(CCSP003) EXPLORING THE GENETIC BASIS OF DYSPNEA IN INDIVIDUALS TREATED WITH TICAGRELOR: RESULTS FROM THREE CLINICAL TRIALS

Background: Context. Ticagrelor is an antiplatelet medication commonly preferred over clopidogrel in the treatment of acute coronary syndromes. However, compared to other antiplatelets drugs, ticagrelor may lead to atypical adverse events, including dyspnea. The exact mechanisms responsible for causing dyspnea with ticagrelor are still not fully understood.

Since genomics can provide insights into the biological mechanisms of traits, we aimed to study the influence of genetic variants on the occurrence of dyspnea in individuals who receive ticagrelor.

METHODS AND RESULTS: We used data from three randomized clinical trials conducted by AstraZeneca (DISPERSE, DISPERSE-II, PHILO) and we performed a genome-wide association study of dyspnea occurrences reported as an adverse event in patients treated with ticagrelor. We used a general linear mixed model with GMMAT to account for genetic relatedness, genetic ancestry and for study as a random factor, and to adjust for age, sex and ticagrelor dosing. We also conducted a literature review to identify genetic variants previously associated with inter-individual variation in ticagrelor response.

The sample consisted of 700 ticagrelor-treated participants of varying ancestry, which included 82 dyspnea cases. Of the 95 genetic variants identified from the literature, only the regulatory region variant rs188845491 near CYP3A5, previously associated with ticagrelor concentrations (area under the curve), was nominally associated with dyspnea in ticagrelor users (P=0.02). The genome-wide analysis identified rs10267192 (MTPN) on chromosome 7 and rs67772185 (APCDD1L) on chromosome 20 as the top signals associated with dyspnea in ticagrelor users (P=1.7 x 10-8 and 2.5 x 10-8 respectively). Genes MTPN and APCDD1L have previously been associated with platelet traits, making them good functional candidates. A replication study in an external dataset (PLATO) is ongoing.

Conclusion: Conclusion. The study highlights the potential contribution of genetics to the incidence of dyspnea in ticagrelor-treated patients, with potential involvement of pharmacodynamic mechanisms.