An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN.
Protease-activated receptor 1 (PAR-1), the main thrombin receptor on vascular cells, plays a key role in platelet activation. We examined the range of PAR-1 expression on platelets, obtained twice, 1 week apart, from 100 healthy subjects and found a 2-fold interindividual variation in receptor numbers (95% CI = 858-1700). Because PAR-1 density was stable with time (r(2) = 76%, P <.001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the alpha(2)beta(1) genotype according to receptor density and platelet mRNA expression data. We found that the number of PAR-1 receptors on the platelet surface is associated with the intervening sequence IVSn-14 A/T intronic variation. The number of receptors was also found to govern the platelet response to the SFLLRN agonist, in terms of aggregation and P-selectin expression. The T allele (allelic frequency, 0.14) can be considered as an allele with decreased expression, because it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn-14 A/T intronic variation may therefore be clinically relevant.
Dupont
Annabelle
A
Service d'Hématologie Biologique and INSERM Unité 428, Hôpital Européen Georges Pompidou, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris V, Paris, France.
Fontana
Pierre
P
Bachelot-Loza
Christilla
C
Reny
Jean-Luc
JL
Biéche
Ivan
I
Desvard
Florence
F
Aiach
Martine
M
Gaussem
Pascale
P
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D038982:Integrin alpha2beta1 / Q000235:genetics; D007438:Introns / Q000235:genetics*; D008297:Male; D019007:P-Selectin / Q000096:biosynthesis; D010446:Peptide Fragments / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects*; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000096:biosynthesis; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000032:analysis / Q000235:genetics* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D038982:Integrin alpha2beta1; D019007:P-Selectin; D010446:Peptide Fragments; D012333:RNA, Messenger; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; C082835:thrombin receptor peptide (42-47)