Impact of genetic variation in the 5-HT transporter and receptor on platelet function in patients with stable CAD taking aspirin.
BACKGROUND
Serotonin (5-HT) induces platelet aggregation by activating its 5-HT2Areceptor. 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-HT2Areceptor 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.
St James Hospital, James' Street, Dublin 8, Ireland. Electronic address: amrit_bajrangee@hotmail.com.
Amrit
A
Bajrangee
St James Hospital, James' Street, Dublin 8, Ireland. Electronic address: nicolaryan@hotmail.com.
Nicola
N
Ryan
Conway Institute of Bimolecular and Biomedical Research, University College Dublin. Electronic address: c.vangjeli@ucd.ie.
Ciara
C
Vangjeli
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. Electronic address: mbrennan@rcsi.ie.
Marian
M
Brennan
Department of Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, 123 St Stephens Green, Dublin 2, Ireland. Electronic address: dcox@rcsi.ie.
Dermot
D
Cox
Conway Institute of Bimolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland. Electronic address: Denisshields@ucd.ie.
Denis C
DC
Shields
Conway Institute of Bimolecular and Biomedical Research, University College Dublin, Dublin 4, Ireland. Electronic address: des.fitzgerald@ucd.ie.
Desmond
D
Fitzgerald
Trinity College Dublin, Institute of Cardiovascular Science, CREST Directorate, St James Hospital, James' Street, Dublin 8, Ireland. Electronic address: andrew.maree@gmail.com.
Andrew
A
Maree
D000595:Amino Acid Sequence; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001241:Aspirin / Q000627:therapeutic use*; D001792:Blood Platelets / Q000378:metabolism*; D002318:Cardiovascular Diseases / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D008875:Middle Aged; D012307:Risk Factors; D012701:Serotonin / Q000097:blood*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D026901:Membrane Transport Proteins; D012701:Serotonin; D001241:Aspirin
Aspirin; Coronary disease; Genetic; Serotonin