Large-scale genomic studies reveal central role of ABO in sP-selectin and sICAM-1 levels

Maja Barbalic, Josée Dupuis, Abbas Dehghan, Joshua C Bis, Ron C Hoogeveen, Renate B Schnabel, Vijay Nambi, Monique Bretler, Nicholas L Smith, Annette Peters, Chen Lu, Russell P Tracy, Nena Aleksic, Jan Heeriga, John F Keaney Jr, Kenneth Rice, Gregory Y H Lip, Ramachandran S Vasan, Nicole L Glazer, Martin G Larson, Andre G Uitterlinden, Jennifer Yamamoto, Peter Durda, Talin Haritunians, Bruce M Psaty, Eric Boerwinkle, Albert Hofman, Wolfgang Koenig, Nancy S Jenny, Jacqueline C Witteman, Christie Ballantyne, Emelia J Benjamin, Maja Barbalic, Josée Dupuis, Abbas Dehghan, Joshua C Bis, Ron C Hoogeveen, Renate B Schnabel, Vijay Nambi, Monique Bretler, Nicholas L Smith, Annette Peters, Chen Lu, Russell P Tracy, Nena Aleksic, Jan Heeriga, John F Keaney Jr, Kenneth Rice, Gregory Y H Lip, Ramachandran S Vasan, Nicole L Glazer, Martin G Larson, Andre G Uitterlinden, Jennifer Yamamoto, Peter Durda, Talin Haritunians, Bruce M Psaty, Eric Boerwinkle, Albert Hofman, Wolfgang Koenig, Nancy S Jenny, Jacqueline C Witteman, Christie Ballantyne, Emelia J Benjamin

Abstract

P-selectin and intercellular adhesion molecule-1 (ICAM-1) participate in inflammatory processes by promoting adhesion of leukocytes to vascular wall endothelium. Their soluble levels have been associated with adverse cardiovascular events. To identify loci affecting soluble levels of P-selectin (sP-selectin) and ICAM-1 (sICAM-1), we performed a genome-wide association study in a sample of 4115 (sP-selectin) and 9813 (sICAM-1) individuals of European ancestry as a part of The Cohorts for Heart and Aging Research in Genome Epidemiology consortium. The most significant SNP association for sP-selectin was within the SELP gene (rs6136, P = 4.05 x 10(-61)) and for sICAM-1 levels within the ICAM-1 gene (rs3093030, P = 3.53 x 10(-23)). Both sP-selectin and sICAM-1 were associated with ABO gene variants (rs579459, P = 1.86 x 10(-41) and rs649129, P = 1.22 x 10(-15), respectively) and in both cases the observed associations could be accounted for by the A1 allele of the ABO blood group. The absence of an association between ABO blood group and platelet-bound P-selectin levels in an independent subsample (N = 1088) from the ARIC study, suggests that the ABO blood group may influence cleavage of the P-selectin protein from the cell surface or clearance from the circulation, rather than its production and cellular presentation. These results provide new insights into adhesion molecule biology.

Figures

Figure 1.
Figure 1.
(A) Genome wide association plot for sP-selectin; (B) Regional plot of ABO locus for association with sP-selectin. Top SNP and corresponding P-value are indicated.
Figure 2.
Figure 2.
(A) Genome wide association plot for sICAM-1; (B) Regional plot of ABO locus for association with sICAM-1. Top SNP and corresponding P-value are indicated.

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