Inhaled corticosteroids (ICS) are considered first-line therapy for the management and control of patients with persistent asthma. Use of inhaled steroids has been associated with reduced airway responsiveness, improved lung function, diminished symptoms, and fewer exacerbations. However studies show considerable inter-subject variability in ICS response with only 33 per cent to 50 per cent of patients demonstrating substantial improvement in forced expiratory volume in 1 second (FEV1) following therapy. It has also been estimated that corticosteroid resistance accounts for half of all asthma-related health care costs. Therefore understanding the factors that contribute to corticosteroid resistance is both clinical and economically important. African-American patients, in particular, appear less likely to respond to corticosteroid therapy when compared with white patients. However, it is not currently known whether this difference results from genetic or environmental factors, or whether differences exist in inhaled steroid responsiveness (i.e., the recommended route of therapy). This question is of particular importance, since African-American patients suffer disproportionately from asthma-related complications. To date there have been studies examining potential mechanisms of corticosteroid responsiveness, but none have addressed inhaled corticosteroid responsiveness, nor were these studies designed to identify potentially causative genetic factors at a population-level. Therefore in this application we first plan to assess differences in inhaled corticosteroid responsiveness (i.e., improvement in FEV1) between African-American and white patients with asthma following 6 weeks of inhaled beclomethasone diproprionate (BD) treatment. Second, we will seek to identify genetic loci associated with ICS responsiveness in this cohort treated with BD for 6 weeks. The diversity of our cohort is a distinct advantage, as it allows us to use both association analysis and admixture mapping to jointly identify loci associated with steroid response. Next, we will take advantage of our ability to assess ICS exposure and clinical outcomes longitudinally in our patient population so as to assess for pharmacogenomic interactions on asthma exacerbations (i.e., asthma-related emergency department visits, asthma-related hospitalizations, and oral steroid bursts) in this same group. Lastly, we will validate observed drug x gene interactions on asthma exacerbations in a separate, larger cohort of patients with asthma. This latter group will also come from our screened asthma population and will comprise those for whom we have both DNA and clinical data (i.e., historic ICS exposure measures and clinical outcomes). Therefore, in this application we plan to identify a set of genetic polymorphisms associated with ICS responsiveness as defined by both an improvement in pulmonary function and an alteration in exacerbation-related clinical outcomes.
Inhaled corticosteroids (ICS) are considered first-line treatment for persistent asthma, yet little is known about the genetic factors that influence response to this therapy. This has particular importance to African American patients who suffer disproportionately from asthma complications and who may be less likely to respond to treatment. This study seeks to quantify response to ICS therapy in African American and white patients, as well as use cutting-edge genetic techniques to look for markers that predict treatment response. Knowledge gained from this study may help clinicians select asthma treatments most likely to work for their patients, as well as provide insight for future asthma therapeutics.
|Myers, Rachel A; Scott, Nicole M; Gauderman, W James et al. (2014) Genome-wide interaction studies reveal sex-specific asthma risk alleles. Hum Mol Genet 23:5251-9|
|Poole, Alex; Urbanek, Cydney; Eng, Celeste et al. (2014) Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease. J Allergy Clin Immunol 133:670-8.e12|
|Ahmedani, Brian K; Peterson, Edward L; Wells, Karen E et al. (2014) Policies and events affecting prescription opioid use for non-cancer pain among an insured patient population. Pain Physician 17:205-16|
|Padhukasahasram, B; Yang, J J; Levin, A M et al. (2014) Gene-based association identifies SPATA13-AS1 as a pharmacogenomic predictor of inhaled short-acting beta-agonist response in multiple population groups. Pharmacogenomics J 14:365-71|
|Lanfear, David E; Chow, Sheryl; Padhukasahasram, Badri et al. (2014) Genetic and nongenetic factors influencing pharmacokinetics of B-type natriuretic peptide. J Card Fail 20:662-8|
|Levin, Albert M; Wang, Yun; Wells, Karen E et al. (2014) Nocturnal asthma and the importance of race/ethnicity and genetic ancestry. Am J Respir Crit Care Med 190:266-73|
|Williams, L Keoki; Padhukasahasram, Badri; Ahmedani, Brian K et al. (2014) Differing effects of metformin on glycemic control by race-ethnicity. J Clin Endocrinol Metab 99:3160-8|
|Bunyavanich, Supinda; Schadt, Eric E; Himes, Blanca E et al. (2014) Integrated genome-wide association, coexpression network, and expression single nucleotide polymorphism analysis identifies novel pathway in allergic rhinitis. BMC Med Genomics 7:48|
|Monda, Keri L; Chen, Gary K; Taylor, Kira C et al. (2013) A meta-analysis identifies new loci associated with body mass index in individuals of African ancestry. Nat Genet 45:690-6|
|Hayek, Sami; Canepa Escaro, Fabrizio; Sattar, Assad et al. (2013) Effect of ezetimibe on major atherosclerotic disease events and all-cause mortality. Am J Cardiol 111:532-9|
Showing the most recent 10 out of 30 publications