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dc.contributor.authorYang, Qiong
dc.contributor.authorKathiresan, Sekar
dc.contributor.authorLin, Jing-Ping
dc.contributor.authorTofler, Geoffrey H
dc.contributor.authorO'Donnell, Christopher Joseph
dc.date.accessioned2011-04-23T15:54:41Z
dc.date.issued2007
dc.identifier.citationYang, Qiong, Sekar Kathiresan, Jing-Ping Lin, Geoffrey H. Tofler, and Christopher J. O'Donnell. 2007. Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study. BMC Medical Genetics 8(Suppl 1): S12.en_US
dc.identifier.issn1471-2350en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:4874797
dc.description.abstractBackground: Increased circulating levels of hemostatic factors as well as anemia have been associated with increased risk of cardiovascular disease (CVD). Known associations between hemostatic factors and sequence variants at genes encoding these factors explain only a small proportion of total phenotypic variation. We sought to confirm known putative loci and identify novel loci that may influence either trait in genome-wide association and linkage analyses using the Affymetrix GeneChip 100K single nucleotide polymorphism (SNP) set. Methods: Plasma levels of circulating hemostatic factors (fibrinogen, factor VII, plasminogen activator inhibitor-1, von Willebrand factor, tissue plasminogen activator, D-dimer) and hematological phenotypes (platelet aggregation, viscosity, hemoglobin, red blood cell count, mean corpuscular volume, mean corpuscular hemoglobin concentration) were obtained in approximately 1000 Framingham Heart Study (FHS) participants from 310 families. Population-based association analyses using the generalized estimating equations (GEE), family-based association test (FBAT), and multipoint variance components linkage analyses were performed on the multivariable adjusted residuals of hemostatic and hematological phenotypes. Results: In association analysis, the lowest GEE p-value for hemostatic factors was p = 4.5*10-16 for factor VII at SNP rs561241, a variant located near the F7 gene and in complete linkage disequilibrium (LD) (r2 = 1) with the Arg353Gln F7 SNP previously shown to account for 9% of total phenotypic variance. The lowest GEE p-value for hematological phenotypes was 7*10-8 at SNP rs2412522 on chromosome 4 for mean corpuscular hemoglobin concentration. We presented top 25 most significant GEE results with p-values in the range of 10-6 to 10-5 for hemostatic or hematological phenotypes. In relating 100K SNPs to known candidate genes, we identified two SNPs (rs1582055, rs4897475) in erythrocyte membrane protein band 4.1-like 2 (EPB41L2) associated with hematological phenotypes (GEE p < 10-3). In linkage analyses, the highest linkage LOD score for hemostatic factors was 3.3 for factor VII on chromosome 10 around 15 Mb, and for hematological phenotypes, LOD 3.4 for hemoglobin on chromosome 4 around 55 Mb. All GEE and FBAT association and variance components linkage results can be found at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 Conclusion: Using genome-wide association methodology, we have successfully identified a SNP in complete LD with a sequence variant previously shown to be strongly associated with factor VII, providing proof of principle for this approach. Further study of additional strongly associated SNPs and linked regions may identify novel variants that influence the inter-individual variability in hemostatic factors and hematological phenotypes.en_US
dc.language.isoen_USen_US
dc.publisherBioMed Centralen_US
dc.relation.isversionofdoi:10.1186/1471-2350-8-S1-S12en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1995619/pdf/en_US
dash.licenseLAA
dc.titleGenome-Wide Association and Linkage Analyses of Hemostatic Factors and Hematological Phenotypes in the Framingham Heart Studyen_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalBMC Medical Geneticsen_US
dash.depositing.authorO'Donnell, Christopher Joseph
dc.date.available2011-04-23T15:54:41Z
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dc.identifier.doi10.1186/1471-2350-8-S1-S12*
dash.contributor.affiliatedO'Donnell, Christopher


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