@article {1011, title = {Common genetic variants associated with plasma fibrin D-dimer concentration in older European- and African-American adults.}, journal = {J Thromb Haemost}, volume = {6}, year = {2008}, month = {2008 Apr}, pages = {654-9}, abstract = {

BACKGROUND AND OBJECTIVES: D-dimer is a hemostasis marker that reflects ongoing fibrin formation and degradation. There is significant inter-individual and inter-population variability in D-dimer concentration, but whether genetic factors underlie these differences is largely unknown. We hypothesized that common coagulation gene variants contribute to differences in circulating D-dimer concentration.

METHODS: The setting was European-American (EA; n = 1858) and African-American (AA; n = 327) unrelated older adults from the Cardiovascular Health Study (CHS), in which we genotyped SNPs in 42 genes related to blood coagulation and fibrinolysis.

RESULTS: Several fibrinogen gene polymorphisms, including the Thr312Ala Aalpha chain variant and the FGG-10034 C/T variant, were associated with approximately 20\% higher plasma D-dimer levels in EA (false discovery rate < 5\% for covariate-adjusted model). There was also some evidence that a Pro41Leu variant of the PLAU gene encoding urinary plasminogen activator and non-coding polymorphism of the plasminogen activator inhibitor type 1 gene (SERPINE1) were associated with higher plasma D-dimer in EA. There were no significant associations between the studied coagulation or fibrinolysis gene SNPs and plasma D-dimer levels in the smaller AA sample. However, each standard deviation increase in European ancestry assessed by ancestry-informative gene markers was associated with approximately 10\% lower mean D-dimer levels in AA.

CONCLUSIONS: Together, common coagulation/fibrinolysis gene SNPs explained only approximately 2\% of the variance in plasma D-dimer levels in EA. These findings suggest that the association of D-dimer with risk of vascular outcomes may be mediated largely by environmental factors, other genes, and/or genetic interactions.

}, keywords = {Africa, African Americans, Aged, Aged, 80 and over, Blood Coagulation, Europe, European Continental Ancestry Group, Female, Fibrin Fibrinogen Degradation Products, Fibrinogen, Fibrinolysis, Genotype, Humans, Male, Middle Aged, Plasminogen Activator Inhibitor 1, Polymorphism, Single Nucleotide, Prospective Studies, United States, Urokinase-Type Plasminogen Activator}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2008.02906.x}, author = {Lange, L A and Reiner, A P and Carty, C L and Jenny, N S and Cushman, M and Lange, E M} } @article {6081, title = {Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts.}, journal = {Biomarkers}, volume = {18}, year = {2013}, month = {2013 May}, pages = {196-203}, abstract = {

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown.

OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables.

METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets.

RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative.

CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

}, keywords = {African Continental Ancestry Group, Biomarkers, Cohort Studies, E-Selectin, Endothelin-1, Endothelium, Vascular, European Continental Ancestry Group, Female, Gene Expression, Humans, Intercellular Adhesion Molecule-1, Lung, Male, Middle Aged, P-Selectin, Pulmonary Disease, Chronic Obstructive, Respiratory Function Tests, Spirometry}, issn = {1366-5804}, doi = {10.3109/1354750X.2012.762805}, author = {Oelsner, E C and Pottinger, T D and Burkart, K M and Allison, M and Buxbaum, S G and Hansel, N N and Kumar, R and Larkin, E K and Lange, L A and Loehr, L R and London, S J and O{\textquoteright}Connor, G T and Papanicolaou, G and Petrini, M F and Rabinowitz, D and Raghavan, S and Redline, S and Thyagarajan, B and Tracy, R P and Wilk, J B and White, W B and Rich, S S and Barr, R G} } @article {6810, title = {Coagulation factor~XII genetic variation, ex~vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {13}, year = {2015}, month = {2015 Oct}, pages = {1867-77}, abstract = {

BACKGROUND: The relationships of thrombin generation (TG) with cardiovascular disease risk are underevaluated in population-based cohorts.

OBJECTIVES: To evaluate the relationships of TG influenced by the contact and tissue factor coagulation pathways ex~vivo with common single-nucleotide polymorphisms (SNPs) and incident cardiovascular disease and stroke.

PATIENTS/METHODS: We measured peak TG (pTG) in baseline plasma samples of Cardiovascular Health Study participants (n~=~5411), both with and without inhibitory anti-factor~XIa antibody (pTG/FXIa(-) ). We evaluated their associations with ~~50~000 SNPs by using the IBCv2 genotyping array, and with incident cardiovascular disease and stroke events over a median follow-up of 13.2~years.

RESULTS: The minor allele for an SNP in the FXII gene (F12), rs1801020, was associated with lower pTG in European-Americans (β~=~-~34.2~{\textpm}~3.5~nm; P~=~3.3~{\texttimes}~10(-22) ; minor allele frequency [MAF]~=~0.23) and African-Americans (β~=~-~31.1~{\textpm}~7.9~nm; P~=~9.0~{\texttimes} 10(-5) ; MAF~=~0.42). Lower FXIa-independent pTG (pTG/FXIa(-) ) was associated with the F12 rs1801020 minor allele, and higher pTG/FXIa(-) was associated with the ABO SNP rs657152 minor allele (β~=~16.3~nm; P~=~4.3~{\texttimes}~10(-9) ; MAF~=~0.37). The risk factor-adjusted ischemic stroke hazard ratios were 1.09 (95\% confidence interval CI~1.01-1.17; P~=~0.03) for pTG, 1.06 (95\% CI~0.98-1.15; P~=~0.17) for pTG/FXIa(-) , and 1.11 (95\% CI~1.02-1.21; P~=~0.02) for FXIa-dependent pTG (pTG/FXIa(+) ), per one standard deviation increment (n~=~834 ischemic strokes). In a multicohort candidate gene analysis, rs1801020 was not associated with incident ischemic stroke (β~=~-~0.02; standard error~=~0.08; P~=~0.81).

CONCLUSIONS: These results support the importance of contact activation pathway-dependent TG as a risk factor for ischemic stroke, and indicate the importance of F12 SNPs for TG ex~vivo and in~vivo.

}, keywords = {African Americans, Age Factors, Aged, Blood Coagulation, Brain Ischemia, European Continental Ancestry Group, Factor XII, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Incidence, Male, Phenotype, Polymorphism, Single Nucleotide, Prospective Studies, Risk Assessment, Risk Factors, Stroke, Thrombin, Time Factors, United States}, issn = {1538-7836}, doi = {10.1111/jth.13111}, author = {Olson, N C and Butenas, S and Lange, L A and Lange, E M and Cushman, M and Jenny, N S and Walston, J and Souto, J C and Soria, J M and Chauhan, G and Debette, S and Longstreth, W T and Seshadri, S and Reiner, A P and Tracy, R P} }