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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.

SUBMITTER: Barbalic M

PROVIDER: S-EPMC2850624 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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

Barbalic Maja M Dupuis Josée J Dehghan Abbas A Bis Joshua C JC Hoogeveen Ron C RC Schnabel Renate B RB Nambi Vijay V Bretler Monique M Smith Nicholas L NL Peters Annette A Lu Chen C Tracy Russell P RP Aleksic Nena N Heeriga Jan J Keaney John F JF Rice Kenneth K Lip Gregory Y H GY Vasan Ramachandran S RS Glazer Nicole L NL Larson Martin G MG Uitterlinden Andre G AG Yamamoto Jennifer J Durda Peter P Haritunians Talin T Psaty Bruce M BM Boerwinkle Eric E Hofman Albert A Koenig Wolfgang W Jenny Nancy S NS Witteman Jacqueline C JC Ballantyne Christie C Benjamin Emelia J EJ

Human molecular genetics 20100218 9

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 an ...[more]

PMID: 20167578

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Project description:BackgroundElevated soluble (s) E-selectin levels have been associated with various cardiovascular diseases. Recently, genetic variants in the ABO blood group have been related to E-selectin levels in a small cohort of patients with type 1 diabetes. We evaluated whether this association is reproducible in two large samples of Caucasians.Methodology/ principal findingsData of the present study was drawn from the population-based MONICA/KORA Augsburg study (n = 1,482) and the patients-based LURIC study (n = 1,546). A high-density genotyping array (50K IBC Chip) containing single-nucleotide polymorphisms (SNPs) from E-selectin candidate genes selected on known biology of E-selectin metabolism, mouse genetic studies, and human genetic association studies, was used for genotyping. Linear regression analyses with adjustment for age and sex (and survey in KORA) were applied to assess associations between gene variants and sE-selectin concentrations. A number of 12 SNPs (in KORA) and 13 SNPs (in LURIC), all from the ABO blood group gene, were significantly associated with the log-transformed concentration of E-selectin. The strongest association was observed for rs651007 with a change of log-transformed sE-selectin per one copy of the minor allele of -0.37 ng/ml (p = 1.87×10(-103)) in KORA and -0.35 ng/ml (p = 5.11×10(-84)) in LURIC. Inclusion of rs651007 increased the explained sE-selectin variance by 0.256 in KORA and 0.213 in LURIC. All SNPs had minor allele frequencies above 20% showing a substantial gene variation.Conclusions/ significanceOur findings in two independent samples indicate that the genetic variants at the ABO locus affect sE-selectin levels. Since distinct genome-wide association studies linked the ABO gene with myocardial infarction (MI) in the presence of coronary atherosclerosis and with coronary artery disease, these findings may not only enhance our understanding of adhesion molecule biology, but may also provide a focus for several novel research avenues.

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

Publications

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

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