergic receptor (ADRB2, key for bronchodilator response [BDR]) in WBCs of patients with asthma.10Miller G.E. Chen E. Life stress and diminished expression of genes encoding glucocorticoid receptor and beta2-adrenergic receptor in children with asthma.Proc Natl Acad Sci U S A. 2006; 103: 5496-5501Crossref PubMed Scopus (153) Google Scholar Interestingly, Puerto Ricans have reduced BDR,11Choudhry S. Ung N. Avila P.C. Ziv E. Nazario S. Casal J. et al.Pharmacogenetic differences in response to albuterol between Puerto Ricans and Mexicans with asthma.Am J Respir Crit Care Med. 2005; 171: 563-570Crossref PubMed Scopus (206) Google Scholar raising the possibility that chronic stress leads to asthma morbidity through downregulation of ADRB2. In support of this hypothesis, we recently showed that high perceived stress is associated with reduced BDR in Puerto Rican and non–Puerto Rican children with or at risk for asthma.12Brehm J.M. Ramratnam S.K. Tse S.M. Croteau-Chonka D.C. Pino-Yanes M. Rosas-Salazar C. et al.Stress and Bronchodilator Response in Children with Asthma.Am J Respir Crit Care Med. 2015; 192: 47-56Crossref PubMed Scopus (71) Google Scholar In that study we also demonstrated that an ADCYAP1R1 SNP is associated with reduced BDR in children with asthma, reduced ADRB2 expression in unstimulated CD4+ T cells of patients with asthma, and increased functional connectivity of the amygdala and insula (an anxiety marker). We also provided preliminary evidence for an interaction between the risk SNP and high stress, further suggesting that stress leads to reduced BDR through downregulation of ADRB2 by persistent secretion of catecholamines, particularly in genetically susceptible subjects.12Brehm J.M. Ramratnam S.K. Tse S.M. Croteau-Chonka D.C. Pino-Yanes M. Rosas-Salazar C. et al.Stress and Bronchodilator Response in Children with Asthma.Am J Respir Crit Care Med. 2015; 192: 47-56Crossref PubMed Scopus (71) Google Scholar A birth cohort study has yet to be conducted in Puerto Ricans, despite clear evidence of a key role for early-life exposures in asthma causation. Such a study should examine hitherto unexplored risk factors in Puerto Ricans (eg, viral infections and the host microbiome) and use an "exposome" approach13Vrijheid M. The exposome: a new paradigm to study the impact of environment on health.Thorax. 2014; 69: 876-878Crossref PubMed Scopus (140) Google Scholar instead of a reductionist strategy (focusing on one risk factor), given the complex cause of asthma in this ethnic group. Moreover, including other racial or ethnic groups within the same birth cohort study would be ideal because it would provide additional opportunities for discovery of risk or protective factors across populations. The exposome encompasses the totality of environmental or behavioral exposures from conception onward, complementing the genome (Fig 1).13Vrijheid M. The exposome: a new paradigm to study the impact of environment on health.Thorax. 2014; 69: 876-878Crossref PubMed Scopus (140) Google Scholar In this context the external exposome (comprising the individual and community-level external environments) and the internal exposome (host biologic factors) need to be characterized through all life stages, given their dynamic nature. Thus repeated assessment of objective measures of exposure and biomarkers are needed to capture both the exposome and its cumulative effect on asthma risk. As for the internal exposome, an "omics" approach (integrating genetics, epigenetics, transcriptomics, proteomics, and metabolomics) is justifiable and more likely to yield groundbreaking insights than compartmental approaches (ie, a genome-wide association study). Studies using an exposome approach require analytic methods to assess multiple and combined exposures, ranging from evaluating the simultaneous effects of multiple exposures (ie, using a regression framework and allowing for interactions) to evaluating risk estimates for combined exposures (ie, using a score summing the weighted contributions of individual exposures or using data-driven dimension-reduction methods).13Vrijheid M. The exposome: a new paradigm to study the impact of environment on health.Thorax. 2014; 69: 876-878Crossref PubMed Scopus (140) Google Scholar Under the exposome causal framework, multifactorial interventions are more likely to be effective in preventing or treating asthma in Puerto Ricans, as well as members of other racial or ethnic groups, than clinical trials of a single intervention. For example, modifying diet, physical activity, and SHS could affect not only asthma but also other health conditions (ie, obesity) during childhood, particularly if a school-based approach is expanded to include caregivers, thus leading to lifestyle changes in both the school and home environments. In parallel with multifactorial clinical trials, sound public health policy is needed to alleviate the burden of asthma in Puerto Ricans. Such efforts should include campaigns for smoking prevention and cessation, clean air, prevention of violence, and adequate care for mental illnesses linked to asthma morbidity. In this context clinicians caring for Puerto Ricans with asthma should provide counseling aimed to modify risk factors (ie, cigarette smoking), treat common comorbidities (ie, depression, posttraumatic stress disorder, allergic rhinitis, and obesity), and remove barriers to care (ie, by communicating and educating in a patient appropriate literacy and language levels and addressing culturally specific beliefs about asthma or its treatment).