-
[show abstract]
[hide abstract]
ABSTRACT: 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. This article is protected by copyright. All rights reserved.
Journal of Thrombosis and Haemostasis 04/2013; · 5.73 Impact Factor
-
David R Crosslin,
Andrew McDavid,
Noah Weston,
Xiuwen Zheng,
Eugene Hart,
Mariza de Andrade,
Iftikhar J Kullo,
Catherine A McCarty,
Kimberly F Doheny,
Elizabeth Pugh, [......],
Dan L Longo,
Jacqueline C M Witteman,
Bruce M Psaty,
Luigi Ferrucci,
Tamara B Harris,
Christopher J O'Donnell,
Santhi K Ganesh,
Eric B Larson,
Chris S Carlson,
Gail P Jarvik
[show abstract]
[hide abstract]
ABSTRACT: With white blood cell count (WBC) 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 (eMERGE) Network. In the joint and European ancestry samples, we identified novel associations in the chromosome 16 interferon regulatory factor 8 (IRF8) gene (p-value=2.78e-16, β=-0.22). Other monocyte associations include novel missense variants in the chemokine binding protein 2 (CCBP2) gene (p-value=1.88e-7, β=0.30) and a region of replication found in ribophorin I (RPN1) (p-value=2.63e-16, β=-0.23) on chromosome 3. The CCBP2 and RPN1 region is located near GATA2 gene, which has been previously shown to be associated with coronary heart disease. On chromosome 9 we found a novel association in the prostaglandin reductase 1 (PTGR1) gene (p-value=2.29e-7, β=0.16), which is downstream from lysophosphatidic acid receptor 1 (LPAR1). This region has previously been shown to be associated with monocyte count. We also replicated monocyte associations of genome-wide significance (p-value=5.68e-17, β=-0.23) at the ITGA4 gene on chromosome 2. The novel IRF8 results and further replications provide supporting evidence of genetic regions associated with monocyte count.
Human Molecular Genetics 01/2013; · 7.64 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied. 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 1 g/dL decrease in hemoglobin and (2) development of anemia by the WHO criteria. Among participants without baseline anemia, hemoglobin decreased by 0.4 g/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 1 g/dL decrease) predicted subsequent mortality in men and women. 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. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.
American Journal of Hematology 09/2012; · 4.67 Impact Factor
-
Dariush Mozaffarian,
Ashkan Afshin,
Neal L Benowitz,
Vera Bittner,
Stephen R Daniels,
Harold A Franch,
David R Jacobs,
William E Kraus,
Penny M Kris-Etherton,
Debra A Krummel,
Barry M Popkin,
Laurie P Whitsel, Neil A Zakai
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Poor lifestyle behaviors, 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 educational 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.
Circulation 08/2012; 126(12):1514-1563. · 14.74 Impact Factor
-
Manjula Kurella Tamura,
Paul Muntner,
Virginia Wadley,
Mary Cushman, Neil A Zakai,
Brian D Bradbury,
Brett Kissela,
Fred Unverzagt,
George Howard,
David Warnock,
William McClellan
[show abstract]
[hide abstract]
ABSTRACT: Albuminuria and estimated glomerular filtration rate (eGFR) are each associated with increased risk of cognitive impairment, but their joint association is unknown.
Prospective cohort study.
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.
Albuminuria was assessed using urine albumin-creatinine ratio (UACR) and GFR was estimated using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
Incident cognitive impairment was defined as score ≤4 on the 6-Item Screener at the last follow-up visit.
During a mean follow-up of 3.8 ± 1.5 years, UACRs of 30-299 and ≥300 mg/g were associated independently with 31% and 57% higher risk of cognitive impairment, respectively, relative to individuals with UACR <10 mg/g. This finding was strongest for those with high eGFRs and attenuated at lower levels (P = 0.04 for trend). Relative to eGFR ≥60 mL/min/1.73 m(2), eGFR <60 mL/min/1.73 m(2) was not associated independently with cognitive impairment. However, after stratifying by UACR, eGFR <60 mL/min/1.73 m(2) was associated with a 30% higher risk of cognitive impairment in participants with UACR <10 mg/g, but not higher UACRs (P = 0.04 for trend).
Single measures of albuminuria and eGFR, screening test of cognition.
When eGFR was preserved, albuminuria was associated independently with incident cognitive impairment. When albuminuria was <10 mg/g, low eGFR was associated independently with cognitive impairment. Albuminuria and low eGFR are complementary, but not additive, risk factors for incident cognitive impairment.
American Journal of Kidney Diseases 08/2011; 58(5):756-63. · 5.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 × 10(9) 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 (P(trend) < 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.
American journal of epidemiology 06/2011; 174(3):284-92. · 5.59 Impact Factor
-
Yukinori Okada,
Tomomitsu Hirota,
Yoichiro Kamatani,
Atsushi Takahashi,
Hiroko Ohmiya,
Natsuhiko Kumasaka,
Koichiro Higasa,
Yumi Yamaguchi-Kabata,
Naoya Hosono,
Michael A Nalls, [......],
Christopher J O'Donnell,
Santhi K Ganesh,
Koichi Matsuda,
Tatsuhiko Tsunoda,
Toshihiro Tanaka,
Michiaki Kubo,
Yusuke Nakamura,
Mayumi Tamari,
Kazuhiko Yamamoto,
Naoyuki Kamatani
[show abstract]
[hide abstract]
ABSTRACT: 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.
PLoS Genetics 06/2011; 7(6):e1002067. · 8.69 Impact Factor
-
Michael A Nalls,
David J Couper,
Toshiko Tanaka,
Frank J A van Rooij,
Ming-Huei Chen,
Albert V Smith,
Daniela Toniolo, Neil A Zakai,
Qiong Yang,
Andreas Greinacher, [......],
Andrew B Singleton,
Dena G Hernandez,
Dan L Longo,
Nicole Soranzo,
Jacqueline C M Witteman,
Bruce M Psaty,
Luigi Ferrucci,
Tamara B Harris,
Christopher J O'Donnell,
Santhi K Ganesh
[show abstract]
[hide abstract]
ABSTRACT: 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.
PLoS Genetics 06/2011; 7(6):e1002113. · 8.69 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: A triple-marker approach for chronic kidney disease (CKD) evaluation has not been well studied.
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.
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 m(2) and ACR of either <30 or ≥30 mg/g.
All-cause mortality and incident end-stage renal disease with median follow-up of 4.6 years.
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.
Adding cystatin C to the combination of creatinine and ACR measures improved the predictive accuracy for all-cause mortality and end-stage renal disease.
JAMA The Journal of the American Medical Association 04/2011; 305(15):1545-52. · 30.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To estimate the likelihood of, and factors associated with, recovery from exhaustion in older adults.
Secondary analysis of a cohort study.
Six annual examinations in four U.S. communities.
Four thousand five hundred eighty-four men and women aged 69 and older.
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?"
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 those who reported exhaustion were exhaustion free the following year. After adjustment for age, sex, race, education, and marital status, 1-year recovery was less likely in individuals with worse self-rated health and in those who were taking six or more medications or were obese, depressed, or had musculoskeletal pain or history of stroke. In proportional hazards models, the following risk factors were associated with more persistent exhaustion over 5 years: poor self-rated health, six or more medications, obesity, and depression. Recovery was not less likely in participants with a history of cancer or heart disease.
Exhaustion is common in old age but is dynamic, even in those with a history of cancer and congestive heart failure. Recovery is especially likely in 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.
Journal of the American Geriatrics Society 02/2011; 59(2):207-13. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
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).
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.
Within a large sample of community-dwelling adults, there was no significant association between hemoglobin concentration and cognitive impairment after multivariable adjustment.
The Journals of Gerontology Series A Biological Sciences and Medical Sciences 12/2010; 65(12):1380-6. · 4.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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 thromboembolism (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 ratios (ORs) 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 (BMI). To evaluate for greater than additive interactions, we calculated the percent relative excess risk due to interaction between TFPI and other VTE risk factors. A total of 534 cases of VTE occurred and matched to 1,091 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, BMI, 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 OR (95% CI) of 1.35 (0.86, 2.12) for VTE. Adjusting for factors VII, VIII, IX, and XI the OR was 1.93 (1.05, 3.53). Further addition of D-dimer and BMI to this model decreased the OR to 1.70 (0.98, 2.93). Low TFPI did not demonstrate greater than additive interaction with other VTE risk factors.
Thrombosis and Haemostasis 08/2010; 104(2):207-12. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Warfarin reduces stroke risk by approximately 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.
REasons for Geographic and Racial Differences in Stroke (REGARDS) is a national, population-based, longitudinal study of 30,239 blacks and whites > or = 45 years old with oversampling from blacks and the southeastern stroke belt states. Participants were enrolled January 2003 to October 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.
From baseline electrocardiograms, 432 individuals (88 black and 344 white) had AF. Of these, 88% (360 of 409) had at least 1 additional CHADS2 stroke risk factor and 60% (258 of 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 to 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 to 0.60).
Blacks were less likely than whites to be aware of having AF or to be treated with warfarin. Potential reasons for the racial disparity in warfarin treatment warrant further investigation.
Stroke 02/2010; 41(4):581-7. · 5.73 Impact Factor
-
Santhi K Ganesh, Neil A Zakai,
Frank J A van Rooij,
Nicole Soranzo,
Albert V Smith,
Michael A Nalls,
Ming-Huei Chen,
Anna Kottgen,
Nicole L Glazer,
Abbas Dehghan, [......],
Bruce M Psaty,
Luigi Ferrucci,
Aravinda Chakravarti,
Andreas Greinacher,
Christopher J O'Donnell,
Jacqueline C M Witteman,
Susan Furth,
Mary Cushman,
Tamara B Harris,
Jing-Ping Lin
[show abstract]
[hide abstract]
ABSTRACT: Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.
Nature Genetics 11/2009; 41(11):1191-8. · 35.53 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To examine the associations of three understudied hemostatic factors--D-dimer, factor VIII(c), and plasmin-antiplasmin (PAP) complex--with incident cardiovascular disease (CVD) and all cause mortality in the Multiethnic Study of Atherosclerosis cohort. Hemostatic factors were measured at baseline in 45-84-year-old patients (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 events, and 210 deaths. D-dimer, factor VIII(c), 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 VIII(c) 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 VIII(c), 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 VIII(c) were associated with increased cancer death.
American Journal of Hematology 07/2009; 84(6):349-53. · 4.67 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: 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.
American journal of epidemiology 01/2009; 169(3):355-64. · 5.59 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Inflammation markers and metabolic syndrome (MetS) are associated with risk of congestive heart failure (CHF). We evaluated whether combining inflammation markers and MetS provided additive information for incident CHF and if incorporating inflammation markers to the MetS definition added prognostic information.
We studied 4017 men and women > or =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 (IL)-6-MetS" were defined as presence of 3 out of 6 components, with elevated CRP (> or =3 mg/L) or IL-6 (> or =2.21 pg/mL) as a sixth component added to ATPIII criteria. Cox models adjusted for CHF risk factors and incident coronary disease were used to calculate hazard ratios for CHF. MetS and elevated inflammation markers were independently associated with CHF risk (hazard ratios, 95% CI: 1.32, 1.16 to 1.51 for MetS; 1.53, 1.34 to 1.75 for CRP; 1.37, 1.19 to 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 with those without MetS.
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.
Circulation Heart Failure 11/2008; 1(4):242-8. · 6.29 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To investigate whether anemia predicts worsening white matter hyperintensities (WMHs) in older community-dwellers.
Prospective cohort study.
Older community-dwellers.
One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7 +/- 4.4, 41% male, 15.6% African American).
Participants had hemoglobin measured and brain magnetic resonance imaging (MRI) in 1992/93 and a second brain MRI in 1997/98. Anemia was defined according to World Health Organization criteria (hemoglobin <12 g/dL in women and <13 g/dL in men). Worsening WMHs were determined according to standardized side-by-side readings.
After 5 years, WMHs worsened in 517 participants (28%). Progression was not associated with anemia in the whole sample, in sex or race strata, or in other prespecified subgroups (participants with renal dysfunction or diabetes mellitus), except in participants with high blood pressure (>or=140/90 mmHg). Of the 678 participants with high blood pressure, those with anemia (10.5%) had a 1.79 times greater risk of WMHs worsening (95% confidence interval=1.06-2.98; P for interaction between anemia and high blood pressure=.01) independent of demographics, baseline WMHs, cardiovascular risk factors and comorbidities, medications, renal function, inflammation, and incident stroke (logistic regression models). There was no greater risk in participants with anemia with normal blood pressure.
Anemia may contribute to worsening of WMHs in older adults with high blood pressure.
Journal of the American Geriatrics Society 09/2008; 56(10):1867-72. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Lower activated partial thromboplastin times are associated with higher levels of some coagulation factors and may represent a procoagulant tendency.
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.
After adjustment for demographics and procoagulant factors reflected in the activated partial thromboplastin time (fibrinogen, factors VIII, IX, and XI, and von Willebrand factor), participants in the lowest 2 quartiles of activated partial thromboplastin time compared with the fourth quartile had 2.4-fold (95% confidence interval [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 (odds ratio 5.5; 95% CI, 2.0-15.5) than secondary venous thromboembolism (odds ratio 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 with those with neither risk factor (P interaction<.01). A lower activated partial thromboplastin time also added to the thrombosis risk associated with obesity and elevated D-dimer.
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.
The American journal of medicine 04/2008; 121(3):231-8. · 4.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear.
Baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women 65 years or older, enrolled in 1989-1990 or 1992-1993 in 4 US communities.
A total of 1205 participants were in the lowest hemoglobin quintile (<13.7 g/dL for men; <12.6 g/dL for women), and 498 (8.5%) were anemic (<13 g/dL for men; <12 g/dL for women). A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95% CI, 1.25-1.62) and 1.24 (95% CI, 1.09-1.42). After multivariate adjustment, these hazard ratios were 1.33 (95% CI, 1.15-1.54) and 1.17 (95% CI, 1.01-1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95% CI, 1.38-1.78) and 1.38 (95% CI, 1.19-1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations.
Lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The World Health Organization criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly and on the increased mortality at the extremes of hemoglobin concentrations.
Archives of Internal Medicine 11/2005; 165(19):2214-20. · 11.46 Impact Factor
