Dataset Information

PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.

ABSTRACT: BACKGROUND AND OBJECTIVES:Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders. METHODS:Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of incident clinical outcomes [coronary heart disease (CHD), stroke, and mortality] in 4547 participants during follow-up. Secondarily, we explored associations between plasma protein C, protein S and sEPCR levels and other candidate genes involved in thrombosis, inflammation, and aging. RESULTS:The PROCR Ser219Gly polymorphism (rs867186) was strongly associated with higher sEPCR levels, explaining 75% of the phenotypic variation. The PROCR Ser219Gly variant was also associated with higher levels of circulating protein C antigen. An IL10 polymorphism was associated with higher free protein S levels. The minor alleles of PROC rs2069901 and PROS1 rs4857343 were weakly associated with lower protein C and free protein S levels, respectively. There was no association between PROCR Ser219Gly and risk of CHD, stroke, or mortality. The minor allele of another common PROCR tagSNP, rs2069948, was associated with lymphoid PROCR mRNA expression and with increased risk of incident stroke and all-cause mortality, and decreased healthy survival during follow-up. CONCLUSIONS:A common PROCR variant may be associated with decreased healthy survival in older adults. Additional studies are warranted to establish the role of PROCR variants in ischemic and aging-related disorders.

SUBMITTER: Reiner AP

PROVIDER: S-EPMC2856703 | biostudies-literature | 2008 Oct

REPOSITORIES: biostudies-literature

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PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.

Reiner A P AP Carty C L CL Jenny N S NS Nievergelt C C Cushman M M Stearns-Kurosawa D J DJ Kurosawa S S Kuller L H LH Lange L A LA

Journal of thrombosis and haemostasis : JTH 20080801 10

<h4>Background and objectives</h4>Genes encoding protein C anticoagulant pathways are candidates for atherothrombotic and other aging-related disorders.<h4>Methods</h4>Using a tagSNP approach, and data from the Cardiovascular Health Study (CHS), we assessed associations of common polymorphisms of PROC, PROS1 and PROCR with: (i) plasma protein C, soluble protein C endothelial receptor (sEPCR) and protein S levels measured in a subsample of 336 participants at study entry; and (ii) risk of inciden ...[more]

PMID: 18680534

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Project description:BackgroundThe epsilon2, epsilon3, and epsilon4 alleles of the apolipoprotein E gene (APOE) encode three isoforms, apoE2, E3, and E4, respectively. The apoE isoforms circulate in different plasma concentrations, but plasma concentrations of the same isoform also differ between individuals. Whereas the isoforms have been associated with cardiovascular disease, the relation between plasma apoE levels and cardiovascular disease is unknown.Methods and findingsWe assessed APOE genotypes, plasma levels of apoE, cardiovascular risk factors, and mortality in a population-based sample of 546 individuals aged 85 y who participated in the Leiden 85-plus Study and were prospectively followed for specific causes of death for 5 y. Participants in the highest tertile of apoE levels suffered a twofold-increased risk of cardiovascular mortality (hazard ratio compared to lowest tertile, 2.08; 95% confidence interval [CI], 1.30 to 3.33). Among the 324 participants with the epsilon3epsilon3 genotype, the hazard from cardiovascular disease was threefold increased (highest versus lowest tertile 3.01; 95% CI 1.60 to 5.66), with similar estimates for men and women. Other causes of death were not increased significantly. Plasma levels of apoE in epsilon3epsilon3 participants were positively correlated with total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p < 0.001) and triglycerides (p < 0.001) and negatively with high-density lipoprotein cholesterol levels (p = 0.010). Adjustment for plasma lipids did not change the hazard ratios, whereas interaction was absent. The risk associated with high levels of apoE, however, was strongest in participants from the lowest tertile of C-reactive protein (CRP) levels and absent in those from the highest tertile (p(interaction) < 0.001). Among participants from the lowest tertile of CRP levels, those with a high apoE levels had a significantly steeper increase in CRP than those with low apoE levels (p = 0.020). Similar cardiovascular mortality risks as in epsilon3epsilon3 participants were found in epsilon2 and epsilon4 carriers.ConclusionsIn old age, high plasma apoE levels precede an increase of circulating CRP and strongly associates with cardiovascular mortality, independent of APOE genotype and plasma lipids.

Dataset Information

PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.

Publications

PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.

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