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Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

Protein C is an important endogenous anticoagulant in hemostasis. Deficiencies of protein C due to genetic mutations or a low level of circulating protein C increase the risk of venous thromboembolism. We performed a genome-wide association scan for plasma protein C antigen concentration with approximately 2.5 million single-nucleotide polymorphisms in 8048 individuals of European ancestry and a replication analysis in a separate sample of 1376 individuals in the Atherosclerosis Risk in Communities Study. Four independent loci from 3 regions were identified with genome-wide significance: 2p23 (GCKR, best SNP rs1260326, P = 2.04 × 10(-17)), 2q13-q14 (PROC, rs1158867, P = 3.77 × 10(-36)), 20q11 (near and within PROCR, rs8119351, P = 2.68 × 10(-203)), and 20q11.22 (EDEM2, rs6120849, P = 7.19 × 10(-37) and 5.23 × 10(-17) before and after conditional analysis, respectively). All 4 loci replicated in the independent sample. Furthermore, pooling the discovery and replication sets yielded an additional locus at chromosome 7q11.23 (BAZ1B, rs17145713, P = 2.83 × 10(-8)). The regions marked by GCKR, EDEM2, and BAZ1B are novel loci that have not been previously reported for association with protein C concentration. In summary, this first genome-wide scan for circulating protein C concentration identified both new and known loci in the general population. These findings may improve the understanding of physiologic mechanisms in protein C regulation.

Background: Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels., Methods and Results: The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated., Conclusions: New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age2, age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD=3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD=3.0 at 182 cM) and 12 (LOD=3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD >or= 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.

Studies have reported a lower burden of calcified atherosclerotic plaque in coronary arteries in African-Americans than in whites. Findings from autopsy studies of sudden cardiac death have suggested a link between left ventricular hypertrophy and severity of coronary atherosclerosis. Echocardiograms and cardiac computed tomograms were analyzed in 334 African-American (84% hypertensive) and 196 white (66% hypertensive) adults with no history of coronary heart disease or revascularization procedures at study entry. The relation of coronary artery calcium (CAC) score to left ventricular mass and left ventricular mass indexed to body surface area was assessed by Spearman's correlations and mixed linear models. Covariates included age, gender, field center, weight, height, systolic blood pressure, number of antihypertensive medications, diabetes, total and high-density lipoprotein cholesterol levels, and current smoking and alcohol consumption. In African-Americans, a significant and independent association between CAC score and left ventricular mass or left ventricular mass indexed to body surface area was present with the 2 analytic strategies. Spearman's correlation coefficients for CAC score with left ventricular mass and left ventricular mass indexed to body surface area were 0.14 (p = 0.015) and 0.13 (p = 0.025), respectively, after multivariable adjustment. In whites, the associations of CAC score with measurements of left ventricular mass were weaker and only marginally significant in mixed linear models. In conclusion, these findings suggest that CAC reflects a different risk burden between African-Americans and whites, and future studies examining the prognostic implications of CAC in African-Americans should consider the potential association between CAC and left ventricular hypertrophy.

Background: Calcineurin is a calcium/calmodulin-regulated protein phosphatase that functions as a key mediator of hypertrophic response of the heart. Calcineurin B (CnB) is a regulatory subunit of calcineurin and is important for the phosphatase activity., Methods: We identified a novel 5-base pair (bp) insertion/deletion (5I/5D) polymorphism within the CnB promoter region and investigated its association with left ventricular hypertrophy (LVH) in 368 severe hypertensive participants (53% African Americans) in the Hypertension Genetic Epidemiology Network study. Traditionally defined LVH was identified by LV mass index >50 g/m(2.7) in men and >47 g/m(2.7) in women. Left ventricular mass predicted from sex, stroke work, and height(2.7) was calculated according to an equation derived from a normal population, and inappropriately high LV mass was defined as observed/predicted LV mass >1.28 based on the equation., Results: The CnB 5I/5D variation was not significantly associated with the traditionally defined LVH. However, there was a significant association between the CnB 5I/5D polymorphism and presence of inappropriately high LV mass. The ethnicity-adjusted ORs for the 5I/5D and 5D/5D genotypes compared with the 5I/5I genotype was 1.23 (95% CI 0.66-2.28) and 3.05 (95% CI 1.28-7.29) (P = .02 for trend test). This association was independent of age, sex, body mass index, heart rate, prevalent coronary heart disease, and/or diabetes and antihypertensive medications., Conclusions: The 5-base pair deletion within the CnB gene may cause excessive LV growth beyond the level appropriate for cardiac workload when exposed to severe hypertension or may be in linkage disequilibrium with the causal mutation.

Background: beta-Adrenergic receptors (ARs), including beta1- and beta2-AR, are involved in modulation of cardiac contractility and heart rate. Arg16Gly, a functional polymorphism in the beta2-AR gene, has been reported to influence exercise capacity in heart failure patients. This study examined the association of the beta2-AR Arg16Gly polymorphism with left ventricular (LV) systolic function in a biethnic population-based sample., Methods: Echocardiograms and the beta2-AR Arg16Gly polymorphism were analyzed in 267 normotensive (54% African Americans) and 252 severe hypertensive (53% African Americans) adults without coronary heart disease or diabetes., Results: The frequencies of Gly16Gly16, Arg16Gly16, and Arg16Arg16 were 28.1%, 54.3%, and 17.6%, respectively, in normotensives, and 31.4%, 47.6%, and 21.0%, respectively, in hypertensives. In normotensives, the Gly16Gly16 homozygotes displayed greater fractional shortening (35.9% +/- 4.3% v 34.1% +/- 4.7% v 34.0% +/- 3.9%, P =.01), ejection fraction (65.0% +/- 5.8% v 62.5% +/- 6.4% v 62.6% +/- 5.4%, P =.01), midwall shortening (18.6% +/- 1.6% v 17.9% +/- 1.9% v 18.0% +/- 1.6%, P =.02), and stress-corrected midwall shortening (110.1% +/- 9.3% v 106.1% +/- 10.6% v 108.1% +/- 10.8%, P =.03) compared to the Arg16Gly16 and Arg16Arg16 groups. These associations were independent of age, sex, ethnicity, heart rate, body mass index, systolic blood pressure, LV end-diastolic dimension, and field center. No significant associations between the beta2-AR Arg16Gly polymorphism and echocardiographic measures were found in hypertensives., Conclusions: The Arg16Gly polymorphism of beta2-AR may be a marker for LV chamber function and contractility in normotensive adults.

Recent studies have demonstrated significant genetic and phenotypic correlation underlying the clustering of traits involved in the multiple metabolic syndrome (MMS). The aim of this study was to identify chromosomal regions contributing to MMS-related traits represented by composite factors derived from factor analysis. Data from the National Heart, Lung, and Blood Institute (NHLBI) Family Heart Study were subjected to a maximum likelihood-based factor analysis. These analyses generated an MMS factor that was loaded by BMI, waist-to-hip ratio, subscapular skinfold, triglycerides, HDL, homeostasis model assessment index, plasminogen activator inhibitor-1 antigen, and serum uric acid. Genetic data were obtained for 2,467 subjects from 387 three-generation families (402 markers, the NHLBI Mammalian Genotyping Service) and 1,082 subjects from 256 sibships (243 markers, the Utah Molecular Genetics Laboratory). Multipoint variance components linkage analysis (GENEHUNTER version 2.1) of the MMS factor was conducted in the combined marker set sample. The greatest evidence for linkage was found on chromosome 2, with a peak LOD of 3.34 at 240 cM. Suggestive linkage was also observed for regions on chromosomes 7, 12, 14, and 15. In summary, a genomic region on chromosome 2 may contain a pleiotropic locus contributing to the clustering of MMS-related phenotypes.

Background: Altered diastolic filling is an important contributor to several cardiovascular disorders. Multiple lines of evidence suggest a genetic contribution to left ventricular (LV) diastolic filling; however, chromosomal locations harboring genes involved in impaired LV diastolic filling have not been reported. The aim of this study was to identify chromosomal regions contributing to variation of LV transmitral early and late peak filling velocities (E and A velocities), Doppler echocardiographic measures of LV diastolic filling., Methods: We adjusted E and A velocities for age, age squared, heart rate, body mass index, systolic blood pressure, field center, and antihypertensive medication in sex- and ethnicity-specific linear regression models. Standardized residuals were calculated and used in multipoint variance components linkage analysis (GENEHUNTER). Anonymous markers (Cooperative Human Linkage Center set 8) were available for 167 white hypertensive sibships (397 subjects, mean age 60 years) and 182 African American (393 subjects, mean age 52 years) hypertensive sibships., Results: For E velocity, linkage was detected on chromosome 5 at 133.6 centimorgan (cM) in African Americans (logarithm of the odds [LOD] = 4.13), and suggestive linkage (LOD >1.9) was observed for regions on chromosome 10 (80.8 cM) and chromosome 20 (1.5 cM). For A velocity, suggestive linkage was found for chromosome 12 (GATA85A04) in whites and for chromosome 8 (122.9 cM) in African Americans. Genes contained in and around the linked region are important candidates for diastolic filling (calcium-modulating cyclophilin ligand [5q23], alpha-1B adrenergic receptor [5q23-32])., Conclusion: Significant linkage was detected for LV early diastolic peak filling velocity on chromosome 5 in African Americans, indicating that a genomic region may contribute to interindividual variation in LV diastolic filling.

Background: The angiotensinogen M235T polymorphism is positively associated with plasma angiotensinogen, hypertension, and coronary heart disease. However, the association of M235T polymorphism with left ventricular (LV) mass and function is not well defined at the population level. We investigated whether 2 tightly linked polymorphisms of angiotensinogen gene, M235T and G-6A, are associated with LV mass and function in a large population-based sample, composed mostly of patients with hypertension., Methods: Two-dimensional guided M-mode and pulsed Doppler scan echocardiograms were performed in 605 participants. The angiotensinogen M235T was analyzed with a standard polymerase chain reaction test, and the G-6A variant was measured with mass spectrophotometry., Results: The association of angiotensinogen gene to LV mass and LV mass indexed to body surface area (LVMI) differed significantly between subjects with normotensive and hypertensive conditions with respect to the direction of association (P <.005). The methionine-threonine/threonine-threonine genotype was negatively associated with LV mass and LVMI in patients with hypertension after adjustment for blood pressure, antihypertensive medication use, weight, and other covariates (P <.001), and patients with normotensive conditions with the methionine-threonine/threonine-threonine genotype had higher LV mass and LVMI (P =.04, for LV mass; P =.14, for LVMI). The association in patients with normotensive conditions was not influenced by blood pressure but was partly confounded by weight., Conclusion: Variation in the angiotensinogen gene was modestly associated with LV mass independently of covariates in patients with hypertensive conditions. The direction of the association was opposite to that observed in patients with normotensive conditions, probably because of the influence of other risk factors or antihypertensive medication use or both.