Genome-wide association and linkage analyses of hemostatic factors and hematological phenotypes in the Framingham Heart Study

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>In association analysis, the lowest GEE p-value for hemostatic factors was p = 4.5*10^-16for factor VII at SNP rs561241, a variant located near the <it>F7 </it>gene and in complete linkage disequilibrium (LD) (r²= 1) with the Arg353Gln <it>F7 </it>SNP previously shown to account for 9% of total phenotypic variance. The lowest GEE p-value for hematological phenotypes was 7*10^-8at 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^-6to 10^-5for 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 (<it>EPB41L2</it>) 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 <url>http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007</url></p> <p>Conclusion</p> <p>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.</p

Effects of gender and race on prognosis after myocardial infarction: Adverse prognosis for women, particularly black women

Controversy has arisen concerning whether gender influences the prognosis after myocardial infarction. Although some studies have shown there to be no difference between the sexes, most have indicated a worse prognosis for women, attributing this to differences in baseline characteristics. It has been further suggested that black women have a particularly poor prognosis after infarction. To determine the contribution of gender and race to the course of infarction, 816 patients with confirmed myocardial infarction who were enrolled in the Multi-center Investigation of the Limitation of Infarct Size (MILIS) were analyzed. Of those patients, 226 were women and 590 were men, 142 were black and 674 were white.The cumulative mortality rate at 48 months was 36% for women versus 21% for men (p < 0.001, mean follow-up 32 months). The cumulative mortality rate by race was 34% for blacks versus 24% for whites (p < 0.005). Both women and blacks exhibited more baseline characteristics predictive of mortality than did their male or white counterparts. It was possible to account for the greater mortality rate of blacks by identifiable baseline variables; however, even after adjustment, the mortality rate for women remained significantly higher (p < 0.002). The poorer prognosis for women was influenced by a particularly high mortality rate among black women (48%); the mortality rate for white women was 32%, for black men 23% and for white men 21%. The mortality for black women was significantly greater than that of the other subgroups. Thus, findings in the MILIS population indicate that the prognosis after myocardial infarction is worse for women, particularly black women

Gene-centric approach identifies new and known loci for FVIII activity and VWF antigen levels in European Americans and African Americans: Genetic associations for FVIII:C and VWF:ag

Coagulation factor VIII and von Willebrand factor (VWF) are key proteins in procoagulant activation. Higher FVIII coagulant activity (FVIII:C) and VWF antigen (VWF:Ag) are risk factors for cardiovascular disease and venous thromboembolism. Beyond associations with ABO blood group, genetic determinants of FVIII and VWF are not well understood, especially in non European-American populations. We performed a genetic association study of FVIII:C and VWF:Ag that assessed 50,000 gene-centric single nucleotide polymorphisms (SNPs) in 18,556 European Americans (EAs) and 5,047 African Americans (AAs) from five population-based cohorts. Previously unreported associations for FVIII:C were identified in both AAs and EAs with KNG1 (most significantly associated SNP rs710446, Ile581Thr, P=5.10 × 10−7 in EAs and P=3.88 × 10−3 in AAs) and VWF rs7962217 (Gly2705Arg, P=6.30 × 10−9 in EAs and P=2.98 × 10−2 in AAs). Significant associations for FVIII:C were also observed with F8/TMLHE region SNP rs12557310 in EAs (P=8.02 × 10−10), with VWF rs1800380 in AAs (P=5.62 × 10−11), and with MAT1A rs2236568 in AAs (P=1.69 × 10−6). We replicated previously reported associations of FVIII:C and VWF:Ag with the ABO blood group, VWF rs1063856 (Thr789Ala), rs216321 (Ala852Gln), and VWF rs2229446 (Arg2185Gln). Findings from this study expand our understanding of genetic influences for FVIII:C and VWF:Ag in both EAs and AAs

Causal effect of plasminogen activator inhibitor type 1 on coronary heart disease

Background--Plasminogen activator inhibitor type 1 (PAI-1) plays an essential role in the fibrinolysis system and thrombosis. Population studies have reported that blood PAI-1 levels are associated with increased risk of coronary heart disease (CHD). However, it is unclear whether the association reflects a causal influence of PAI-1 on CHD risk. Methods and Results--To evaluate the association between PAI-1 and CHD, we applied a 3-step strategy. First, we investigated the observational association between PAI-1 and CHD incidence using a systematic review based on a literature search for PAI-1 and CHD studies. Second, we explored the causal association between PAI-1 and CHD using a Mendelian randomization approach using summary statistics from large genome-wide association studies. Finally, we explored the causal effect of PAI-1 on cardiovascular risk factors including metabolic and subclinical atherosclerosis measures. In the systematic meta-analysis, the highest quantile of blood PAI-1 level was associated with higher CHD risk comparing with the lowest quantile (odds ratio=2.17; 95% CI: 1.53, 3.07) in an age- and sex-adjusted model. The effect size was reduced in studies using a multivariable-adjusted model (odds ratio=1.46; 95% CI: 1.13, 1.88). The Mendelian randomization analyses suggested a causal effect of increased PAI-1 level on CHD risk (odds ratio=1.22 per unit increase of log-transformed PAI-1; 95% CI: 1.01, 1.47). In addition, we also detected a causal effect of PAI-1 on elevating blood glucose and high-density lipoprotein cholesterol. Conclusions--Our study indicates a causal effect of elevated PAI-1 level on CHD risk, which may be mediated by glucose dysfunction

No Evidence for Genome-Wide Interactions on Plasma Fibrinogen by Smoking, Alcohol Consumption and Body Mass Index : Results from Meta-Analyses of 80,607 Subjects

Peer reviewe

The impact of hospitalisation on a visiting family member : A case study and discussion

Evidence suggests that when an immediate family member of a spouse is hospitalised, the partner's risk of death significantly increases. Hospitalisation can represent a time of great vulnerability and imposed stress for both the patient and their family members. Family members have been reported to give priority to the welfare of their ill relative and in their heightened emotional state, often adversely put their own health at risk. The paper presents a case study highlighting how an intensive care hospitalisation and discharge to rehabilitation experience for a patient's mother triggered an episode of myocardial infarction for her adult son. Discussion focuses on the caregiving burden and potential mechanisms for how hospitalisation may contribute to the health risk of immediate family members of hospitalised patients. Discussion also highlights the importance of family members receiving clear, continuous and consistent information from a limited number of clinicians to help reduce the stress associated with caregiving during acute hospitalisation

Psychological responses and coping behaviour of visiting family members during and following unplanned hospital admission

Aims To describe the psychological symptoms and coping behaviours of visiting family members following the unplanned hospitalisation of their relative. Background Hospitalisation of a patient is recognised as a stressful time for visiting family members, who experience psychological morbidity and elevated health risk. Design This prospective longitudinal evaluation included 40 family members of patients with unplanned admission to coronary or intensive care. Assessments were conducted at 3 timepoints: in-hospital within 1 week of admission and again at 2 weeks and 3 months post-discharge. Measures included symptoms of anxiety, depression, and anger, coping strategies and social support. This paper adhered to STROBE guidelines. Results At the initial in-hospital assessment study participants reported higher anxiety, depression and anger symptoms levels compared to community matched control participants. Compared to in-hospital assessment, anxiety and depression levels were lower at 2 weeks and 3 months following hospital discharge. The use of active coping and the use of religion during early hospitalisation were associated with higher anxiety and depression symptoms at 3 months post-discharge. Conversely, use of instrumental support (getting help and advice from others), planning and venting during early hospitalisation were associated with lower depression symptoms at 3 months. Venting during the hospitalisation period was also associated with lower anxiety symptoms at 3 months. Conclusion Results demonstrate the significant psychological impact of unplanned hospitalisation on visiting family members both during and following hospitalisation. The finding that prolonged psychological response is associated with individual coping strategies employed in the early hospitalised period informs potential preventative approaches for family members at risk of prolonged psychological morbidity following hospitalisation of their loved one. Relevance to clinical practice The reported psychological impact of hospitalisation on family members provides a strong imperative for nurses and health professionals to provide early individualised support to reduce the risk of long-term psychological morbidity