Céline Verdier1, Jean-Bernard Ruidavets2, Annelise Genoux1, Guillaume Combes1, Vanina Bongard2, Dorota Taraszkiewicz3, Michel Galinier3, Meyer Elbaz4, Jean Ferrières2, Laurent O Martinez5, Bertrand Perret1. 1. Inserm, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Paul Sabatier University, University of Toulouse, 31330 Toulouse, France; Service de biochimie, Pôle Biologie, Hôpital Purpan, CHU de Toulouse, 31300 Toulouse, France. 2. Paul Sabatier University, University of Toulouse, 31330 Toulouse, France; Inserm, UMR 1027, épidémiologie et analyse en santé publique, 31000 Toulouse, France; Department of Cardiology, hôpital de Rangueil, CHU de Toulouse, 31400 Toulouse, France. 3. Department of Cardiology, hôpital de Rangueil, CHU de Toulouse, 31400 Toulouse, France. 4. Inserm, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Paul Sabatier University, University of Toulouse, 31330 Toulouse, France; Department of Cardiology, hôpital de Rangueil, CHU de Toulouse, 31400 Toulouse, France. 5. Inserm, UMR 1048, Institute of Metabolic and Cardiovascular Diseases, 31432 Toulouse, France; Paul Sabatier University, University of Toulouse, 31330 Toulouse, France. Electronic address: laurent.Martinez@inserm.fr.
Abstract
BACKGROUND: The P2Y13 purinergic receptor regulates hepatic high-density lipoprotein uptake and biliary sterol secretion; it acts downstream of the membrane ecto-F1-adenosine triphosphatase, which generates extracellular adenosine diphosphate that selectively activates P2Y13, resulting in high-density lipoprotein endocytosis. Previous studies have shown that the serum concentration of the F1-adenosine triphosphatase inhibitor inhibitory factor 1 is negatively associated with cardiovascular risk. AIM: To evaluate whether p2y13 genetic variants affect cardiovascular risk. METHODS: Direct sequencing of the p2y13 coding and flanking regions was performed in a subcohort of 168 men aged 45-74 years with stable coronary artery disease and 173 control subjects from the GENES study. The two most frequent mutations, rs3732757 and rs1466684, were genotyped in 767 patients with coronary artery disease and 789 control subjects, and their association with cardiovascular risk markers was analysed. RESULTS: Carriers of the rs3732757 261T and rs1466684 557G alleles represented 9% and 27.5% of the entire population, respectively. The allele frequencies were identical in patients with coronary artery disease and control subjects. The presence of 261T was associated with higher concentrations of plasma lipoprotein A-I and inhibitory factor 1, increased fat mass and a lower heart rate. Moreover, the proportion of patients with coronary artery disease with a pejorative systolic ankle-brachial index was lower in carriers of the 261T allele. In both populations, the 557G allele was associated with increased concentrations of lipoprotein(a), and an allele dose effect was observed. CONCLUSIONS: Two frequent p2y13 variants are associated with specific bioclinical markers of cardiovascular risk. Although neither one of these variants appears to be related to the development of atherosclerotic disease, they may modulate the risk of additional cardiovascular complications.
BACKGROUND: The P2Y13 purinergic receptor regulates hepatic high-density lipoprotein uptake and biliary sterol secretion; it acts downstream of the membrane ecto-F1-adenosine triphosphatase, which generates extracellular adenosine diphosphate that selectively activates P2Y13, resulting in high-density lipoprotein endocytosis. Previous studies have shown that the serum concentration of the F1-adenosine triphosphatase inhibitor inhibitory factor 1 is negatively associated with cardiovascular risk. AIM: To evaluate whether p2y13 genetic variants affect cardiovascular risk. METHODS: Direct sequencing of the p2y13 coding and flanking regions was performed in a subcohort of 168 men aged 45-74 years with stable coronary artery disease and 173 control subjects from the GENES study. The two most frequent mutations, rs3732757 and rs1466684, were genotyped in 767 patients with coronary artery disease and 789 control subjects, and their association with cardiovascular risk markers was analysed. RESULTS: Carriers of the rs3732757 261T and rs1466684 557G alleles represented 9% and 27.5% of the entire population, respectively. The allele frequencies were identical in patients with coronary artery disease and control subjects. The presence of 261T was associated with higher concentrations of plasma lipoprotein A-I and inhibitory factor 1, increased fat mass and a lower heart rate. Moreover, the proportion of patients with coronary artery disease with a pejorative systolic ankle-brachial index was lower in carriers of the 261T allele. In both populations, the 557G allele was associated with increased concentrations of lipoprotein(a), and an allele dose effect was observed. CONCLUSIONS: Two frequent p2y13 variants are associated with specific bioclinical markers of cardiovascular risk. Although neither one of these variants appears to be related to the development of atherosclerotic disease, they may modulate the risk of additional cardiovascular complications.