Longitudinal analysis of bronchodilator response in asthmatics and effect modification of age-related trends by genotype.

Abstract

Genome Wide Association Studies (GWAS) have identified genetic polymorphisms associated with bronchodilator response (BDR), but it is unknown how these associations change across life stages. We examined the impact of genetic variants on BDR from childhood to adulthood in asthmatics to uncover potential effect modification by age. We searched the National Human Genome Research Institute (NHGRI) catalog of published GWAS to obtain a list of genetic associations with BDR, and tested them for effect modification by age in 604 subjects from the Childhood Asthma Management Program (CAMP), a clinical trial with longitudinal measures of BDR (age range 5-30 years). We performed longitudinal analyses using linear mixed models and visualized longitudinal changes in BDR using generalized additive models with repeated measures, adjusting for treatment group, sex, and main effects of age and additive genotype. Increasing age was associated with decreased BDR (-0.24% per year). Polymorphisms rs295137 (T allele) near SPATS2L and rs2626393 (C allele) near ASB3 demonstrated their strongest associations with BDR in early childhood through adolescence, with a large decrease in their magnitude of effect from adolescence onward. The effect estimate for % BDR associated with rs295137 genotype (Beta = 1.3; 95%CI 0.6-2.1) was diminished by age (interaction term = -0.06, P = 0.004). The effect estimate for rs2626393 (Beta = -0.92 (95%CI -1.7 to -0.2) was also modified by age (interaction term = 0.05, P = 0.0004). Polymorphisms associated with BDR in childhood may not be relevant for predicting adolescent and adult BDR, which could reflect age-related changes in asthma phenotypes.