NEW YORK (GenomeWeb News) – A variant in the glucocorticoid-induced transcript 1 gene GLCCI1 can influence individuals' response to glucocorticoid treatment for asthma, according to a study online this week in the New England Journal of Medicine.
Researchers from the US and Japan used a family-based screening algorithm and association testing to help narrow in on genetic variants mediating differences in lung function following treatment with inhaled glucocorticoid. From their analyses of genotype data for hundreds of individuals from asthma-affected families, followed by validation studies in additional replication groups, the team uncovered a pharmacogenetic association between glucocorticoid response and a variant in GLCCI1 that influences the gene's expression.
"[O]ur genome-wide association study of more than 530,000 SNPs revealed a novel functional SNP, rs37973, that decreases the expression of GLCCI1, a gene influencing the pharmacologic response to inhaled glucocorticoids in asthma," first author Kelan Tantisira, a researcher with Brigham and Women's Hospital and Harvard Medical School's Channing Laboratory, and co-authors wrote.
"The response to treatment for asthma is characterized by wide inter-individual variability, with a significant number of patients who have no response," the researchers explained, noting that as many as 40 percent of individuals with asthma do not respond to treatments such as inhaled glucocorticoids.
Because glucocorticoid response in particular seems to stem from complex, largely inherited, genetic patterns, the researchers decided to incorporate family information to help interpret GWAS data in their search for variants influencing treatment response.
To do this, they genotyped a subset of the participants from a randomized control trial known as Childhood Asthma Management Program, along with their parents. They then used an algorithm that takes into account parental genotype patterns when analyzing the potential treatment-related associations for the individuals with asthma.
"The [family-based screening] algorithm uses parental genotype information to rank [SNPs] that have the greatest potential for association," they explained. "A small subset of statistically powerful SNPs can then be tested in the probands with the use of the family-based association test."
For the family-based screening stage of the study, the team used the Illumina HumanHap550 BeadChip to genotype 422 CAMP study participants and their parents. Of these, they explained, 118 trios included individuals who had been assigned to receive treatment with the inhaled glucocorticoid budesonide.
After the family-based screening and association testing phases of the study, followed by replication testing using data on 935 individuals from four more cohorts, the researchers' search led them to a SNP in the chromosome 7 gene GLCCI1 known as rs37972.
The variant is in linkage disequilibrium with another SNP called rs37973, the team noted, and both rs37972 and rs37973 appear to affect glucocorticoid treatment outcomes by altering the expression of the GLCCI1 gene.
The researchers reported that individuals with the version of rs37973 that curbs GLCCI1 expression also tended to have more modest lung function — for instance, forced expiratory volume in one second — following treatment with inhaled glucocorticoids.
"[T]he mean increase in [FEV1] in the treated subjects who were homozygous for the mutant rs37973 allele was only about one-third of that seen in similarly treated subjects who were homozygous for the wild-type allele," they noted, "and their risk of poor response was significantly higher."
Based on their findings so far, the researchers estimated that genotype explains around 6.6 percent of the variation that exists in response to inhaled glucocorticoid treatment for asthma.
Moreover, those involved in the study noted that the "family-based screening method used to identify the associated variant is ideally suited to pharmacogenetic studies in which sample sizes are limited and P values for true associations are likely to be modest."