@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 {6133, title = {Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.}, journal = {Cytokine}, volume = {65}, year = {2014}, month = {2014 Jan}, pages = {10-6}, abstract = {

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9{\texttimes}10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3{\texttimes}10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7{\texttimes}10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

}, keywords = {Aged, Aged, 80 and over, Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Chromosomes, Human, Pair 2, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Male, Polymorphism, Single Nucleotide}, issn = {1096-0023}, doi = {10.1016/j.cyto.2013.10.002}, author = {Matteini, A M and Li, J and Lange, E M and Tanaka, T and Lange, L A and Tracy, R P and Wang, Y and Biggs, M L and Arking, D E and Fallin, M D and Chakravarti, A and Psaty, B M and Bandinelli, S and Ferrucci, L and Reiner, A P and Walston, J D} } @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} } @article {7581, title = {Associations of activated coagulation factor VII and factor VIIa-antithrombin levels with genome-wide polymorphisms and cardiovascular disease risk.}, journal = {J Thromb Haemost}, volume = {16}, year = {2018}, month = {2018 Jan}, pages = {19-30}, abstract = {

ESSENTIALS: Essentials A fraction of coagulation factor VII circulates in blood as an activated protease (FVIIa). We evaluated FVIIa and FVIIa-antithrombin (FVIIa-AT) levels in the Cardiovascular Health Study. Polymorphisms in the F7 and PROCR loci were associated with FVIIa and FVIIa-AT levels. FVIIa may be an ischemic stroke risk factor in older adults and FVIIa-AT may assess mortality risk.

SUMMARY: Background A fraction of coagulation factor (F) VII circulates as an active protease (FVIIa). FVIIa also circulates as an inactivated complex with antithrombin (FVIIa-AT). Objective Evaluate associations of FVIIa and FVIIa-AT with genome-wide single nucleotide polymorphisms (SNPs) and incident coronary heart disease, ischemic stroke and mortality. Patients/Methods We measured FVIIa and FVIIa-AT in 3486 Cardiovascular Health Study (CHS) participants. We performed a genome-wide association scan for FVIIa and FVIIa-AT in European-Americans (n~=~2410) and examined associations of FVII phenotypes with incident cardiovascular disease. Results In European-Americans, the most significant SNP for FVIIa and FVIIa-AT was rs1755685 in the F7 promoter region on chromosome 13 (FVIIa, β~=~-25.9~mU~mL-1 per minor allele; FVIIa-AT, β~=~-26.6~pm per minor allele). Phenotypes were also associated with rs867186 located in PROCR on chromosome 20 (FVIIa, β~=~7.8~mU~mL-1 per minor allele; FVIIa-AT, β~=~9.9 per minor allele). Adjusted for risk factors, a one standard deviation higher FVIIa was associated with increased risk of ischemic stroke (hazard ratio [HR],~1.12; 95\% confidence interval [CI], 1.01, 1.23). Higher FVIIa-AT was associated with mortality from all causes (HR, 1.08; 95\% CI, 1.03, 1.12). Among European-American CHS participants the rs1755685 minor allele was associated with lower ischemic stroke (HR, 0.69; 95\% CI, 0.54, 0.88), but this association was not replicated in a larger multi-cohort analysis. Conclusions The results support the importance of the F7 and PROCR loci in variation in circulating FVIIa and FVIIa-AT. The findings suggest FVIIa is a risk factor for ischemic stroke in older adults, whereas higher FVIIa-AT may reflect mortality risk.

}, issn = {1538-7836}, doi = {10.1111/jth.13899}, author = {Olson, N C and Raffield, L M and Lange, L A and Lange, E M and Longstreth, W T and Chauhan, G and Debette, S and Seshadri, S and Reiner, A P and Tracy, R P} }