Association of c.681G>A (rs4244285) Loss-of-function Allele with Cardiovascular Disease Risk in the Kosovo Population.

The loss-of-function () allele has been associated with reduced clopidogrel efficacy and increased risk of major adverse cardiovascular events (MACE). PGx-guided treatment, despite the recommendations, is not fully implemented in routine clinical practice. The primary aim of this hybrid retrospective-prospective study was to determine whether identifying LOF patients may benefit the antiplatelet drug prescribing decisions made in Kosovo. The study cohort consisted of clopidogrel treated patients presenting at the University Clinical Center in the period from December 2023 to May 2024. To evaluate the correlation between LOF and the treatment outcome in a follow-up period of 2 years, we first assessed the genotype using the Taq Man Real Time PCR method. Among 150 patients, 58 (19.33%) were identified as carriers allele. The observed allele distribution was significantly different when compared with the one reported for a healthy Kosovar population (13.03%). LOF carriers exhibited a 1.6-fold higher probability of developing cardiovascular disease compared to non-carriers, based on allelic and codominant model of statistical analysis (OR=1.60; 95% CI=1.08-2.37; p=0.018 and OR=1.64; 95% CI=1.04-2.57; p=0.031, respectively). The median observation time of follow up was not reached until this analysis was conducted. Our data supports the potential association of the allele with an increased risk for CVD in the population of Kosovo. Our data add to the evidence advising careful consideration of genetic diversity when recommending PGx-guided clopidogrel therapy, particularly in populations, such the Kosovar, where genetic determinants are not yet fully elucidated.