Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Hur, Gyu Young; Broide, David H.

Epidemiologic studies of longitudinal lung function over a 15-year period in adult asthmatics compared to non-asthmatics demonstrated that asthmatics had a greater decline in forced expiratory volume in 1 second (FEV1) over time than non-asthmatic controls. 4 In that large study of 17,506 subjects, asthmatics had a greater decline in FEV1 (38 mL/year) than nonasthmatics (22 mL/year). In addition, asthmatics who smoked tobacco had a greater decline in lung function than those who did not. Studies have also examined lung function changes in childhood asthmatics. As children have lungs that continue to grow until the age of 18 to 25 years, 5 childhood asthmatics with airway remodeling may or may not attain normal lung function by adulthood before they exhibit decline in lung function. For example, longitudinal measurements of lung function in 684 childhood asthmatics followed up for 13 years demonstrated that those with persistent childhood asthma may have either normal lung function growth (25% of childhood asthmatics) or impaired lung function growth outcomes (75% of childhood asthmatics). 6 A normal pattern of lung-function growth in childhood is characterized by a normal steep increase during adolescence, a plateau in early adulthood and a gradual decline at old ages. Abnormal trajectories include 1) reduced lung function growth (i.e. do not attain normal adult lung function) (23% of childhood asthmatics), 2) normal lung function growth and an early decline in lung function (26% of childhood asthmatics), and 3) reduced lung function growth and an early decline in lung function (26% of childhood asthmatics). 6 At the last lung function test in that 13-year longitudinal study of lung function in childhood asthma, 11% of childhood asthmatics met the global initiative of chronic obstructive lung disease criteria for lung function impairment that was consistent with chronic obstructive pulmonary disease (COPD). 6 Such longitudinal epidemiologic studies of lung function in adults and children with asthma demonstrate that the potential for a subset of adult asthmatics to progress with an accelerated lung function decline over time, or for a subset of childhood asthmatics either to not attain normal long function and/or to have an accelerated decline in lung function. As not all asthmatics exhibit these lung function changes, it is likely that genetic and environmental factors contribute to the different patterns of lung function growth and/or decline in each asthmatic subject. In terms of genetic factors for decline in lung function in childhood-onset asthmatics, a recent genome-wide association study (GWAS) study investigated genes associated with decline in lung function in adults with self-reported childhood asthma who were adult tobacco smokers. 7 Among 10,199 adult smokers, 730 (7%) reported childhood asthma. 7 The subjects were smokers and reported a history of childhood asthma, had reduced lung function as adults, and an increased risk for COPD (odds ratio, 3.42; 95% confidence interval [CI], 2.81-4.18). 7 Genetic associations were also found in these subjects who had childhood asthma with known asthma loci, including IL1RL1, IL13, LINC01149 and GSDMB. 7 These findings in childhood asthmatics who smoke underscore the interaction of genetic factors in childhood asthma and environmental factors such as tobacco smoke in contributing to decline in lung function and the development of features of early COPD.