Amrit Bajrangee1, Nicola Ryan2, Ciara Vangjeli3, Marian Brennan4, Dermot Cox5, Denis C Shields6, Desmond Fitzgerald7, Andrew Maree8. 1. St James Hospital, James' Street, Dublin 8, Ireland. Electronic address: amrit_bajrangee@hotmail.com. 2. St James Hospital, James' Street, Dublin 8, Ireland. Electronic address: nicolaryan@hotmail.com. 3. Conway Institute of Bimolecular and Biomedical Research, University College Dublin. Electronic address: c.vangjeli@ucd.ie. 4. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. Electronic address: mbrennan@rcsi.ie. 5. Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. Electronic address: dcox@rcsi.ie. 6. Conway Institute of Bimolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland. Electronic address: Denisshields@ucd.ie. 7. Conway Institute of Bimolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland. Electronic address: des.fitzgerald@ucd.ie. 8. Trinity College Dublin, Institute of Cardiovascular Science, CREST Directorate, St James Hospital, James' Street, Dublin 8, Ireland. Electronic address: andrew.maree@gmail.com.
Abstract
BACKGROUND: Serotonin (5-HT) induces platelet aggregation by activating its 5-HT2A receptor. Platelet uptake is mediated by the 5-HT transporter (5-HTT). A common 5-HTT promoter (5-HTTLPR) splice variant results in long (L) and short (S) alleles. 5-HTTLPR genotype has been associated with increased platelet activation and risk of MI. Variation within HTR2A gene (C1354T) that encodes the 5-HT2A receptor has also been associated with enhanced platelet aggregation. We hypothesised that 5-HTT and/or HTR2A variation may influence platelet response to aspirin in patients with stable CAD. METHODS: Patients (n=144) with stable cardiovascular disease taking aspirin were genotyped for the 5-HTTLPR and HTR2A variants. Platelet inhibition was assessed by serum thromboxane and arachidonic acid-induced platelet aggregation assay. RESULTS: 5-HTT genotype (LL vs *S) was a significant determinant of serum TX level (8.9±2.6ng/ml vs 6.0±1.6ng/ml respectively; p<0.02) and 5-HTT LL genotype predicted an incomplete aspirin response (serum TXB2>2.2ng/ml) (p=0.04; OR=2.22, CI=1.03-4.79). Odds ratio of the effect of LL genotype on TX elevation was 3.8 (95% CI 1.2-11.6) in younger patients (under 64) compared to 1.0 (95% CI=0.3-3.8) in older subjects. LL genotype did not influence AA aggregation (p=0.83, OR=1.2, CI=0.3-4.1). The HTR2A variant had no effect on TX generation (p=0.70; OR=1.22, CI=0.45-3.26) nor AA aggregation (p=0.99; OR=1.0, CI=0.2-4.9). CONCLUSIONS: In younger patients with stable CAD 5HTT LL genotype carried by almost one third of our cohort is associated with a diminished response to aspirin that may increase cardiovascular risk. Genotypic variation in platelet activation may be a contributing mechanism.
BACKGROUND:Serotonin (5-HT) induces platelet aggregation by activating its 5-HT2A receptor. Platelet uptake is mediated by the 5-HT transporter (5-HTT). A common 5-HTT promoter (5-HTTLPR) splice variant results in long (L) and short (S) alleles. 5-HTTLPR genotype has been associated with increased platelet activation and risk of MI. Variation within HTR2A gene (C1354T) that encodes the 5-HT2A receptor has also been associated with enhanced platelet aggregation. We hypothesised that 5-HTT and/or HTR2A variation may influence platelet response to aspirin in patients with stable CAD. METHODS:Patients (n=144) with stable cardiovascular disease taking aspirin were genotyped for the 5-HTTLPR and HTR2A variants. Platelet inhibition was assessed by serum thromboxane and arachidonic acid-induced platelet aggregation assay. RESULTS:5-HTT genotype (LL vs *S) was a significant determinant of serum TX level (8.9±2.6ng/ml vs 6.0±1.6ng/ml respectively; p<0.02) and 5-HTT LL genotype predicted an incomplete aspirin response (serum TXB2>2.2ng/ml) (p=0.04; OR=2.22, CI=1.03-4.79). Odds ratio of the effect of LL genotype on TX elevation was 3.8 (95% CI 1.2-11.6) in younger patients (under 64) compared to 1.0 (95% CI=0.3-3.8) in older subjects. LL genotype did not influence AA aggregation (p=0.83, OR=1.2, CI=0.3-4.1). The HTR2A variant had no effect on TX generation (p=0.70; OR=1.22, CI=0.45-3.26) nor AA aggregation (p=0.99; OR=1.0, CI=0.2-4.9). CONCLUSIONS: In younger patients with stable CAD 5HTT LL genotype carried by almost one third of our cohort is associated with a diminished response to aspirin that may increase cardiovascular risk. Genotypic variation in platelet activation may be a contributing mechanism.
Authors: Marina L Butovskaya; Polina R Butovskaya; Vasiliy A Vasilyev; Jane M Sukhodolskaya; Dania I Fekhredtinova; Dmitri V Karelin; Julia N Fedenok; Audax Z P Mabulla; Alexey P Ryskov; Oleg E Lazebny Journal: J Physiol Anthropol Date: 2018-04-16 Impact factor: 2.867