The iron(y) in COPD patients’ response to ICS: pharmacogenetic insights into the HISTORIC study

COPD is significantly impacted by iron sequestration in the lungs, primarily regulated by the <italic>IREB2</italic> gene, a key player in intracellular iron homeostasis. Our study investigated the association of <italic>IREB2</italic> single nucleotide variants (SNVs) with response of COPD patients to treatment with inhaled corticosteroid (ICS). 165 COPD patients of the HISTORIC study, an investigator -initiated and -driven, double-blind, randomized, placebo-controlled trial (<ext-link>ISRCTN11017699</ext-link>), were genotyped for three common SNVs in the <italic>IREB2</italic> gene (rs13180, rs2568494 & rs1062980). Patients were randomized to receive either ICS or placebo, alongside LAMA/LABA, for 12 months. Possible associations between the SNVs and response to treatment in relation with FEV₁ change and health-related QoL questionnaires, were examined. Significant differences in FEV1 change were noted between patients treated with LAMA/LABA/placebo and those on LAMA/LABA/ICS across the various genotypes of rs13180 (p=0.005), rs2568494 (p=0.03), and rs1062980 (p=0.02). CC carriers of rs13180, GG carriers of rs2568494, and CC carriers of rs1062980 exhibited a more favorable response to ICS, with FEV1 average improvement over 12 months by 289, 214 and 249 ml, respectively. The same patients exhibited clinically relevant (≥4 units) average reduction in SGRQ total score (10.4, 6.5 and 9.6 units, respectively). Similarly, CC carriers of rs13180 and rs1062980 show clinically relevant (≥3–5 points) CAT score improvement under ICS compared to placebo. Our study revealed significant associations between <italic>IREB2</italic> variants and response to ICS, highlighting the positive effect of the rs13180/rs1062980 CC genotypes on treatment efficacy of ICS combined with LAMA/LABA.