Editors' ChoiceGenetics

Individualizing Asthma Treatment

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Science Translational Medicine  12 Oct 2011:
Vol. 3, Issue 104, pp. 104ec164
DOI: 10.1126/scitranslmed.3003281

Asthma is a chronic condition characterized by marked airway inflammation and reduced airflow and affects a striking 300 million persons worldwide. Orally inhaled steroids (glucocorticoids) typically are the most effective treatment in reducing the frequency and severity of asthma attacks. However, wide inter-individual variability in response to inhaled steroids exists, with some studies documenting glucocorticoid nonresponder rates as high as 40%. In addition, family studies have shown that glucocorticoid response rates are highly heritable. Now, Tantisira et al. shed light on the genetic underpinnings of the response to glucocorticoids in a genome-wide association study (GWAS).

These researchers assessed over 530,000 single-nucleotide polymorphisms (SNPs) for an association with glucocorticoid response in 118 trios (probands suffering from asthma and their parents). A validated family-based statistical algorithm was then used to select 13 SNPs for validation in four separate replication cohorts. A single variant (rs37972) in the glucocorticoid-induced transcript 1 gene (GLCCI1) was found to be statistically associated with the forced expiratory volume (FEV1) in one second, a standardized measurement used in assessing asthma treatment response. Notably, homozygous mutant allele carriers had a modest 2 to 3% increase in FEV1 versus a more marked 10 to 12% improvement in FEV1 seen in homozygous wild-type allele carriers. Furthermore, rs37972 was statistically linked to expression of GLCCI1 in lymphoblastoid B cells derived from probands in the trio population. Specifically, individuals homozygous for the mutant alleles had greatly reduced expression of GLCCI1 upon dexamethasone exposure when compared with B cells from individuals with the wild-type alleles.

Although it remains unclear how a change in GLCCI1 expression results in a reduced glucocorticoid response, the current study illustrates how GWASs can serve to uncover new biological pathways involved in drug responses that might otherwise remain elusive. Moreover, given that more than 16% of Europeans are homozygous for the at-risk alleles and alternatives to glucocorticoids are readily available, the time to individualize asthma treatment on the basis of pharmacogenetic information may be here.

K. G. Tantisira et al., Genomewide association between GLCCI1 and response to glucocorticoid therapy in asthma. N. Engl. J. Med. 365, 1173–1183 (2011). [Full Text]

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