Asthma and genes: Polymorphism discovered that may cause steroid resistance

People with asthma have an impressive and frustrating variability in their response to treatment, with corticosteroids and other drugs. As many as 40% of people with asthma don't respond to inhaled steroids. Asthma's familial basis is well-known: 60% of the variability in the response to albuterol may be inherited, and more than 80% of the treatment response to inhaled steroids. Genome studies have identified candidate single-nucleotide polymorphisms (SNPs) based on their distribution in families with strong histories of asthma.

Tantisira et al take this work to the next step, identifying one SNP, rs37972, common in affected families and associated with change in FEV1 during clinical trials. Asthmatics with wild-type rs37972 respond to steroids (an increase in FEV1 of ~10% in trials); those homozygous for a mutated rs37972 did not respond to steroids (FEV1 increase by 2-4%).

The allele is on the GLCCI1 gene, involved in glucocorticoid signaling (but whose function is not understood).  GLCCI1's expression is increased by dexamethasone -- but by much less in those with the homozygous mutant allele. Authors estimate this polymorphism could be responsible for ~7% of the genetic variation among the most steroid-resistant patients. About 16% of the population are likely homozygous for the rs37972 steroid-resistance mutation.

Detecting a disposition to steroid resistance could help us avoid saturating asthmatics with inhaled corticosteroids that don't help and cause mild toxicity. Also, it would prevent the distracting and unfair labeling of adherent but treatment-unresponsive patients as "noncompliant." Another potential benefit would be to stratify or tier the patients in clinical trials, making findings more precise and avoiding a "dilution" of observed benefit due to inclusion of steroid-unresponsive patients.

Tantisira KG et al. Genomewide Association between GLCCI1 and Response to Glucocorticoid Therapy in Asthma. N Engl J Med 2011;365:1173-1183.