This article reviews the progress in the search for the genetic determinants of severe asthma.
Twin studies estimate that approximately 25% of the phenotypic variability in asthma severity is determined by genetic factors, with the remainder determined by nongenetic factors including environmental and psychosocial factors, behavioral traits, and comorbidities. Most genetic association studies of asthma severity performed to date are underpowered and not designed to clearly distinguish asthma severity variants from asthma susceptibility variants. However, the most recent genome-wide asthma severity association study, conducted in more than 57 000 individuals, demonstrated significant associations for 25 loci, including three not previously associated with asthma: GATA3, MUC5AC, and KIAA1109. Of these, the MUC5AC association was restricted to cohorts that included moderate-to-severe (but not mild) asthma. Additional insights from rare monogenic disorders that can present as severe asthma include recognition that loss-of-function variants in the filaggrin gene known to cause ichthyosis vulgaris are consistently associated with more severe asthma outcomes. Other notable loci of interest include RAD50-IL13 on chromosome 5q and the ORMDL3-GSDMB locus on chromosome 17q21.
Severe asthma is a polygenic trait. Future research should explore the role of rare genetic variation and gene-by-environment interaction.
aDivision of Pulmonary Medicine, Department of Pediatrics, Boston Children's Hospital
bChanning Division of Network Medicine and Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital
cHarvard Medical School, Boston, USA
Correspondence to Benjamin A. Raby, MD, MPH, Division of Pulmonary Medicine, Department of Pediatrics, Boston Children's Hospital, 300 Longwood Avenue, BCH 3121, Boston, MA 02115, USA. Tel: +1 617 355 4584; e-mail: Benjamin.Raby@childrens.harvard.edu