Rs10044254

This SNP is in the intronic region of the F-box and leucine-rich repeat protein 7 (FBXL7), and it is associated with response to inhaled corticosteroid (ICS) treatment in children with asthma. In an ICS treatment trial for children, rs10044254 was associated with downregulation of FBXL7 expression, a gene encoding one of four subunits of the SKP1-cullin-F-box ubiquitin protein ligase complex. In the same study, in two independent cohorts, children with at least one copy of the reference allele (A) had better symptomatic response to inhaled corticosteroids (ICSs), the main treatment for asthma, when compared to children homozygous for the variant allele (G), whose symptoms worsened during the treatment.

The first cohort group, composed of 124 white children in an ICS treatment trial (average age 8.9 years), relied on daily self-reported (with parents&#8217; participation) asthma symptoms ranked from 0 to 3. They tested 440,862 SNPs and then followed up on the 3 most significantly associated SNPs in a second cohort, made up of three independent populations: one of children (average age 10.4) and two of adults (33-34 years old on average). In total, there were 421 subjects, which is a very small sample size. All children were treated and followed up over the course of 8 weeks. The combined p-value for rs10044254 was 9.12 x 10-8. Another SNP, rs2388639, had a p-value of 8.56 x 10-9. These significant associations were not replicated in the adult cohorts, suggesting the associations only apply to children. Additionally, the effect size (the reduction in asthma symptoms rank) was small for both groups and the standard deviation really high, so it is not clear whether this result is clinically relevant. Adding the fact that the sample size was really small makes the evidence even weaker.

Expression profiles of FBXL7 in response to dexamethasone (an ICS) stimulation was measured in B-cell lines derived from 70 patients in the first cohort. The rs10044254 GG genotype corresponded to lower levels of FBXL7 expression, although this effect was incredibly small and these results are highly questionable. Even if this SNP is actually an eQTL of FBXL7, its effect is very weak. Furthermore, the possible interactions of this protein with dexamethasone are not known, although some theories are provided by the authors.

Reference: Park, et al. (2014). Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids. J Allergy Clin Immunol, 133(3): 664-669.