Table 3.

Prospective relationship between genetic variants and inhaled corticosteroid use on asthma exacerbations within the SAPPHIRE validation population (n=803)^*

SNP	Chr	Position	Allele†	MAF†	Gene	Parameter estimate for ICS‡	P-value for ICS‡	Parameter estimate for SNP‡	P-value for SNP‡	Parameter estimate for SNP × ICS interaction‡	P-value for interaction‡	P-value for joint test§
rs3827907	14	21238798	C/T	0.13	EDDM3B	−1.75	7.13×10−5	0.35	0.007	−0.07	0.679	0.023
rs2629529	10	126534415	C/A	0.06	--	−1.75	2.06×10−5	0.39	0.042	−1.27	1.58×10−4	5.65×10−6
rs73906251	20	29991274	T/C	0.05	--	−1.92	5.06×10−6	0.22	0.173	0.28	0.182	0.043

SAPPHIRE, denotes the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity; SNP, single nucleotide polymorphism; Chr, chromosome; MAF, minor allele frequency; and ICS, inhaled corticosteroid.

^*The validation analyses used Cox proportional hazards models to assess the time-to-severe asthma exacerbation (i.e., burst oral corticosteroid use, asthma-related emergency department visits, and hospitalizations for asthma).

^†The effect allele (minor allele) is shown first, and the referent allele follows. The allele frequency of the “effect” allele is provided, and in the current table, this estimate is based on the observed frequency in the validation set.

^‡The parameter estimates represent the risk (i.e., hazard) of having a severe asthma exacerbation following the baseline assessment (i.e., the assessment at study enrollment). A negative parameter estimate indicates that the variable was associated with a lower risk of experiencing a severe asthma exacerbation. The parameter estimate for ICS can be interpreted as the effect of increasing ICS use (i.e., average number of ICS doses taken per day over the preceding 6 months).^{15, 18} The parameter estimate for the SNP can be interpreted as the effect on exacerbation risk for each additional “effect” allele (i.e., none [=0], one [=1], or two alleles [=2]). The parameter estimate for the interaction term can be interpreted as the combined effect of increasing ICS use and the number of “effect” alleles on the risk of a severe asthma exacerbation. The parameter estimates and P-values for the ICS, SNP, and SNP x ICS interaction variables are shown for the model simultaneously including variables, as well as adjusting for patient age, sex, BMI, smoking status, ACT score at baseline (i.e., time of study enrollment), baseline asthma severity score, LABA use (an indicator variable denoting use of an ICSLABA combination inhaler), time-updated measures of SABA MDI and nebulizer use, and the first 3 principal components.

^§The likelihood ratio test assessed the significance of the difference in model fit between the full model (i.e., all of the aforementioned variables included) and the reduced model (i.e., the full model minus both the SNP and SNP x ICS interaction terms). In other words, a joint test was used to simultaneously assess the combined significance of the SNP and SNP x ICS interaction terms.