– The randomized, placebo-controlled COLchicine Cardiovascular Outcomes Trial (COLCOT) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post-hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine. – There were 1522 participants of European descent from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study’s primary cardiovascular (CV) endpoint was defined as for the main trial, as time to first occurrence of CV death, resuscitated cardiac arrest, myocardial infarction, stroke or urgent hospitalization for angina requiring coronary revascularization. The safety endpoint was time to the first report of gastrointestinal events. Patients’ DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study (GWAS) in colchicine-treated patients. – None of the genetic variants passed the GWAS significance threshold for the primary CV endpoint conducted in 702 patients in the colchicine arm who were compliant to medication. The GWAS for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found two significant association signals, one with lead variant rs6916345 (hazard ratio (HR)=1.89, 95% confidence interval (CI) 1.52-2.35, P=7.41×10) in a locus which colocalizes with Crohn’s disease, and one with lead variant rs74795203 (HR= 2.51, 95% CI 1.82-3.47; P=2.70×10), an intronic variant in gene . The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant. – We found two genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.
Pharmacogenomics of the Efficacy and Safety of Colchicine in COLCOT.
Feb 8, 2021