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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2149.
Submitted July 18, 2002
Accepted October 4, 2002
An intronic polymorphism in the PAR-1 gene is associated with platelet receptor density and the response to SFLLRN
Annabelle Dupont, Pierre Fontana, Christilla Bachelot-Loza, Jean-Luc Reny, Ivan Bieche, Florence Desvard, Martine Aiach, and Pascale Gaussem*
Service d'Hematologie Biologique, Hopital Europeen Georges Pompidou, Paris, France
INSERM, Unite 428, Hopital Europeen Georges Pompidou, Paris, France
Laboratoire de Genetique Moleculaire, UPRES-JE 2195, Faculte des Sciences Pharmaceutiques et Biologiques, Paris, France
* Corresponding author; email: pascale.gaussem{at}egp.ap-hop-paris.fr.
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 from 100 healthy subjects sampled twice one week apart, and found a two-fold interindividual variation in receptor numbers (95% confidence interval = 858-1700). As PAR-1 density was stable with time (r2 = 76 %, p < 0.001), we sought a genetic explanation for the observed variability. To validate this approach, we also analyzed the  2ß1 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 IVSn-14A/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, as it was associated with lower PAR-1 expression on the platelet surface and with a lower response to SFLLRN. The IVSn-14A/T intronic variation may therefore be clinically relevant.
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