Discovery of rs9984273 in clinical trials investigating intravenous IFN β-1a for the treatment of ARDS
death, ARDS
MINOR, DISEASE, ARDS
We have performed two significant clinical trials investigating the use of intravenous IFN β-1a for the treatment of ARDS [Further, pre-defined targeted resequencing and genetic analyses of entire gene regions were performed for genes encoding CD73 (The effect of the rs9984273 genotype on mortality and cytokine levels in the INTEREST trial investigating intravenous IFN β-1a for ARDS treatment. A genetic sample was available from 202/296 (104/144 in the IFN β-1a treatment arm and 98/152 in the placebo arm) of the study subjects. Number of the subjects at risk is indicated on the x- axis. The polymorphism affected differently the outcome of men and women in the INTEREST trial. Majority of the patients (70%) in the trial were male. 42.4% of men and 51.4% of women had CC/CT. Mortality of women was 11.8% for TT and 8.3% for CC/CT patients; mortality of men was 28.9% for TT patients and 12.5% for CC/CT patients. Thus, TT increases risks of death only in men, OR 2.85, Contribution of the SNP rs9984273 polymorphism was further investigated by a retrospective analysis, in which we performed focused genetic analyses of IFNAR2 on the earlier Phase I/II study population. Phase I/II and III study populations were comparable according to demographics and disease severity; however, we identified one major difference. In the Phase I/II study 40% of the study subjects receiving IFN β received overlapping glucocorticoids, but 73% of these patients had the rs9984273 the minor C allele. In contrast, in the phase III study 54% of the patients received glucocorticoids, but only 46% of the subjects receiving overlapping glucocorticoids with IFN β-1a carried the minor C allele. Hence, the rs9984273 C allele was highly enriched in the Phase I/II study population compared to the Phase III study, and more patients received glucocorticoids in the Phase III than in the Phase I/II study, thus suggesting a possible explanation for the difference between mortality in the studies.