BACKGROUND: 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 webcite. 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.
Pubmed ID: 17903294 RIS Download
Mesh terms: Adult | Blood Coagulation Factors | Cardiovascular Diseases | Cohort Studies | Female | Genetic Markers | Genome, Human | Hemostasis | Humans | Male | Middle Aged | Multivariate Analysis | Phenotype | Polymorphism, Single Nucleotide
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A longitudinal, epidemiologic study to identify the common risk factors or characteristics that contribute to cardiovascular disease by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms or suffered a heart attack or stroke. Since that time the FHS has studied three generations of participants resulting in biological specimens and data from nearly 15,000 participants. Since 1994, two groups from minority populations, including related individuals have been added to the FHS. FHS welcomes proposals from outside investigators for data and biospecimens. The researchers recruited 5,209 men and women between the ages of 30 and 62 from the town of Framingham, Massachusetts, and began the first round of extensive physical examinations and lifestyle interviews that they would later analyze for common patterns related to CVD development. Since 1948, the subjects have continued to return to the study every two years for a detailed medical history, physical examination, and laboratory tests, and in 1971, the Study enrolled a second generation - 5,124 of the original participants'''' adult children and their spouses - to participate in similar examinations. In 1994, the need to establish a new study reflecting a more diverse community of Framingham was recognized, and the first Omni cohort of the Framingham Heart Study was enrolled. In April 2002 the Study entered a new phase, the enrollment of a third generation of participants, the grandchildren of the Original Cohort. In 2003, a second group of Omni participants was enrolled. Over the years, careful monitoring of the Framingham Study population has led to the identification of major CVD risk factors, as well as valuable information on the effects of these factors such as blood pressure, blood triglyceride and cholesterol levels, age, gender, and psychosocial issues. Risk factors for other physiological conditions such as dementia have been and continue to be investigated. In addition, the relationships between physical traits and genetic patterns are being studied. FHS clinical and research data is stored in the dbGaP and NHLBI Repository repositories and may be accessed by application. Please check the following repositories before applying for data through FHS. Investigators seeking data that is not available through dbGaP or BioLINCC or seeking biological specimens may submit a proposal through the FHS web-based research application. The FHS data repository may be accessed through this FHS website, under the For Researchers link, then Description of Data, in order to determine if and how the desired data is stored. Proposals may involve the use of existing data, the collection of new data, either directly from participants or from previously collected samples, images, or other materials (e.g., medical records). The FHS Repository also has biological specimens available for genetic and non-genetic research proposals. Specimens include urine, blood and blood products, as well as DNA.
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