Kehua Wu (1,2), Eric R. Gamazon (1,3), George Clemmer (4), Scott T. Weiss (4), Kelan G. Tantisira (4), Nancy J. Cox (1,3), Wei Lu (2) and R. Stephanie Huang (1*)
(1) Department of Medicine, The University of Chicago, Chicago, IL 60637, USA; (2) State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China; (3) Institue of Genome, Vanderbilt University, and (4) Channing Division of Network Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115, USA.
Objectives: Most genomic studies of lung function have used phenotypic data derived from a single time-point (e.g., disease/not) ignoring the dynamic progression of a chronic disease. This study aimed to characterize lung function changes over time in asthmatics and identify genetic contributors to a longitudinal phenotype.
Methods: We present a population model that captures both natural growth of FEV1 (forced expiratory volume in 1 second) in asthmatic children and airway responsiveness to the treatments, including three different long-term treatments (budesonide, nedocromil or placebo) and single inhalation of albuterol (a bronchodilator) at each of the clinical visit. Our model was built based on the data from 1041 asthmatic children who participated in the Childhood Asthma Management Program (CAMP) [1]. This longitudinal progression model was built using population-based nonlinear mixed-effects modeling (NONMEM) with an exponential structure and the determinants of age and height.
Results: We found ethnicity was a key covariate for FEV1 level. African-American asthmatic children have worse observed FEV1 than Caucasians and Mexican-Americans. Budesonide treated asthmatic children had a significant improvement in FEV1 when compared to those treated with placebo or nedocromil (p<0.001).
FEV1=exp(theta1*age+theta2*height+theta3+theta4)+theta5
Where, theta4 and theta5 refer to the drug effect of short-term albuterol and long-term budesonide treatment, respectively. Theta3 is a constant.
Upon evaluating those genetic variants that are located in the strong enhancer region in human lung fibroblasts, we found that a genetic variant (rs8106664; p=1.1×10–5) strongly associated with airway responsiveness (theta4 ) in these CAMP subjects.
Conclusions: We developed an integrative method that combines mixed-effects longitudinal disease modeling and genome-wide association study. This study offers a strategy to explore the genetic determinants of disease progression and treatment effects, provide a comprehensive picture of disease pathophysiology and suggest potential treatment targets.
References:
[1] The Childhood Asthma Management Program (CAMP): design, rationale, and methods. Childhood Asthma Management Program Research Group. Control Clin Trials 1999; 20: 91-120.
Reference: PAGE 24 () Abstr 3438 [www.page-meeting.org/?abstract=3438]
Poster: Drug/Disease modeling - Other topics