PROK2, HRNR, and FIG4 as potential genetic biomarkers of high bleeding propensity in East Asian patients with acute coronary syndrome using ticagrelor.

Study Objective: East Asians have a higher risk of bleeding than Europeans when treated with ticagrelor. This study aimed to explore genetic indicators related to the high bleeding propensity in East Asian patients with acute coronary syndrome (ACS) using ticagrelor.
Design: A multicenter prospective cohort study.
Setting: Four sub center hospitals participating the study.
Patients: Between March 2018 and July 2021, 208 patients with ACS were administered ticagrelor and underwent genetic testing.
Invertention: Patients were enrolled and followed up for bleeding events for 12 months. Single-nucleotide polymorphisms (SNPs) were detected using whole-exome sequencing. SNPs significantly associated with cumulative bleeding events within 1-, 6-, and 12-month follow-ups were selected (p < 0.01). Among these, SNPs showing a difference of ≥2 fold in their distribution frequency among East Asians and Europeans were selected.
Measurements and Main Results: Among all patients, 96.60% received ticagrelor plus aspirin or cilostazol, and 42.3% suffered from bleeding events during 12-month follow-up. Furthermore, 22 SNPs of 15 genes were found to have a significant association with cumulative bleeding events within 1-, 6-, and 12-month follow-ups. Among these SNPs, FIG4 rs2295837 (A>T) variant had the strongest association with bleeding events within 1 month (p = 1.28 × 10 ^-4 ), with an increased risk of bleeding in T allele carriers (odds ratio [OR]: 3.07, 95% confidence interval [CI]: 1.68-5.63). PROK2 rs3796224 (C>T) variant was most strongly associated with cumulative bleeding events within 6 months (p = 4.57 × 10 ^-4 ) with an increased risk of bleeding in T allele carriers (OR: 2.16, 95% CI: 1.20-3.89). Moreover, HRNR rs6662450 (C>T) variant showed the strongest relation with cumulative bleeding events within 12 months (p = 4.86 × 10 ^-4 ) with a reduced risk of bleeding in T allele carriers (OR: 0.48, 95% CI: 0.24-0.95).
Conclusion: Fifteen genes, including PROK2, HRNR, and FIG4, were potential biomarkers of high bleeding propensity in East Asian patients with ACS using ticagrelor.
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