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

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.

Association of ABO Blood Group and Risk of Breast Cancer

“…Previous studies reported that blood group A may influence the systemic inflammatory response as they found associations between the genotype of the A blood group antigen and circulating levels of soluble intercellular adhesion molecule 1, E-selection and P Selection suggesting that [44,45]. These may resulted in the increased incidence of breast cancer in blood type A cases.…”

ABO Blood Groups and Risk of Cancer: a Systematic Review and Meta-analysis

“…Modified expression of blood group antigens on the surface of cancer cells may alter cell motility, sensitivity to apoptosis and immune escape, and thus influence the initiation and spread of cancer (Le Pendu et al, 2001). In addition, recent studies have reported associations between ABO blood groups and circulating levels of tumor necrosis factor-alpha and soluble ICAM-1, E-selectin and P-selectin (Melzer et al, 2008;Paterson et al, 2009;Barbalic et al, 2010;Qi et al, 2010), suggesting that blood group antigens may influence the systemic inflammatory response. Chronic inflammation has been extensively linked with cancer development (Grivennikov et al, 2010), and provides a further potential mechanism by which ABO antigens may influence cancer risk.…”

Association of ABO blood groups with type-2 diabetes mellitus and its complications

“…29 In addition, the ABO blood groups have been associated with plasma soluble intercellular adhesion molecule 1 (ICAM-1) and TNF receptor 2 (TNF-R2) levels. 30 These markers have both been associated with an increased type 2 diabetes risk, thus providing a potential explanation for the observed relationships. 31,32 Finally, a recent paper suggested that the ABO blood group is one of the genetically determined host factors that modulate the composition of the intestinal microbiota 33 which participates in metabolism by affecting the energy balance, glucose metabolism and low-grade inflammation.…”