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1.  Statin Therapy and Levels of Hemostatic Factors in a Healthy Population: the Multi-Ethnic Study of Atherosclerosis 
Background
HMG CoA reductase inhibitors (statins) reduce risk of venous thromboembolism (VTE) in healthy people. Statins reduce levels of inflammation biomarkers, however the mechanism for reduction in VTE risk is unknown. In a large cohort of healthy people, we studied associations of statin use with plasma hemostatic factors related to VTE risk.
Methods
Cross-sectional analyses were performed in the Multi-Ethnic Study of Atherosclerosis (MESA), a cohort study of 6814 healthy men and women age 45–84, free of clinical cardiovascular disease at baseline; 1001 were using statins at baseline. Twenty-three warfarin users were excluded. Age, race, and sex-adjusted mean hemostatic factor levels were compared between statin users and nonusers, and multivariable linear regression models were used to assess associations of statin use with hemostasis factors, adjusted for age, race/ethnicity, education, income, hormone replacement therapy (in women), and major cardiovascular risk factors.
Results
Participants using statins had lower adjusted levels of D-dimer (−9%), C-reactive protein (−21%) and factor VIII (−3%) than non-users (p<0.05). Homocysteine and von Willebrand factor were non-significantly lower with statin use. Higher fibrinogen (2%) and PAI-1 (22%) levels were observed among statin users than nonusers (p<0.05). Further adjustment for LDL and triglyceride levels did not attenuate the observed differences in these factors by statin use.
Conclusions
Findings of lower D-dimer, factor VIII and C-reactive protein levels with statin use suggest hypotheses for mechanisms whereby statins might lower VTE risk. A prospective study or clinical trial linking these biochemical differences to VTE outcomes in statin users and nonusers is warranted.
doi:10.1111/jth.12223
PMCID: PMC3702638  PMID: 23565981
statins; thrombosis; risk factor; blood coagulation; inflammation; fibrinolysis
2.  Genetic variation associated with circulating monocyte count in the eMERGE Network 
Human Molecular Genetics  2013;22(10):2119-2127.
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.
doi:10.1093/hmg/ddt010
PMCID: PMC3633369  PMID: 23314186
3.  AHA Scientific Statement Population Approaches to Improve Diet, Physical Activity, and Smoking Habits A Scientific Statement From the American Heart Association 
Circulation  2012;126(12):10.1161/CIR.0b013e318260a20b.
Background
Poor lifestyle, including suboptimal diet, physical inactivity, and tobacco use are leading causes of preventable diseases globally. Although even modest population shifts in risk substantially alter health outcomes, the optimal population-level approaches to improve lifestyle are not well established.
Methods and Results
For this American Heart Association Scientific Statement, the writing group systematically reviewed and graded the current scientific evidence for effective population approaches to improve dietary habits, increase physical activity, and reduce tobacco use. Strategies were considered in 6 broad domains: (1) media and education campaigns; (2) labeling and consumer information; (3) taxation, subsidies, and other economic incentives; (4) school and workplace approaches; (5) local environmental changes; and (6) direct restrictions and mandates. The writing group also reviewed the potential contributions of healthcare systems and surveillance systems to behavior change efforts. Several specific population interventions that achieved a Class I or IIa recommendation with grade A or B evidence were identified, providing a set of specific evidence-based strategies that deserve close attention and prioritization for wider implementation. Effective interventions included specific approaches in all 6 domains evaluated for improving diet, increasing activity, and reducing tobacco use. The writing group also identified several specific interventions in each of these domains for which current evidence was less robust, as well as other inconsistencies and evidence gaps, informing the need for further rigorous and interdisciplinary approaches to evaluate population programs and policies.
Conclusions
This systematic review identified and graded the evidence for a range of population-based strategies to promote lifestyle change. The findings provide a framework for policy makers, advocacy groups, researchers, clinicians, communities, and other stakeholders to understand and implement the most effective approaches. New strategic initiatives and partnerships are needed to translate this evidence into action.
doi:10.1161/CIR.0b013e318260a20b
PMCID: PMC3881293  PMID: 22907934
4.  Hemoglobin Decline, Function and Mortality in the Elderly: The Cardiovascular Health Study 
American journal of hematology  2012;88(1):10.1002/ajh.23336.
Background
While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied.
Methods
We evaluated the determinants and consequences of hemoglobin decline in 3.758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly ≥65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: 1) per each 1g/dL decrease in hemoglobin and 2) development of anemia by the WHO criteria.
Results
Among participants without baseline anemia, hemoglobin decreased by 0.4g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1g/dL decrease) predicted subsequent mortality in men and women.
Conclusions
Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.
doi:10.1002/ajh.23336
PMCID: PMC3860593  PMID: 23044913
Anemia; Hemoglobin; Elderly; Mortality; Function; Epidemiology
5.  Detection of Chronic Kidney Disease With Creatinine, Cystatin C, and Urine Albumin-to-Creatinine Ratio and Association With Progression to End-Stage Renal Disease and Mortality 
Context
A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.
Objective
To evaluate whether combining creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) would improve identification of risks associated with CKD compared with creatinine alone.
Design, Setting, and Participants
Prospective cohort study involving 26 643 US adults enrolled in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study from January 2003 to June 2010. Participants were categorized into 8 groups defined by estimated glomerular filtration rate (GFR) determined by creatinine and by cystatin C of either <60 or ≥60 mL/min/1.73 m2 and ACR of either <30 or ≥30 mg/g.
Main Outcome Measures
All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.
Results
Participants had a mean age of 65 years, 40% were black, and 54% were women. Of 26 643 participants, 1940 died and 177 developed end-stage renal disease. Among participants without CKD defined by creatinine, 24% did not have CKD by either ACR or cystatin C. Compared with those with CKD defined by creatinine alone, the hazard ratio for death in multivariable-adjusted models was 3.3 (95% confidence interval [CI], 2.0–5.6) for participants with CKD defined by creatinine and ACR; 3.2 (95% CI, 2.2–4.7) for those with CKD defined by creatinine and cystatin C, and 5.6 (95% CI, 3.9–8.2) for those with CKD defined by all biomarkers. Among participants without CKD defined by creatinine, 3863 (16%) had CKD detected by ACR or cystatin C. Compared with participants who did not have CKD by any measure, the HRs for mortality were 1.7 (95% CI, 1.4–1.9) for participants with CKD defined by ACR alone, 2.2 (95% CI, 1.9–2.7) for participants with CKD defined by cystatin C alone, and 3.0 (95% CI, 2.4–3.7) for participants with CKD defined by both measures. Risk of incident end-stage renal disease was higher among those with CKD defined by all markers (34.1 per 1000 person-years; 95% CI, 28.7–40.5 vs 0.33 per 1000 person-years; 95% CI, 0.05–2.3) for those with CKD defined by creatinine alone. The second highest end-stage renal disease rate was among persons missed by the creatinine measure but detected by both ACR and cystatin C (rate per 1000 person-years, 6.4; 95% CI, 3.6–11.3). Net reclassification improvement for death was 13.3% (P<.001) and for end-stage renal disease was 6.4% (P<.001) after adding estimated GFR cystatin C in fully adjusted models with estimated GFR creatinine and ACR.
Conclusion
Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
doi:10.1001/jama.2011.468
PMCID: PMC3697771  PMID: 21482744
6.  Persistence and Remission of Musculoskeletal Pain in Community-Dwelling Older Adults: Results from the Cardiovascular Health Study 
OBJECTIVES
To characterize longitudinal patterns of musculoskeletal pain in a community sample of older adults over a 6-year period and to identify factors associated with persistence of pain.
DESIGN
Secondary analysis of the Cardiovascular Health Study.
SETTING
Community-based cohort drawn from four U.S. counties.
PARTICIPANTS
Five thousand ninety-three men and women aged 65 and older.
MEASUREMENTS
Over a 6-year period, pain was assessed each year using a single question about the presence of pain in any bones or joints during the last year. If affirmative, participants were queried about pain in seven locations (hands, shoulders, neck, back, hips, knees, feet). Participants were categorized according to the percentage of time that pain was present and according to the intermittent or chronic pattern of pain. Factors associated with persistent pain during five remaining years of the study were identified.
RESULTS
Over 6 years, 32% of participants reported pain for three or more consecutive years, and 32% reported pain intermittently. Of those who reported pain the first year, 54% were pain free at least once during the follow-up period. Most of the pain at specific body locations was intermittent. Factors associated with remission of pain over 5 years included older age, male sex, better self-rated health, not being obese, taking fewer medications, and having fewer depressive symptoms. Approximately half of those with pain reported fewer pain locations the following year.
CONCLUSION
Musculoskeletal pain in older adults, despite high prevalence, is often intermittent. The findings refute the notion that pain is an inevitable, unremitting, or progressive consequence of aging.
doi:10.1111/j.1532-5415.2012.04082.x
PMCID: PMC3633775  PMID: 22861385
pain; musculoskeletal; longitudinal analysis; remission; persistence; symptoms
7.  Albuminuria, Kidney Function, and the Incidence of Cognitive Impairment Among Adults in the United States 
Background
Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk for cognitive impairment, but their joint association is unknown.
Study Design
Prospective cohort study.
Setting and Participants
A US national sample of 19,399 adults without cognitive impairment at baseline participating in the REGARDS )REasons for Geographic And Racial Disparities in Stroke) study.
Predictors
Albuminuria was assessed by the urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (CKD Epidemiology Collaboration) equation.
Outcomes
Incident cognitive impairment was defined as a score of 4 or less on the Six-item Screener at the last follow-up visit.
Results
Over a mean follow-up of 3.8 ± 1.5 years, UACR 30 – 299 and ≥300 mg/g were independently associated with 31% and 57% higher risk for cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest among those with high eGFR and attenuated at lower levels (P=0.04 for trend). Relative an eGFR ≥60 ml/min/1.73m2, eGFR <60 ml/min/1.73m2 was not independently associated with cognitive impairment. However, after stratifying by UACR, eGFR <60 ml/min/1.73m2 was associated with 30% higher risk for cognitive impairment among participants with UACR <10 mg/g but not higher UACR levels (P=0.04 for trend).
Limitations
single measure of albuminuria and eGFR, screening test of cognition
Conclusions
When eGFR was preserved, albuminuria independently associated with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR independently associated with cognitive impairment. Albuminuria and low eGFR are complementary but not additive risk factors for incident cognitive impairment.
doi:10.1053/j.ajkd.2011.05.027
PMCID: PMC3199339  PMID: 21816528
albuminuria; chronic kidney disease; cognitive impairment
8.  Inflammation Biomarkers and Risk of All-Cause Mortality in the Reasons for Geographic and Racial Differences in Stroke Cohort 
American Journal of Epidemiology  2011;174(3):284-292.
Inflammation biomarkers, including higher high-sensitivity C-reactive protein (hsCRP) levels, higher white blood cell (WBC) counts, and lower serum albumin levels, are associated with an increased risk of all-cause mortality. Many studies have examined these biomarkers individually, but less is known about their joint association with mortality. hsCRP, WBC count, and serum albumin were measured at baseline in the Reasons for Geographic and Racial Differences in Stroke Study cohort members, who were enrolled in 2003–2007. Over 4.5 years, there were 1,062 deaths in 17,845 participants. High-risk categories were defined as hsCRP or WBC levels above the 75th percentile (5.1 mg/L and 6.9 × 109 cells/L, respectively) and albumin levels below the 25th percentile (4.00 g/dL). The authors derived 4 groups that corresponded to 0 (n = 8,341), 1 (n = 6,277), 2 (n = 2,635), or 3 (n = 592) biomarkers in the high-risk category. After adjustment for age, sex, waist circumference, race, region, smoking, alcohol use, income, educational level, physical activity frequency, and medical history and compared with those with no biomarkers in the high-risk category, the hazard ratios for all-cause mortality for 1, 2, and 3 biomarkers in the high-risk category were 1.56 (95% confidence interval: 1.33, 1.82), 2.19 (95% confidence interval: 1.84, 2.62), and 2.96 (95% confidence interval: 2.30, 3.80), respectively (Ptrend < 0.0001). Adding the 3 inflammation biomarkers to a fully adjusted model improved risk discrimination by 23.7% (95% confidence interval: 9.3, 39.9). Measurement of more than 1 biomarker is more useful in risk prediction than single biomarkers.
doi:10.1093/aje/kwr085
PMCID: PMC3202158  PMID: 21685411
biological markers; cohort studies; C-reactive protein; inflammation; leukocytes; mortality; prospective studies
9.  Patterns and Predictors of Recovery from Exhaustion in Older Adults: The Cardiovascular Health Study 
Objectives
To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults
Design and Setting
Retrospective analysis of data from six annual examinations of a community-based cohort study
Participants
4584 men and women aged 69 years or older
Measurements
Exhaustion was considered present when a participant responded “a moderate amount” or “most of the time” to either of two questions: “How often have you had a hard time getting going?” and “How often does everything seem an effort?”
Results
Of the 964 participants who originally reported exhaustion, 634 (65.8%) were exhaustion-free at least once during follow up. When data from all time points were considered, 48% of exhaustion-reporters were exhaustion-free the following year. After adjustment for age, sex, race, education, and marital status, one-year recovery was less likely among individuals with worse self-rated health, ≥ six medications, obesity, depression, musculoskeletal pain, and history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over five years: poor self-rated health, ≥ six medications, obesity, and depression. Recovery was not less likely among participants with a history of cancer or heart disease.
Conclusion
Exhaustion is common in old age but is quite dynamic, even among those with a history of cancer and congestive heart failure. Recovery is especially likely among seniors who have a positive perception of their overall health, take few medications, and are not obese or depressed. These findings support the notion that resiliency is associated with physical and psychological well-being.
doi:10.1111/j.1532-5415.2010.03238.x
PMCID: PMC3059104  PMID: 21288229
symptoms; frailty; fatigue; transition analysis
10.  Hemoglobin Concentration and Cognitive Impairment in the Renal REasons for Geographic And Racial Differences in Stroke (REGARDS) Study 
Background.
There is growing interest in determining the degree of anemia, which is clinically significant. The goal of this study was to determine the association between hemoglobin concentration and cognitive impairment in a large sample of U.S. adults.
Methods.
We used cross-sectional data from 19,701 adults participating in the REasons for Geographic And Racial Differences in Stroke study. Cognitive impairment was defined as a score of 4 or less on the six-item screener. Hemoglobin was analyzed in 1 g/dL increments relative to the World Health Organization (WHO) threshold (<13 g/dL for men and <12 g/dL for women).
Results.
The mean hemoglobin concentration was 13.7 ± 1.5 g/dL. The prevalence of cognitive impairment increased from 4.3% among individuals with a hemoglobin >3 g/dL above the WHO threshold to 16.8% for those with a hemoglobin ≥2 g/dL below the WHO threshold. After adjustment for demographics, chronic health conditions, health status, and inflammation, the association between reduced hemoglobin and cognitive impairment was attenuated and no longer significant, including among those with hemoglobin ≥2 g/dL below the WHO threshold (odds ratio 1.39, 95% confidence interval = 0.94–2.04). A test for linear trend was of borderline significance (p value = .06). For 94% of the sample within 2 g/dL of the WHO threshold, there was no relationship between hemoglobin concentration and the odds of cognitive impairment. The associations did not differ by sex and race.
Conclusions.
Within a large sample of community-dwelling adults, there was no significant association between hemoglobin concentration and cognitive impairment after multivariable adjustment.
doi:10.1093/gerona/glq126
PMCID: PMC2990263  PMID: 20634281
Hemoglobin; Anemia; Cognitive impairment
11.  Kidney Function, Albuminuria, and All-Cause Mortality in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study 
Background
Chronic kidney disease (CKD) and albuminuria are associated with increased risk of all-cause mortality.
Study Design
Prospective observational cohort study
Setting and Participants
17,393 participants (mean age, 64.3 ± 9.6 years) in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) Study.
Predictor
Estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (ACR).
Outcome
All-cause mortality (710 deaths); median duration of follow-up: 3.6 years.
Measurements and Analysis
Categories of eGFR (90– <120, 60–<90, 45–<60, 30–<45, and 15–<30 mL/min/1.73 m2) and urinary ACR (<10 mg/g or normal, 10–<30 mg/g or high normal, 30–300 mg/g or high, and >300 mg/g or very high). Cox’s proportional hazards models were adjusted for demographic factors, cardiovascular covariates, and hemoglobin.
Results
The background all-cause mortality rate for participants with normal ACR, eGFR of 90–<120 mL/min/1.73 m2 and no CHD was 4.3 deaths/1,000 person-years. Higher ACR was associated with an increased multivariable adjusted hazard ratio for all-cause mortality within each eGFR category. Reduced eGFR was associated with higher adjusted hazard ratio for all-cause mortality for participants with high normal (P value = 0.01) and high (P value <0.001) ACR values, but not for those with normal or very high ACR values.
Limitations
Only one laboratory assessment for serum creatinine and ACR was available
Conclusions
Increased albuminuria was an independent risk factor for all-cause mortality. Reduced eGFR was associated with increased mortality risk among those with high normal and high ACR. The mortality rate was low in the normal ACR group and increased in the very high ACR group but did not vary with eGFR in these groups.
doi:10.1053/j.ajkd.2010.05.017
PMCID: PMC2963678  PMID: 20692752
12.  Identification of Nine Novel Loci Associated with White Blood Cell Subtypes in a Japanese Population 
PLoS Genetics  2011;7(6):e1002067.
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.
Author Summary
White blood cells (WBCs) are blood cells that mediate immune systems and defend the body against foreign microorganisms. It is well known that WBCs consist of various subtypes of cells with distinct roles, although the genetic background of each of the WBC subtypes has yet to be examined. In this study, we report genome-wide association studies (GWAS) for the 5 main WBC subtypes (neutrophils, lymphocytes, monocytes, basophils, and eosinophils) using 14,792 Japanese subjects. We identified 12 significantly associated genetic loci, and 9 of them were novel. Evaluation of the associations of these identified loci in cohorts of Caucasian populations demonstrated both ethnically common and divergent genetic backgrounds of the WBC subtypes. These loci also indicated a variety of patterns of pleiotropic associations within the hematological traits, including the other WBC subtypes, total WBC count, platelet count, or red blood cell-related traits, which suggests unique and common functional roles of these loci in the processes of hematopoiesis.
doi:10.1371/journal.pgen.1002067
PMCID: PMC3128095  PMID: 21738478
13.  Multiple Loci Are Associated with White Blood Cell Phenotypes 
Nalls, Michael A. | Couper, David J. | Tanaka, Toshiko | van Rooij, Frank J. A. | Chen, Ming-Huei | Smith, Albert V. | Toniolo, Daniela | Zakai, Neil A. | Yang, Qiong | Greinacher, Andreas | Wood, Andrew R. | Garcia, Melissa | Gasparini, Paolo | Liu, Yongmei | Lumley, Thomas | Folsom, Aaron R. | Reiner, Alex P. | Gieger, Christian | Lagou, Vasiliki | Felix, Janine F. | Völzke, Henry | Gouskova, Natalia A. | Biffi, Alessandro | Döring, Angela | Völker, Uwe | Chong, Sean | Wiggins, Kerri L. | Rendon, Augusto | Dehghan, Abbas | Moore, Matt | Taylor, Kent | Wilson, James G. | Lettre, Guillaume | Hofman, Albert | Bis, Joshua C. | Pirastu, Nicola | Fox, Caroline S. | Meisinger, Christa | Sambrook, Jennifer | Arepalli, Sampath | Nauck, Matthias | Prokisch, Holger | Stephens, Jonathan | Glazer, Nicole L. | Cupples, L. Adrienne | Okada, Yukinori | Takahashi, Atsushi | Kamatani, Yoichiro | Matsuda, Koichi | Tsunoda, Tatsuhiko | Tanaka, Toshihiro | Kubo, Michiaki | Nakamura, Yusuke | Yamamoto, Kazuhiko | Kamatani, Naoyuki | Stumvoll, Michael | Tönjes, Anke | Prokopenko, Inga | Illig, Thomas | Patel, Kushang V. | Garner, Stephen F. | Kuhnel, Brigitte | Mangino, Massimo | Oostra, Ben A. | Thein, Swee Lay | Coresh, Josef | Wichmann, H.-Erich | Menzel, Stephan | Lin, JingPing | Pistis, Giorgio | Uitterlinden, André G. | Spector, Tim D. | Teumer, Alexander | Eiriksdottir, Gudny | Gudnason, Vilmundur | Bandinelli, Stefania | Frayling, Timothy M. | Chakravarti, Aravinda | van Duijn, Cornelia M. | Melzer, David | Ouwehand, Willem H. | Levy, Daniel | Boerwinkle, Eric | Singleton, Andrew B. | Hernandez, Dena G. | Longo, Dan L. | Soranzo, Nicole | Witteman, Jacqueline C. M. | Psaty, Bruce M. | Ferrucci, Luigi | Harris, Tamara B. | O'Donnell, Christopher J. | Ganesh, Santhi K. | Visscher, Peter M.
PLoS Genetics  2011;7(6):e1002113.
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.
Author Summary
WBC traits are highly variable, moderately heritable, and commonly assayed as part of clinical complete blood count (CBC) examinations. The counts of constituent cell subtypes comprising the WBC count measure are assayed as part of a standard clinical WBC differential test. In this study we employed meta-analytic techniques and identified ten associations with WBC measures at seven genomic loci in a large sample set of over 31,000 participants. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We confirm previous associations of WBC traits with three loci and identified seven novel loci. We also utilize a number of additional analytic methods to infer the functional relatedness of independently implicated loci across WBC phenotypes, as well as investigate direct functional consequences of these loci through analyses of genomic variation affecting the expression of proximal genes in samples of whole blood. In addition, subsequent collaborative efforts with studies of WBC traits in African-American and Japanese cohorts allowed for the investigation of the effects of these genomic variants across populations of diverse continental ancestries.
doi:10.1371/journal.pgen.1002113
PMCID: PMC3128114  PMID: 21738480
14.  Racial disparities in awareness and treatment of atrial fibrillation: The REasons for Geographic and Racial Differences in Stroke (REGARDS) study 
Background and Objective
Warfarin reduces stroke risk by about 60% in patients with atrial fibrillation (AF). Differences in awareness and treatment of AF may contribute to racial and geographic disparities in stroke mortality. The objective was to examine predictors of awareness of the diagnosis of AF and treatment with warfarin.
Methods
REasons for Geographic and Racial Differences in Stroke (REGARDS) is a national, population-based, longitudinal study of 30,239 blacks and whites ≥ 45 years old with oversampling from African Americans and the southeastern stroke belt states. Participants were enrolled Jan 2003–Oct 2007. Data were collected using telephone interview, in-home evaluation, and self-administered questionnaires. The main variable of awareness of AF was defined by a positive answer to “Has a doctor or other health professional ever told you that you had atrial fibrillation?” and whether there was evidence of treatment on the basis of an in-home medications inventory.
Results
From baseline ECG, 432 individuals (88 black and 344 white) had AF. Of these, 88% (360/409) had at least one additional CHADS2 stroke risk factor and 60% (258/432) were aware of their AF. The odds of blacks being aware of their AF were one-third that of whites (OR=0.32 {95% CI: 0.20-0.52}). Among those aware, the odds of blacks being treated with warfarin were only one-fourth as great as whites (OR=0.28 {0.13-0.60}).
Conclusion
Blacks were less likely than whites to be aware of having atrial fibrillation or to be treated with warfarin. Potential reasons for the racial disparity in warfarin treatment warrant further investigation.
doi:10.1161/STROKEAHA.109.573907
PMCID: PMC2885129  PMID: 20190000
Racial disparities; warfarin; atrial fibrillation
16.  Association of Coagulation and Inflammation Related Genes and Factor VIIc Levels with Stroke: The Cardiovascular Health Study 
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 (SNP) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events in the 5,888 participants ≥ 65 of the observational Cardiovascular Health Study cohort.
Patients
/Methods: With 16 years of follow-up, age and sex-adjusted Cox models were used to estimate associations of SNPs and factor VIIc levels with future stroke.
Results
815 strokes occurred in 5,255 genotyped participants without baseline stroke (748 ischemic strokes, 586 among whites). Among whites, 6 SNPs were associated with stroke with a nominal p <0.01: rs6046 and rs3093261 (F7 gene); rs4918851 and rs3781387 (HABP2 gene); rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with factor VIIc levels (units = percent activity): rs6046 (β = −18.5, p = 2.38 × 10−83) and rs3093261 (β = 2.99, p = 3.93 × 10−6). Adjusting for age, sex, race, and cardiovascular risk factors, the association of factor VIIc quintiles (Q) with stroke were (HR: 95% CI): Q1 (reference); Q2 (1.4; 1.1, 1.9); Q3 (1.1; 0.8, 1.5); Q4 (1.5; 1.1, 2.0); Q5 (1.6; 1.2, 2.2). Associations between SNPs and stroke were independent of factor VIIc levels.
Conclusions
Variation in factor VII-related genes and factor VIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for factor VII in stroke etiology.
doi:10.1111/j.1538-7836.2010.04149.x
PMCID: PMC3030667  PMID: 21114618
Stroke; Genetic Epidemiology; factor VII; hemostasis; inflammation; cardiovascular disease risk
18.  Associations of factor VIIIc, D-dimer and plasmin-antiplasmin with incident cardiovascular disease and all-cause mortality 
American journal of hematology  2009;84(6):349-353.
To examine the associations of three understudied hemostatic factors – D-dimer, factor VIIIc, and antiplasmin (PAP) complex -- with incident CVD and all cause mortality in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Hemostatic factors were measured at baseline in 45–84 year olds (n =6,391) who were free of clinically recognized CVD. Over 4.6 years of follow-up, we identified 307 CVD events, 207 hard coronary heart disease (CHD) events, and 210 deaths. D-dimer, factor VIIIc, and PAP were not associated with CVD incidence after adjustment for other risk factors. In contrast, each factor was associated positively with total mortality, and D-dimer and factor VIIIc were associated positively with cancer mortality. When modeled as ordinal variables and adjusted for risk factors, total mortality was greater by 33% (95% CI = 15–54%) for each quartile increment of D-dimer, 26% (11–44%) for factor VIIIc, and 20% (4–38%) for PAP. This prospective cohort study did not find D-dimer, factor VIIIc, or PAP to be risk factors for CVD. Instead, elevated levels of these three hemostatic factors were associated independently with increased risk of death. Elevated D-dimer and factor VIIIc were associated with increased cancer death.
doi:10.1002/ajh.21429
PMCID: PMC2950108  PMID: 19472201
cancer; cardiovascular disease; CHD; D-dimer; factor VIII; plasmin-antiplasmin
19.  Total Tissue Factor Pathway Inhibitor and Venous Thrombosis: The Longitudinal Investigation of Thromboembolism Etiology 
Thrombosis and haemostasis  2010;104(2):207-212.
Tissue factor pathway inhibitor (TFPI) inhibits tissue factor, a potent coagulation initiator. Limited evidence suggests that low TFPI levels are associated with increased risk of venous thrombosis (VTE). We measured total TFPI in a nested case-control study in the Longitudinal Investigation of Thromboembolism Etiology. Control subjects were frequency matched 2:1 to cases on age, sex, race, and cohort. Odds ratio for VTE by TFPI levels were computed using logistic regression models adjusting for age, race, sex, coagulation factors (factors VII, VIII, IX, XI, D-dimer), and body mass index. To evaluate for greater than additive interactions, we calculated the percent relative excess risk due to interaction between TFPI and other VTE risk factors. 534 cases of VTE occurred and matched to 1091 controls. Mean baseline TFPI in ng/mL (standard deviation) in those who developed VTE and controls was 36.4 (12.8) and 35.0 (11.1), respectively. Higher TFPI was associated with male sex, age, body mass index, factors VII, VIII, IX, XI, and D-dimer. TFPI level did not differ by ethnicity, factor V Leiden, or prothrombin G20210A. Compared with those in the upper 95%, the bottom 5% of TFPI had an age-, sex-, race-, and study-adjusted odds ratio (95% CI) of 1.35 (0.86, 2.12) for VTE. Adjusting for factors VII, VIII, IX, and XI the odds ratio was 1.93 (1.05, 3.53). Further addition of D-dimer and BMI to this model the odds ratio was 1.70 (0.98, 2.93). Low TFPI did not demonstrate greater than additive interaction with other VTE risk factors.
doi:10.1160/TH09-10-0693
PMCID: PMC2943145  PMID: 20431849
Venous Thrombosis; Tissue Factor Pathway Inhibitor; Epidemiologic Studies
20.  Anemia is associated with the progression of white matter disease in older adults with high blood pressure: the Cardiovascular Health Study 
OBJECTIVES
To investigate whether anemia predicts worsening white matter hyperintensities (WMH) in older community-dwellers.
DESIGN
Prospective cohort study.
SETTING
Older community-dwellers.
PARTICIPANTS
One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7±4.4 years, 41% men, 15.6% African-Americans).
MEASUREMENTS
Participants had hemoglobin measured and a brain MRI in 1992–93, and a second brain MRI in 1997–98. Anemia was defined according to WHO criteria (hemoglobin <12 g/dl in women and <13 g/dl in men). Worsening WMH was determined by standardized side-by-side readings.
RESULTS
After 5 years, WMH worsened in 517 participants (28%). Progression was not associated with anemia in the whole sample, in gender- or race-strata or in other pre-specified subgroups (participants with renal dysfunction or diabetes), except in participants with high blood pressure (≥140/90 mmHg). Among the 678 participants with high blood pressure, those with anemia (10.5%) had a 1.79-fold increased risk of WMH worsening (95%CI 1.06–2.98; p for interaction between anemia and high blood pressure = 0.013), independent of demographics, baseline WMH, cardiovascular risk factors and comorbidities, medications, renal function, inflammation and incident stroke (logistic regression models). There was no increased risk in anemic participants with normal blood pressure.
CONCLUSION
Anemia may contribute to WMH worsening in older adults with high blood pressure.
doi:10.1111/j.1532-5415.2008.01950.x
PMCID: PMC2897005  PMID: 18811608
21.  Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium 
Nature genetics  2009;41(11):1191-1198.
Erythrocyte measures are heritable and have important health implications, yet their genetic determinants are largely unknown. We performed genome-wide association analyses in 24,167 European-ancestry individuals for six erythrocyte traits and identified associations at 23 loci (P values 5×10-8 to 1×10-57). Replication testing in an independent set of 9,456 European-ancestry individuals showed strong evidence of association in all 23 loci in meta-analysis of the discovery and replication cohorts. Our findings include previously identified loci (HBS1L/MYB, HFE, TMPRSS6, TFR2, SPTA1) and novel associations (EPO, TFRC, SH2B3, and 15 other loci). This study has identified novel determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
doi:10.1038/ng.466
PMCID: PMC2778265  PMID: 19862010
22.  TIMI Risk Index Predicts Long-term Mortality and Heart Failure in Patients with ST-Elevation Myocardial Infarction in the TIMI-II Clinical Trial 
American heart journal  2009;157(4):673-9.e1.
Background
TIMI Risk Index (TRI) is a simple bedside score that predicts 30-day mortality in ST-elevation myocardial infarction (MI) patients. We sought to evaluate whether TRI was predictive of long-term mortality and clinical events.
Methods
In the TIMI II trial, 3153 patients (mean age 57 ±10 years, 82% men) were randomized to invasive (n=1583) versus conservative (n=1570) strategy post-fibrinolysis with median follow-up of 3 years. TRI was divided into the 5 previously-specified groups. Primary endpoint was all-cause mortality. Secondary analyses included recurrent MI, congestive heart failure (CHF), and combined endpoints.
Results
When compared to Group 1, mortality in Group 5 was more than 5-fold higher (HR 5.83, p<0.0001), and was also increased in Group 4 (HR 2.80, p<0.0001) and Group 3 (HR 1.96, p=0.002) (c statistic 0.69). No difference was seen between Groups 1 and 2 (p=0.74). A similar increasing gradient effect was seen across TRI strata with Group 5 having the highest risk for CHF (HR 4.13, p<0.0001), and composite death/CHF (HR 4.35, p<0.0001) over Group 1. There was no difference in recurrent MI between the groups (p=0.22). After controlling for other risk indicators, the relationship between TRI and mortality remained significant: Group 5 (HR 4.11, p<0.0001), Group 4 (HR 2.14, p=0.0009), Group 3 (HR 1.69, p=0.02). When stratified by TRI groups, no differences in mortality or composite death/MI were found between treatment strategies.
Conclusion
The simple TRI can predict increased long-term mortality, CHF, and composite death/CHF.
doi:10.1016/j.ahj.2008.12.010
PMCID: PMC2694948  PMID: 19332194
ST elevation myocardial infarction; mortality; congestive heart failure; TIMI Risk Index; prognosis
23.  Correlates of Anemia in American Blacks and Whites 
American Journal of Epidemiology  2008;169(3):355-364.
For unclear reasons, anemia is more common in American blacks than whites. The authors evaluated anemia prevalence (using World Health Organization criteria) among 19,836 blacks and whites recruited in 2003–2007 for the REasons for Geographic And Racial Differences in Stroke Renal Ancillary study and characterized anemia by 3 anemia-associated conditions (chronic kidney disease, inflammation, and microcytosis). They used multivariable models to assess potential causes of race differences in anemia. Anemia was 3.3-fold more common in blacks than whites, with little attenuation after adjusting for demographic variables, socioeconomic factors, and comorbid conditions. Increasing age, residence in the US southeast, lower income, vascular disease, diabetes, hypertension, and never smoking were associated with anemia. Age, diabetes, and vascular disease were stronger correlates of anemia among whites than blacks (P < 0.05). Among those with anemia, chronic kidney disease was less common among blacks than whites (22% vs. 34%), whereas inflammation (18% vs. 14%) and microcytosis (22% vs. 11%) were more common. In this large, geographically diverse cohort, anemia was 3-fold more common in blacks than whites with different characteristics and correlates. Race differences in anemia prevalence were not explained by the factors studied. Future research into the causes and consequences of anemia in different racial groups is needed.
doi:10.1093/aje/kwn355
PMCID: PMC2720717  PMID: 19066309
anemia; chronic disease; health status disparities; kidney diseases; population groups
24.  Metabolic Syndrome, Inflammation, and the Incident Heart Failure in the Elderly: the Cardiovascular Health Study 
Circulation. Heart failure  2008;1(4):242-248.
Background
Inflammation markers and MetS are associated with risk of CHF. We evaluated whether combining inflammation markers and metabolic syndrome (MetS) provided additive information for incident congestive heart failure (CHF), and if incorporating inflammation markers to the MetS definition added prognostic information.
Methods and Results
We studied 4017 men and women ≥ 65 years old, without baseline CHF or diabetes, participating in the Cardiovascular Health Study, an observational study with 12.2 years follow-up and 966 cases of incident CHF. Baseline “C-reactive protein (CRP)-MetS” or “interleukin-6 (IL-6)-MetS” were defined as presence of 3 out of 6 components, with elevated CRP (≥3 mg/L) or IL-6 (≥2.21 pg/mL) as a 6th component added to ATPIII criteria. Cox models adjusted for CHF risk factors and incident coronary disease, were used to calculate HRs for CHF. MetS and elevated inflammation markers were independently associated with CHF risk (HRs, 95 % CI: 1.32, 1.16–1.51 for MetS; 1.53, 1.34–1.75 for CRP; 1.37, 1.19–1.55 for IL-6). There was a 20% relative excess risk attributed to the combination of MetS and CRP (95% CI −44% to 88%). CRP-MetS and IL-6-MetS definitions reclassified 18% and 13%, respectively of participants as MetS. Both CRP-MetS and IL-6-MetS increased risk of CHF by 60% compared to those without MetS.
Conclusion
MetS and inflammation markers provided additive information on CHF risk in this elderly cohort. Inflammation-incorporated MetS definitions identified more participants with the same risk level as ATPIII MetS. Considering inflammation markers and MetS together may be useful in clinical and research settings.
doi:10.1161/CIRCHEARTFAILURE.108.785485
PMCID: PMC2762642  PMID: 19808298
heart failure; metabolism; inflammation
25.  Activated Partial Thromboplastin Time and Risk of Future Venous Thromboembolism 
The American journal of medicine  2008;121(3):231-238.
Background
Lower activated partial thromboplastin times are associated with higher levels of some coagulation factors and may represent a procoagulant tendency.
Methods
In the Atherosclerosis Risk in Communities Study, we studied the 13-year risk of venous thromboembolism in relation to baseline activated partial thromboplastin time in 13,880 individuals. We also studied 258 venous thromboembolism cases and 589 matched controls with measurements of additional coagulation factors.
Results
Adjusting for demographics and procoagulant factors reflected in the activated partial thromboplastin time (fibrinogen, factors VIII, IX, XI, and von Willebrand factor), participants in the lowest two quartiles of activated partial thromboplastin time compared with the fourth quartile had 2.4-fold (95% CI 1.4, 4.2) and 1.9-fold (95% CI 1.1, 3.2) higher risks of venous thromboembolism. The risk associated with activated partial thromboplastin times below the median was higher for idiopathic (OR 5.5; 95% CI 2.0, 15.5) than secondary venous thromboembolism (OR 1.74; 95% CI 0.88, 3.43). Subjects with both activated partial thromboplastin times below the median and factor V Leiden were 12.6-fold (95% CI 5.7, 28.0) more likely to develop venous thromboembolism compared to those with neither risk factor (p-interaction <0.01). A lower activated partial thromboplastin time also added to the thrombosis risk associated with obesity and elevated D-dimer.
Conclusions
A single determination of the activated partial thromboplastin time below the median increased the risk of future venous thromboembolism. Findings were independent of coagulation factor levels, and a low activated partial thromboplastin time added to the risk associated with other risk factors.
doi:10.1016/j.amjmed.2007.10.025
PMCID: PMC2295205  PMID: 18328308

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