@article {950, title = {Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {5}, year = {2007}, month = {2007 Jun}, pages = {1128-35}, abstract = {

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults.

OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals.

PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications.

RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95\% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95\% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95\% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low.

CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.

}, keywords = {Aged, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, Cohort Studies, Factor VIII, Female, Fibrinogen, Hemostasis, Homocysteine, Humans, Inflammation Mediators, Interleukin-6, Leukocyte Count, Lipoprotein(a), Male, Prospective Studies, Risk Factors}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2007.02528.x}, author = {Zakai, N A and Katz, R and Jenny, N S and Psaty, B M and Reiner, A P and Schwartz, S M and Cushman, M} } @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 {1047, title = {PROC, PROCR and PROS1 polymorphisms, plasma anticoagulant phenotypes, and risk of cardiovascular disease and mortality in older adults: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {6}, year = {2008}, month = {2008 Oct}, pages = {1625-32}, 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.

}, keywords = {Aged, Aged, 80 and over, Aging, Antigens, CD, Blood Coagulation Factor Inhibitors, Cardiovascular Diseases, Coronary Disease, Endothelial Protein C Receptor, Female, Humans, Inflammation, Male, Middle Aged, Mortality, Polymorphism, Genetic, Protein C, Protein S, Receptors, Cell Surface, Risk, Stroke, Thrombosis}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2008.03118.x}, author = {Reiner, A P and Carty, C L and Jenny, N S and Nievergelt, C and Cushman, M and Stearns-Kurosawa, D J and Kurosawa, S and Kuller, L H and Lange, L A} } @article {1106, title = {Common hemostasis and inflammation gene variants and venous thrombosis in older adults from the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {7}, year = {2009}, month = {2009 Sep}, pages = {1499-505}, abstract = {

BACKGROUND/OBJECTIVES: Age-related changes in blood coagulation and fibrinolysis are associated with increased risk of thrombotic events. Inherited deficiencies of coagulation proteins, such as factor V (FV) Leiden and prothrombin G20210A, explain a small fraction of venous thromboembolic disease (VTE). Additional genetic factors are likely to underlie the etiology of VTE, some of which may become manifest at older ages.

METHODS: We tested 290 common SNPs within 51 thrombosis and inflammation genes for association with VTE in the Cardiovascular Health Study, a large, prospective cohort of older adults followed for up to 12 years.

RESULTS: There were 184 VTE events that occurred at mean age of 78 years. TagSNPs within four genes encoding FXIII subunit A (F13A), FVII activating protease (HABP2), protease activated receptor-1 (F2R) and the urokinase receptor (PLAUR) showed the strongest evidence for association with VTE, with each gene having a global P-value < 0.05 and at least one tagSNP false discovery rate (FDR) q-value < 0.05. The rs3024409 variant allele of F13A1 was associated with 1.66-fold increased risk of VTE, while the minor alleles of HABP2 rs6585234 and rs3862019, F2R rs253061 and rs153311, and PLAUR rs344782 were each associated with lower risk of VTE (hazard ratios in the range of 0.49-0.66). Consistent with the observed protective association for VTE risk, the HABP2 rs3862019 variant allele was also associated with lower activity levels of coagulation factors FVIII, FIX, FX and plasminogen. We also confirm previously reported associations between common variants of the coagulation FII, FV, FVIII, FXI, alpha-fibrinogen and protein C genes and risk of VTE.

CONCLUSIONS: These findings suggest that several novel common coagulation gene variants may be related to risk of VTE in older adults. Further studies in older adults are needed to validate these findings and assess functional molecular mechanisms.

}, keywords = {Aged, Alleles, Factor V, Factor VIII, Female, Hemostasis, Humans, Inflammation, Male, Middle Aged, Models, Genetic, Plasminogen, Prothrombin, Risk, Serine Endopeptidases, Venous Thrombosis}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2009.03522.x}, author = {Reiner, A P and Lange, L A and Smith, N L and Zakai, N A and Cushman, M and Folsom, A R} } @article {1121, title = {Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis.}, journal = {J Thromb Haemost}, volume = {7}, year = {2009}, month = {2009 Oct}, pages = {1743-6}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Hemostasis, Humans, Incidence, Male, Menopause, Middle Aged, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk, Thrombophilia, Venous Thrombosis, Young Adult}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2009.03567.x}, author = {Smith, N L and Wiggins, K L and Reiner, A P and Lange, L A and Cushman, M and Heckbert, S R and Lumley, T and Rice, K M and Folsom, A R and Psaty, B M} } @article {1109, title = {Admixture mapping of ankle-arm index: identification of a candidate locus associated with peripheral arterial disease.}, journal = {J Med Genet}, volume = {47}, year = {2010}, month = {2010 Jan}, pages = {1-7}, abstract = {

BACKGROUND: Peripheral arterial disease (PAD) is associated with significant morbidity and mortality, and has a higher prevalence in African Americans than Caucasians. Ankle-arm index (AAI) is the ratio of systolic blood pressure in the leg to that in the arm, and, when low, is a marker of PAD.

METHODS: The authors used an admixture mapping approach to search for genetic loci associated with low AAI. Using data from 1040 African American participants in the observational, population based Health, Aging, and Body Composition Study who were genotyped at 1322 single nucleotide polymorphisms (SNPs) that are informative for African versus European ancestry and span the entire genome, we estimated genetic ancestry in each chromosomal region and then tested the association between AAI and genetic ancestry at each locus.

RESULTS: The authors found a region of chromosome 11 that reaches its peak between 80 and 82 Mb associated with low AAI (p<0.001 for rs12289502 and rs9665943, both within this region). 753 African American participants in the observational, population based Cardiovascular Health Study were genotyped at rs9665943 to test the reproducibility of this association, and this association was also statistically significant (odds ratio (OR) for homozygous African genotype 1.59, 95\% confidence interval (CI) 1.12 to 2.27). Another candidate SNP (rs1042602) in the same genomic region was tested in both populations, and was also found to be significantly associated with low AAI in both populations (OR for homozygous African genotype 1.89, 95\% CI 1.29 to 2.76).

CONCLUSION: This study identifies a novel region of chromosome 11 representing an area with a potential candidate gene associated with PAD in African Americans.

}, keywords = {African Americans, Aged, Ankle Brachial Index, Chromosome Mapping, Chromosomes, Human, Pair 11, Female, Genetic Loci, Genotype, Humans, Male, Odds Ratio, Peripheral Vascular Diseases, Polymorphism, Single Nucleotide}, issn = {1468-6244}, doi = {10.1136/jmg.2008.064808}, author = {Scherer, M L and Nalls, M A and Pawlikowska, L and Ziv, E and Mitchell, G and Huntsman, S and Hu, D and Sutton-Tyrrell, K and Lakatta, E G and Hsueh, W-C and Newman, A B and Tandon, A and Kim, L and Kwok, P-Y and Sung, A and Li, R and Psaty, B and Reiner, A P and Harris, T} } @article {1251, title = {Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {9}, year = {2011}, month = {2011 Feb}, pages = {267-74}, abstract = {

BACKGROUND: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive.

OBJECTIVES: To test the associations between 736 single-nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged >= 65 years of the observational Cardiovascular Health Study cohort.

PATIENTS/METHODS: With 16 years of follow-up, age-adjusted and sex-adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke.

RESULTS: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P-value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = -18.5, P = 2.38 {\texttimes} 10(-83)) and rs3093261 (β = 2.99, P = 3.93 {\texttimes} 10(-6)). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95\% confidence interval): Q1, reference; Q2, 1.4, 1.1-1.9); Q3, 1.1, 0.8-1.5); Q4, 1.5, 1.1-2.0); and Q5, 1.6, 1.2-2.2). Associations between SNPs and stroke were independent of FVIIc levels.

CONCLUSIONS: Variations in FVII-related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.

}, keywords = {Blood Coagulation Factors, Cardiovascular Diseases, Cohort Studies, Factor VII, Female, Humans, Inflammation, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, Stroke}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2010.04149.x}, author = {Zakai, N A and Lange, L and Longstreth, W T and O{\textquoteright}Meara, E S and Kelley, J L and Fornage, M and Nikerson, D and Cushman, M and Reiner, A P} } @article {1335, title = {The association of genetic variants in interleukin-1 genes with cognition: findings from the cardiovascular health study.}, journal = {Exp Gerontol}, volume = {46}, year = {2011}, month = {2011 Dec}, pages = {1010-9}, abstract = {

The inflammatory cytokine interleukin-1 (IL1) potentially plays a role in cognitive deterioration through pathology due to a dementing disorder or due to an aging process. Study of genetic variants in the IL1 genes has been mostly limited to diseases such as Alzheimer{\textquoteright}s, however, there may be benefit to studying a continuous measure of cognition. Using data from the Cardiovascular Health Study, we evaluate genetic variation in the genes encoding inflammatory agonists IL1A and IL1B, and the antagonist IL1RN, with repeated measures of global cognition (3MS) and processing speed (DSST), using mixed effects models. We found statistically significant minor allele SNP associations with baseline performance on the 3MS in the IL1RN gene for Caucasians (rs17042917: beta=0.47, 95\%CI=0.09, 0.85, p=0.016; rs4251961: beta=-0.36, 95\%CI=-0.13,-0.60, p=0.0027; rs931471: beta=0.39, 95\%CI=0.13, 0.65, p=0.0032), and the IL1B gene for African Americans (rs1143627: beta=1.6, 95\%CI=0.48, 2.8; p=0.006 and rs1143634: beta=2.09, 95\%CI=0.39, 3.8; p=0.016). Associations appear to be weaker in a subgroup with higher education level. Upon removing those diagnosed with dementia, effect sizes and statistical significance attenuated. These results provide supporting evidence that genetic variants in IL1 genes may be involved in inflammatory-related lowered cognition, that higher education may modify genetic predisposition, and that these associations may be driven by a dementia process.

}, keywords = {African Americans, Aged, Aged, 80 and over, Cognition, Cognition Disorders, Dementia, Educational Status, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Interleukin 1 Receptor Antagonist Protein, Interleukin-1alpha, Interleukin-1beta, Linkage Disequilibrium, Longitudinal Studies, Male, Polymorphism, Single Nucleotide, Prospective Studies, Risk Factors, United States}, issn = {1873-6815}, doi = {10.1016/j.exger.2011.09.005}, author = {Benke, K S and Carlson, M C and Doan, B Q and Walston, J D and Xue, Q L and Reiner, A P and Fried, L P and Arking, D E and Chakravarti, A and Fallin, M D} } @article {6063, title = {Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Mar}, pages = {401-8}, abstract = {

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P<=2.5{\texttimes}10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98{\texttimes}10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

}, keywords = {Adult, African Americans, Aged, Arrhythmias, Cardiac, Connexin 43, Electrocardiography, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Rest, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2012.11.014}, author = {Deo, R and Nalls, M A and Avery, C L and Smith, J G and Evans, D S and Keller, M F and Butler, A M and Buxbaum, S G and Li, G and Miguel Quibrera, P and Smith, E N and Tanaka, T and Akylbekova, E L and Alonso, A and Arking, D E and Benjamin, E J and Berenson, G S and Bis, J C and Chen, L Y and Chen, W and Cummings, S R and Ellinor, P T and Evans, M K and Ferrucci, L and Fox, E R and Heckbert, S R and Heiss, G and Hsueh, W C and Kerr, K F and Limacher, M C and Liu, Y and Lubitz, S A and Magnani, J W and Mehra, R and Marcus, G M and Murray, S S and Newman, A B and Njajou, O and North, K E and Paltoo, D N and Psaty, B M and Redline, S S and Reiner, A P and Robinson, J G and Rotter, J I and Samdarshi, T E and Schnabel, R B and Schork, N J and Singleton, A B and Siscovick, D and Soliman, E Z and Sotoodehnia, N and Srinivasan, S R and Taylor, H A and Trevisan, M and Zhang, Z and Zonderman, A B and Newton-Cheh, C and Whitsel, E A} } @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 {7253, title = {Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.}, journal = {Pharmacogenomics J}, year = {2016}, month = {2016 Dec 13}, abstract = {

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 {\texttimes} 10(-8)), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.The Pharmacogenomics Journal advance online publication, 13 December 2016; doi:10.1038/tpj.2016.90.

}, issn = {1473-1150}, doi = {10.1038/tpj.2016.90}, author = {Floyd, J S and Sitlani, C M and Avery, C L and Noordam, R and Li, X and Smith, A V and Gogarten, S M and Li, J and Broer, L and Evans, D S and Trompet, S and Brody, J A and Stewart, J D and Eicher, J D and Seyerle, A A and Roach, J and Lange, L A and Lin, H J and Kors, J A and Harris, T B and Li-Gao, R and Sattar, N and Cummings, S R and Wiggins, K L and Napier, M D and St{\"u}rmer, T and Bis, J C and Kerr, K F and Uitterlinden, A G and Taylor, K D and Stott, D J and de Mutsert, R and Launer, L J and Busch, E L and M{\'e}ndez-Gir{\'a}ldez, R and Sotoodehnia, N and Soliman, E Z and Li, Y and Duan, Q and Rosendaal, F R and Slagboom, P E and Wilhelmsen, K C and Reiner, A P and Chen, Y-DI and Heckbert, S R and Kaplan, R C and Rice, K M and Jukema, J W and Johnson, A D and Liu, Y and Mook-Kanamori, D O and Gudnason, V and Wilson, J G and Rotter, J I and Laurie, C C and Psaty, B M and Whitsel, E A and Cupples, L A and Stricker, B H} } @article {6793, title = {Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans.}, journal = {Mol Psychiatry}, volume = {21}, year = {2016}, month = {2016 May}, pages = {601-7}, abstract = {

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstr{\"o}m Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 {\texttimes} coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 {\texttimes} 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

}, issn = {1476-5578}, doi = {10.1038/mp.2015.105}, author = {Olfson, E and Saccone, N L and Johnson, E O and Chen, L-S and Culverhouse, R and Doheny, K and Foltz, S M and Fox, L and Gogarten, S M and Hartz, S and Hetrick, K and Laurie, C C and Marosy, B and Amin, N and Arnett, D and Barr, R G and Bartz, T M and Bertelsen, S and Borecki, I B and Brown, M R and Chasman, D I and van Duijn, C M and Feitosa, M F and Fox, E R and Franceschini, N and Franco, O H and Grove, M L and Guo, X and Hofman, A and Kardia, S L R and Morrison, A C and Musani, S K and Psaty, B M and Rao, D C and Reiner, A P and Rice, K and Ridker, P M and Rose, L M and Schick, U M and Schwander, K and Uitterlinden, A G and Vojinovic, D and Wang, J-C and Ware, E B and Wilson, G and Yao, J and Zhao, W and Breslau, N and Hatsukami, D and Stitzel, J A and Rice, J and Goate, A and Bierut, L J} } @article {7491, title = {Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.}, journal = {Pharmacogenomics J}, year = {2017}, month = {2017 Jul 18}, abstract = {

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66\%), African American (15\%) and Hispanic (19\%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 {\texttimes} 10(-8)), we found suggestive evidence (P<5 {\texttimes} 10(-6)) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.The Pharmacogenomics Journal advance online publication, 18 July 2017; doi:10.1038/tpj.2017.10.

}, issn = {1473-1150}, doi = {10.1038/tpj.2017.10}, author = {Seyerle, A A and Sitlani, C M and Noordam, R and Gogarten, S M and Li, J and Li, X and Evans, D S and Sun, F and Laaksonen, M A and Isaacs, A and Kristiansson, K and Highland, H M and Stewart, J D and Harris, T B and Trompet, S and Bis, J C and Peloso, G M and Brody, J A and Broer, L and Busch, E L and Duan, Q and Stilp, A M and O{\textquoteright}Donnell, C J and Macfarlane, P W and Floyd, J S and Kors, J A and Lin, H J and Li-Gao, R and Sofer, T and M{\'e}ndez-Gir{\'a}ldez, R and Cummings, S R and Heckbert, S R and Hofman, A and Ford, I and Li, Y and Launer, L J and Porthan, K and Newton-Cheh, C and Napier, M D and Kerr, K F and Reiner, A P and Rice, K M and Roach, J and Buckley, B M and Soliman, E Z and de Mutsert, R and Sotoodehnia, N and Uitterlinden, A G and North, K E and Lee, C R and Gudnason, V and St{\"u}rmer, T and Rosendaal, F R and Taylor, K D and Wiggins, K L and Wilson, J G and Chen, Y-DI and Kaplan, R C and Wilhelmsen, K and Cupples, L A and Salomaa, V and van Duijn, C and Jukema, J W and Liu, Y and Mook-Kanamori, D O and Lange, L A and Vasan, R S and Smith, A V and Stricker, B H and Laurie, C C and Rotter, J I and Whitsel, E A and Psaty, B M and Avery, C L} } @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} } @article {8260, title = {Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.}, journal = {Pharmacogenomics J}, year = {2019}, month = {2019 Dec 06}, abstract = {

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 {\texttimes} 10) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

}, issn = {1473-1150}, doi = {10.1038/s41397-019-0132-y}, author = {de Las Fuentes, L and Sung, Y J and Sitlani, C M and Avery, C L and Bartz, T M and Keyser, C de and Evans, D S and Li, X and Musani, S K and Ruiter, R and Smith, A V and Sun, F and Trompet, S and Xu, H and Arnett, D K and Bis, J C and Broeckel, U and Busch, E L and Chen, Y-D I and Correa, A and Cummings, S R and Floyd, J S and Ford, I and Guo, X and Harris, T B and Ikram, M A and Lange, L and Launer, L J and Reiner, A P and Schwander, K and Smith, N L and Sotoodehnia, N and Stewart, J D and Stott, D J and St{\"u}rmer, T and Taylor, K D and Uitterlinden, A and Vasan, R S and Wiggins, K L and Cupples, L A and Gudnason, V and Heckbert, S R and Jukema, J W and Liu, Y and Psaty, B M and Rao, D C and Rotter, J I and Stricker, B and Wilson, J G and Whitsel, E A} }