ABO blood type, factor VIII, and incident cognitive impairment in the REGARDS cohort

OBJECTIVE: To assess the relationships among ABO group, factor VIII (FVIII), and incident cognitive impairment in a large, prospective cohort study of black and white adults in the United States using a nested case-control design. METHODS: Incident cognitive impairment was defined using cognitive domain tests over a mean follow-up of 3.4 years. ABO blood group was measured by genotyping in a nested case-control sample of 495 cases with cognitive impairment and 587 controls. RESULTS: Those with blood group AB and those with higher FVIII had an increased risk of cognitive impairment, adjusting for age, race, region, and sex (respective odds ratios 1.82, 95% confidence interval [CI] 1.15-2.90; and 1.24, 95% CI 1.10-1.38 for 40 IU/dL higher FVIII). Mean FVIII was higher in those with blood type AB (142 IU/dL; 95% CI 119-165) compared with O (104 IU/dL; 95% CI 101-107), and FVIII mediated 18% of the association between AB group and incident cognitive impairment (95% CI for mediation -30% to 68%). CONCLUSIONS: Blood group AB and higher FVIII were associated with increased incidence of cognitive impairment in this prospective study. The association of blood group AB with incident cognitive impairment was not significantly mediated by FVIII levels

Body size measures, hemostatic and inflammatory markers and risk of venous thrombosis: The Longitudinal Investigation of Thromboembolism Etiology

Obesity is an important venous thrombosis (VT) risk factor but the reasons for this are unclear

Sickle cell trait and risk of cognitive impairment in African-Americans: The REGARDS cohort

Background: Sickle cell anemia may be associated with cognitive dysfunction, and some complications of sickle cell anemia might affect those with sickle cell trait (SCT), so we hypothesized that SCT is a risk factor for cognitive impairment. Methods: The Reasons for Geographic and Racial Differences in Stroke (REGARDS) study enrolled a national cohort of 30,239 white and black Americans from 2003 to 7, who are followed every 6 months. Baseline and annual global cognitive function testing used the Six-Item Screener (SIS), a validated instrument (scores range 0-6; ≤ 4 indicates cognitive impairment). Participants with baseline cognitive impairment and whites were excluded. Logistic regression was used to calculate the association of SCT with incident cognitive impairment, adjusted for risk factors. Linear mixed models assessed multivariable-adjusted change in test scores on a biennially administered 3-test battery measuring learning, memory, and semantic and phonemic fluency. Findings: Among 7743 participants followed for a median of 7·1 years, 85 of 583 participants with SCT (14·6%) developed incident cognitive impairment compared to 902 of 7160 (12·6%) without SCT. In univariate analysis, the odds ratio (OR) of incident cognitive impairment was 1·18 (95% CI: 0·93, 1·51) for those with SCT vs. those without. Adjustment did not impact the OR. There was no difference in change on 3-test battery scores by SCT status (all p > 0·11). Interpretation: In this prospective cohort study of black Americans, SCT was not associated with incident cognitive impairment or decline in test scores of learning, memory and executive function. Funding: National Institutes of Health, American Society of Hematology

Inpatient versus outpatient acute venous thromboembolism management: Trends and postacute healthcare utilization from 2011 to 2018

Background - Acute outpatient management of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is perceived to be as safe as inpatient management in some settings. How widely this strategy is used is not well documented. Methods and Results - Using MarketScan administrative claims databases for years 2011 through 2018, we identified patients with International Classification of Diseases (ICD) codes indicating incident VTE and trends in the use of acute outpatient management. We also evaluated healthcare utilization and hospitalized bleeding events in the 6 months following the incident VTE event. A total of 200 346 patients with VTE were included, of whom 50% had evidence of PE. Acute outpatient management was used for 18% of those with PE and 57% of those with DVT only, and for both DVT and PE its use increased from 2011 to 2018. Outpatient management was less prevalent among patients with cancer, higher Charlson comorbidity index scores, and whose primary treatment was warfarin as compared with a direct oral anticoagulant. Healthcare utilization in the 6 months following the incident VTE event was generally lower among patients managed acutely as outpatients, regardless of initial presentation. Acute outpatient management was associated with lower hazard ratios of incident bleeding risk for both patients who initially presented with PE (0.71 [95% CI, 0.61, 0.82]) and DVT only (0.59 [95% CI, 0.54, 0.64]). Conclusions - Outpatient management of VTE is increasing. In the present analysis, it was associated with lower subsequent healthcare utilization and fewer bleeding events. However, this may be because healthier patients were managed on an outpatient basis

Autoimmune disease and risk of postpartum venous thromboembolism

Background - The risk of pregnancy-related mortality in the United States has nearly doubled since 1990, with venous thromboembolism (VTE) accounting for approximately 10% of these deaths. Objectives - The objective of this study was to assess whether preexisting autoimmune disease is a risk factor for postpartum VTE. Methods - Using the MarketScan Commercial and Medicare Supplemental administrative databases, a retrospective cohort study analyzed whether postpartum persons with autoimmune disease had a higher risk of postpartum VTE incidence than postpartum persons without autoimmune disease. Using International Classification of Diseases codes, we identified 757,303 individuals of childbearing age who had a valid delivery date with at least 12 weeks of follow-up. Results - Individuals were, on average, 30.7 years old (SD, 5.4), and 3.7% (N = 27,997 of 757,303) of them had evidence of preexisting autoimmune disease. In covariate-adjusted models, postpartum persons with preexisting autoimmune disease had higher rates of postpartum VTE than postpartum persons without autoimmune disease (hazard ratio [HR], 1.33; 95% CI, 1.07-1.64). When analyzed by individual autoimmune disease, those with systemic lupus erythematosus (HR, 2.49; 95% CI, 1.47-4.21) and Crohn’s disease (HR, 2.49; 95% CI, 1.34-4.64) were at an elevated risk of postpartum VTE compared with those without autoimmune disease. Conclusion - Autoimmune disease was associated with a higher rate of postpartum VTE, with evidence that the association was most pronounced among individuals with systemic lupus erythematosus and Crohn’s disease. These findings suggest that postpartum persons of childbearing age with autoimmune disease may require more monitoring and prophylactic care after delivery to prevent potentially fatal VTE events

Myeloid Neoplasms with t(5;12) and ETV6-ACSL6 Gene Fusion, Potential Mimickers of Myeloid Neoplasm with PDGFRB Rearrangement: Case Report with Imatinib Therapy and Review of the Literature

We report the second case of ETV6-ACSL6 associated myeloproliferative neoplasm that has received a full course of imatinib therapy. The patient was a 51-year-old previously healthy man who presented with three months of worsening dyspnea and was found to have a white count of 216,000/cmm, of which 84% were eosinophil lineage. Cytogenetic analysis revealed a t(5;12)(q31~33;p13). FISH was negative for PDGFRB rearrangement but additional FISH testing demonstrated an ACSL6 rearrangement. ETV6-ACSL6 gene fusion is a rare abnormality that most often presents as a myeloproliferative-type disorder with prominent eosinophilia or basophilia. Review of the literature yielded a total of 11 previous cases. This gene fusion results in a t(5;12)(q31~33;p13) that mimics the t(5;12) found in ETV6-PDGFRB neoplasms. Identification of the fusion genes involved in t(5;12) in eosinophilia-associated myeloproliferative disorders is crucial to direct an effective treatment plan. In particular, while tyrosine kinase inhibitor therapy is effective in patients with PDGFRB rearrangement, there is little information on imatinib efficacy in patients with ETV6-ACSL6 gene fusion. Our patient was found to be nonresponsive to imatinib therapy

Multiple Loci Are Associated with White Blood Cell Phenotypes

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count—6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count—17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count—6p21, 19p13 at EPS15L1; monocyte count—2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds

Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population

White blood cells (WBCs) mediate immune systems and consist of various subtypes with distinct roles. Elucidation of the mechanism that regulates the counts of the WBC subtypes would provide useful insights into both the etiology of the immune system and disease pathogenesis. In this study, we report results of genome-wide association studies (GWAS) and a replication study for the counts of the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects enrolled in the BioBank Japan Project. We identified 12 significantly associated loci that satisfied the genome-wide significance threshold of P<5.0×10−8, of which 9 loci were novel (the CDK6 locus for the neutrophil count; the ITGA4, MLZE, STXBP6 loci, and the MHC region for the monocyte count; the SLC45A3-NUCKS1, GATA2, NAALAD2, ERG loci for the basophil count). We further evaluated associations in the identified loci using 15,600 subjects from Caucasian populations. These WBC subtype-related loci demonstrated a variety of patterns of pleiotropic associations within the WBC subtypes, or with total WBC count, platelet count, or red blood cell-related traits (n = 30,454), which suggests unique and common functional roles of these loci in the processes of hematopoiesis. This study should contribute to the understanding of the genetic backgrounds of the WBC subtypes and hematological traits

Genetic variation associated with circulating monocyte count in the eMERGE Network

With white blood cell count emerging as an important risk factor for chronic inflammatory diseases, genetic associations of differential leukocyte types, specifically monocyte count, are providing novel candidate genes and pathways to further investigate. Circulating monocytes play a critical role in vascular diseases such as in the formation of atherosclerotic plaque. We performed a joint and ancestry-stratified genome-wide association analyses to identify variants specifically associated with monocyte count in 11 014 subjects in the electronic Medical Records and Genomics Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (P-value = 2.78×10(−16), β = −0.22). Other monocyte associations include novel missense variants in the chemokine-binding protein 2 (CCBP2) gene (P-value = 1.88×10(−7), β = 0.30) and a region of replication found in ribophorin I (RPN1) (P-value = 2.63×10(−16), β = −0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA binding protein2 gene that has been previously shown to be associated with coronary heart disease. On chromosome 9, we found a novel association in the prostaglandin reductase 1 gene (P-value = 2.29×10(−7), β = 0.16), which is downstream from lysophosphatidic acid receptor 1. This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (P-value = 5.68×10(−17), β = −0.23) at the integrin, alpha 4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count

Natriuretic peptides and integrated risk assessment for cardiovascular disease: an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention. FUNDING: British Heart Foundation, Austrian Science Fund, UK Medical Research Council, National Institute for Health Research, European Research Council, and European Commission Framework Programme 7