Pharmacogenetic mechanism of cilostazol-induced headaches: Splicing-mediated loss of ABCC5 gene function

Cilostazol, a phosphodiesterase 3 inhibitor, causes intolerable headaches in over one third of patients, frequently leading to treatment discontinuation. We investigated whether ABCC5 variant rs7636910 (NM_005688.4:c.1146A > G) protects against cilostazol-induced headaches through altered cyclic nucleotide signalling.

Analysis included 101 healthy Korean volunteers from Phase 1 clinical trials, with independent replication in a multi-ethnic cohort (n = 369) from the All of Us Research Program. Functional consequences of rs7636910 were evaluated through splicing analysis, expression studies, transport assays and cellular models examining cyclic nucleotide dynamics and vascular responses.

G allele carriers showed a reduced risk of moderate-to-severe headaches (OR = 0.29, 95% CI 0.12-0.73), replicated in the multi-ethnic cohort (OR = 0.26, dominant model). The variant disrupted canonical splicing, causing a 38-bp deletion, premature termination, and nonsense-mediated decay, reducing ABCC5 expression by more than 20% in blood and thyroid tissues. Cilostazol was not an MRP5 substrate, and pharmacokinetics were genotype-independent. In ABCC5-knockdown HCASMCs (Human Coronary Artery Smooth Muscle Cells), baseline cAMP was elevated tonically with paradoxical cGMP accumulation, whereas drug-induced cAMP fold-increases remained comparable to controls. Tonic cAMP elevation desensitised PKA, abolishing PDE3 inhibitor-induced vascular relaxation despite elevated cAMP-a loss recapitulated by PKA inhibition in MRP5-normal cells.

The rs7636910 variant reduces cilostazol-induced headaches through a signalling-based mechanism independent of drug pharmacokinetics, suggesting that transporter variants affecting endogenous substrate handling are as clinically important as drug-metabolising enzyme polymorphisms. This variant represents a candidate pharmacogenetic biomarker for identifying cilostazol-tolerant patients.