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1.  Genome-Wide Association Study of White Blood Cell Count in 16,388 African Americans: the Continental Origins and Genetic Epidemiology Network (COGENT) 
PLoS Genetics  2011;7(6):e1002108.
Total white blood cell (WBC) and neutrophil counts are lower among individuals of African descent due to the common African-derived “null” variant of the Duffy Antigen Receptor for Chemokines (DARC) gene. Additional common genetic polymorphisms were recently associated with total WBC and WBC sub-type levels in European and Japanese populations. No additional loci that account for WBC variability have been identified in African Americans. In order to address this, we performed a large genome-wide association study (GWAS) of total WBC and cell subtype counts in 16,388 African-American participants from 7 population-based cohorts available in the Continental Origins and Genetic Epidemiology Network. In addition to the DARC locus on chromosome 1q23, we identified two other regions (chromosomes 4q13 and 16q22) associated with WBC in African Americans (P<2.5×10−8). The lead SNP (rs9131) on chromosome 4q13 is located in the CXCL2 gene, which encodes a chemotactic cytokine for polymorphonuclear leukocytes. Independent evidence of the novel CXCL2 association with WBC was present in 3,551 Hispanic Americans, 14,767 Japanese, and 19,509 European Americans. The index SNP (rs12149261) on chromosome 16q22 associated with WBC count is located in a large inter-chromosomal segmental duplication encompassing part of the hydrocephalus inducing homolog (HYDIN) gene. We demonstrate that the chromosome 16q22 association finding is most likely due to a genotyping artifact as a consequence of sequence similarity between duplicated regions on chromosomes 16q22 and 1q21. Among the WBC loci recently identified in European or Japanese populations, replication was observed in our African-American meta-analysis for rs445 of CDK6 on chromosome 7q21 and rs4065321 of PSMD3-CSF3 region on chromosome 17q21. In summary, the CXCL2, CDK6, and PSMD3-CSF3 regions are associated with WBC count in African American and other populations. We also demonstrate that large inter-chromosomal duplications can result in false positive associations in GWAS.
Author Summary
Although recent genome-wide association studies have identified common genetic variants associated with total white blood cell (WBC) and WBC sub-type counts in European and Japanese ancestry populations, whether these or other loci account for differences in WBC count among African Americans is unknown. By examining >16,000 African Americans, we show that, in addition to the previously identified Duffy Antigen Receptor for Chemokines (DARC) locus on chromosome 1, another variant, rs9131, and other nearby variants on human chromosome 4 are associated with total WBC count in African Americans. The variants span the CXCL2 gene, which encodes an inflammatory mediator involved in WBC production and migration. We show that the association is not restricted to African Americans but is also present in independent samples of European Americans, Hispanic Americans, and Japanese. This finding is potentially important because WBC mediate or have altered counts in a variety of acute and chronic disorders.
PMCID: PMC3128101  PMID: 21738479
2.  Effect of Different Doses of Aerobic Exercise on Total White Blood Cell (WBC) and WBC Subfraction Number in Postmenopausal Women: Results from DREW 
PLoS ONE  2012;7(2):e31319.
Elevated total white blood cell (WBC) count is associated with an increased risk of coronary heart disease and death. Aerobic exercise is associated with lower total WBC, neutrophil, and monocyte counts. However, no studies have evaluated the effect of the amount of aerobic exercise (dose) on total WBC and WBC subfraction counts.
To examine the effects of 3 different doses of aerobic exercise on changes in total WBC and WBC subfraction counts and independent effects of changes in fitness, adiposity, markers of inflammation (IL-6, TNF-α, C-reactive protein), fasting glucose metabolism, and adiponectin.
Data from 390 sedentary, overweight/obese postmenopausal women from the DREW study were used in these analyses. Women were randomized to a non-exercise control group or one of 3 exercise groups: energy expenditure of 4, 8, or 12 kcal kg−1⋅week−1 (KKW) for 6 months at an intensity of 50% VO2peak.
A dose-dependent decrease in total WBC counts (trend P = 0.002) was observed with a significant decrease in the 12KKW group (−163.1±140.0 cells/µL; mean±95%CI) compared with the control (138.6±144.7 cells/µL). A similar response was seen in the neutrophil subfraction (trend P = 0.001) with a significant decrease in the 12KKW group (−152.6±115.1 cells/µL) compared with both the control and 4KKW groups (96.4±119.0 and 21.9±95.3 cells/µL, respectively) and in the 8KKW group (−102.4±125.0 cells/µL) compared with the control. When divided into high/low baseline WBC categories (median split), a dose-dependent decrease in both total WBCs (P = 0.003) and neutrophils (P<0.001) was observed in women with high baseline WBC counts. The effects of exercise dose on total WBC and neutrophil counts persisted after accounting for significant independent effects of change in waist circumference and IL-6.
Aerobic exercise training reduces total WBC and neutrophil counts, in a dose-dependent manner, in overweight/obese postmenopausal women and is especially beneficial for those with systemic low grade inflammation.
Clinical Trials Identifier: NCT00011193
PMCID: PMC3281960  PMID: 22363616
3.  Acute appendicitis: relationships between CT-determined severities and serum white blood cell counts and C-reactive protein levels 
The British Journal of Radiology  2011;84(1008):1115-1120.
The aim of this study was to evaluate the relationships between the severity of appendicitis as depicted on CT and blood inflammatory markers of serum white blood cell (WBC) count and C-reactive protein (CRP).
CT images in 128 patients (109 surgically proven and 19 with clinically excluded appendicitis) were retrospectively reviewed. Two radiologists by consensus evaluated and scored (using a 0, 1 or 2 point scale) severities based on CT-determined appendiceal diameters, appendiceal wall changes, caecal changes, periappendiceal inflammatory stranding and phlegmon or abscess formation. We investigated whether CT findings were significantly related to elevated WBC counts or CRP levels and performed the correlations of WBC counts and CRP levels with CT severity scores. Patients were also subjectively classified using four grades from normal (Grade I) to perforated appendicitis (Grade IV) on the basis of CT findings to evaluate differences in WBC counts and CRP levels between grades.
Only appendiceal wall changes and the phlegmon or abscess formation were related to elevated WBC counts and CRP levels, respectively (p<0.05). CT severity scores were found to be more strongly correlated with CRP levels (r = 0.669) than with WBC counts (r = 0.222). On the basis of CT grades, the WBC counts in Grade I were significantly lower than in other grades (p<0.001), whereas CRP levels in Grade IV were significantly higher than in other grades (p<0.001).
CRP levels were found to correlate with CT-determined acute appendicitis severity and could be a useful predictor for perforated appendicitis, whereas WBC counts might be useful to detect early acute appendicitis.
PMCID: PMC3473821  PMID: 21123307
4.  White Blood Cell Count in Women: Relation to Inflammatory Biomarkers, Haematological Profiles, Visceral Adiposity, and Other Cardiovascular Risk Factors 
The role of white blood cell (WBC) count in pathogenesis of diabetes, cardiovascular disease, and obesity-related disorders has been reported earlier. Recent studies revealed that higher WBC contributes to atherosclerotic progression and impaired fasting glucose. However, it is unknown whether variations in WBC and haematologic profiles can occur in healthy obese individuals. The aim of this study is to further evaluate the influence of obesity on WBC count, inflammatory biomarkers, and metabolic risk factors in healthy women to establish a relationship among variables analyzed. The sample of the present study consisted of 84 healthy women with mean age of 35.56±6.83 years. They were categorized into two groups based on their body mass index (BMI): obese group with BMI >30 kg/m2 and non-obese group with BMI <30 kg/m2. We evaluated the relationship between WBC and platelet count (PLT) with serum interleukin 6 (IL-6), C-reactive protein (CRP), angiotensin Π (Ang Π), body fat percentage (BF %), waist-circumference (WC), and lipid profile. WBC, PLT, CRP, and IL-6 in obese subjects were significantly higher than in non-obese subjects (p< 0.05). The mean WBC count in obese subjects was 6.4±0.3 (×109/L) compared to 4.4±0.3 (×109/L) in non-obese subjects (p=0.035). WBC correlated with BF% (r=0.31, p=0.004), CRP (r=0.25, P=0.03), WC (r=0.22, p=0.04), angiotensin Π (r=0.24, p=0.03), triglyceride (r=0.24, p=0.03), and atherogenic index of plasma (AIP) levels (r=0.3, p=0.028) but not with IL-6. Platelet count was also associated with WC and waist-to-hip ratio (p<0.05). Haemoglobin and haematocrit were in consistent relationship with LDL-cholesterol (p<0.05). In conclusion, obesity was associated with higher WBC count and inflammatory parameters. There was also a positive relationship between WBC count and several inflammatory and metabolic risk factors in healthy women.
PMCID: PMC3702359  PMID: 23617205
Angiotensin Π; C-reactive protein; Interleukin 6; Obesity; White blood cell count
5.  Attenuated cerebrospinal fluid leukocyte count and sepsis in adults with pneumococcal meningitis: a prospective cohort study 
A low cerebrospinal fluid (CSF) white-blood cell count (WBC) has been identified as an independent risk factor for adverse outcome in adults with bacterial meningitis. Whereas a low CSF WBC indicates the presence of sepsis with early meningitis in patients with meningococcal infections, the relation between CSF WBC and outcome in patients with pneumococcal meningitis is not understood.
We examined the relation between CSF WBC, bacteraemia and sepsis in a prospective cohort study that included 352 episodes of pneumococcal meningitis, confirmed by CSF culture, occurring in patients aged >16 years.
CSF WBC was recorded in 320 of 352 episodes (91%). Median CSF WBC was 2530 per mm3 (interquartile range 531–6983 per mm3) and 104 patients (33%) had a CSF WBC <1000/mm3. Patients with a CSF WBC <1000/mm3 were more likely to have an unfavourable outcome (defined as a Glasgow Outcome Scale score of 1–4) than those with a higher WBC (74 of 104 [71%] vs. 87 of 216 [43%]; P < 0.001). CSF WBC was significantly associated with blood WBC (Spearman's test 0.29), CSF protein level (0.20), thrombocyte count (0.21), erythrocyte sedimentation rate (-0.15), and C-reactive protein levels (-0.18). Patients with a CSF WBC <1000/mm3 more often had a positive blood culture (72 of 84 [86%] vs. 138 of 196 [70%]; P = 0.01) and more often developed systemic complications (cardiorespiratory failure, sepsis) than those with a higher WBC (53 of 104 [51%] vs. 69 of 216 [32%]; P = 0.001). In a multivariate analysis, advanced age (Odds ratio per 10-year increments 1.22, 95%CI 1.02–1.45), a positive blood culture (Odds ratio 2.46, 95%CI 1.17–5.14), and a low thrombocyte count on admission (Odds ratio per 100,000/mm3 increments 0.67, 95% CI 0.47–0.97) were associated with a CSF WBC <1000/mm3.
A low CSF WBC in adults with pneumococcal meningitis is related to the presence of signs of sepsis and systemic complications. Invasive pneumococcal infections should possibly be regarded as a continuum from meningitis to sepsis.
PMCID: PMC1618396  PMID: 17038166
6.  Sex based levels of C-reactive protein and white blood cell count in subjects with metabolic syndrome: Isfahan Healthy Heart Program 
C-reactive protein (CRP) and white blood cell (WBC) are proinflammatory markers. They are major pathophysiological for the development of metabolic syndrome (MetS). This study aimed to address the independent associations between MetS and WBC counts and serum CRP levels and evaluation of their magnitude in relation to the MetS, based on the sex in the Iranian adults.
Materials and Methods:
In this cross-sectional study, subjects who met the MetS criteria, based on the Adult Treatment Panel III were selected from the Isfahan Healthy Heart Program database. A questionnaire containing the demographic data, weight, height, waist, and hip circumference of the respondents was completed for each person. Blood pressure was measured and the anthropometric measurements were done, and fasting blood samples were taken for 2 h postload plasma glucose (2 hpp). Serum [total, high-density lipoprotein (HDL), and low-density lipoprotein] levels of cholesterol, triglyceride, and CRP as well as WBC counts were determined. The univariate analyses were carried out to assess the relation between the CRP levels, WBC counts with the MetS in both sexes the.
In men with the abdominal obesity, the higher levels of WBC count, high serum triglyceride and blood glucose levels, a low serum HDL level, and raised systolic and diastolic blood pressure were observed. However, the higher serum CRP levels were only observed in those with the low serum HDL-cholesterol levels. The mean values of the WBC counts were statistically different between the men with and without MetS, but the mean values of the CRP levels were similar between the two groups. In women, the mean values of WBC count and CRP levels were statistically different in the subjects with and without a MetS components (except for the low serum HDL levels and high diastolic blood pressure for the WBC measures and abdominal obesity for the CRP measures) and for those with and without MetS. The age and smoking adjusted changes in the CRP levels and WBC counts correlated with the number of Mets components in the women.
The findings of this study suggest substantial implications for the prevention and management of the MetS and atherosclerotic diseases, as these involve the suppression of inflammatory conditions rather than the incitement of anti-inflammatory conditions.
PMCID: PMC3818614  PMID: 24250693
C-reactive protein level; metabolic syndrome; white blood cell count
7.  Comparative Value of Simple Inflammatory Markers in the Prediction of Left Ventricular Systolic Dysfunction in Postacute Coronary Syndrome Patients 
Mediators of Inflammation  2009;2009:826297.
Objectives. We sought to assess the comparative value of inflammatory markers on the occurrence of left ventricular systolic dysfunction (LVSD) after an acute coronary syndrome (ACS). Methods. During 2006–2008, 760 patients with an ACS were enrolled. C-reactive protein (CRP) and white blood cell (WBC) count were measured during the first 12 hours of hospital admission. Results. CRP levels and WBC count were significantly higher in those who developed LVSD compared to those who did not. The analysis revealed that a 10 mg/dL increase of CRP levels and a 1000/μL increase in WBC are associated with a 6% and a 7% increase in the likelihood of developing LVSD, respectively. Furthermore, WBC count at entry and CRP have almost the same predictive value for development of LVSD after an ACS (R2 = 0.109 versus R2 = 0.093). Conclusions. Serum CRP levels and WBC count at entry are almost equally powerful independent predictors of LVSD, after an ACS.
PMCID: PMC2686251  PMID: 19503842
8.  Blood cell counts and their correlation with creatine kinase and C-reactive protein in patients with acute myocardial infarction 
This study reports differential blood cells counts and their correlations with creatine kinase (CK) and C-reactive protein (CRP) levels in acute myocardial infarction (AMI) patients and normal subjects. Peripheral blood samples were obtained from all 39 AMI patients and 35 controls for blood cell counts and CK and CRP analyses. Total WBC, WBC fractions, RBC and platelets were measured with an automated hematology analyzer. The results showed a significant increase in total WBC (8.688 × 109/L versus 6.148 × 109/L), monocytes (1.271 versus 0.497 × 109/L), and neutrophils (8.367 versus 3.223 × 109/L) counts in AMI patients than controls. The RBC count was significantly less in AMI patients (4.638 × 1012/L) as compared to controls (5.105 × 1012/L). However, there was no significant difference in lymphocytes, eosinophils, basophils and platelet counts between AMI patients and controls. Both, serum CK (215.38 ± 43.15 versus 100.82 ± 8.86 U/L) and CRP (29.49 ± 7.61 versus 3.48 ± 0.60 mg/L) were significantly higher in AMI patients as compared to controls. Age of the subjects was neither correlated with blood cell counts nor CK indicating the validity of these markers irrespective of patient age. A significant correlation was observed between WBC counts and CK (R = 0.242, P = 0.041) as well as CRP (R = 0.416, P = 0.000). In conclusion, this study clearly showed significant increase in total and differential leukocyte counts indicating a pro-inflammatory cascade in AMI patients. A significant correlation between WBC counts and CK or CRP levels suggest a possible biomarker value of WBC for a quick prediction of both myocardial necrosis and inflammation in AMI patients.
PMCID: PMC3272686  PMID: 22328948
Acute myocardial infarction; blood cells count; creatine kinase; inflammation; biomarker
9.  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.
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.
PMCID: PMC3128114  PMID: 21738480
10.  Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene 
PLoS Genetics  2009;5(1):e1000360.
Persistently low white blood cell count (WBC) and neutrophil count is a well-described phenomenon in persons of African ancestry, whose etiology remains unknown. We recently used admixture mapping to identify an approximately 1-megabase region on chromosome 1, where ancestry status (African or European) almost entirely accounted for the difference in WBC between African Americans and European Americans. To identify the specific genetic change responsible for this association, we analyzed genotype and phenotype data from 6,005 African Americans from the Jackson Heart Study (JHS), the Health, Aging and Body Composition (Health ABC) Study, and the Atherosclerosis Risk in Communities (ARIC) Study. We demonstrate that the causal variant must be at least 91% different in frequency between West Africans and European Americans. An excellent candidate is the Duffy Null polymorphism (SNP rs2814778 at chromosome 1q23.2), which is the only polymorphism in the region known to be so differentiated in frequency and is already known to protect against Plasmodium vivax malaria. We confirm that rs2814778 is predictive of WBC and neutrophil count in African Americans above beyond the previously described admixture association (P = 3.8×10−5), establishing a novel phenotype for this genetic variant.
Author Summary
Many African Americans have white blood cell counts (WBC) that are persistently below the normal range for people of European descent, a condition called “benign ethnic neutropenia.” Because most African Americans have both African and European ancestors, selected genetic variants can be analyzed to assign probable African or European origin to each region of each such person's chromosomes. Previously, we found a region on chromosome 1 where increased local African ancestry completely accounted for differences in WBC between African and European Americans, suggesting the presence of an African-derived variant causing low WBC. Here, we show that low neutrophil count is predominantly responsible for low WBC; that a dominant, European-derived allele contributes to high neutrophil count; and that the frequency of this allele differs in Africans and Europeans by >91%. Across the chromosome 1 locus, only the well-characterized “Duffy” polymorphism was this differentiated. Neutrophil count was more strongly associated to the Duffy variant than to ancestry, suggesting that the variant itself causes benign ethnic neutropenia. The African, or “null,” form of this variant abolishes expression of the “Duffy Antigen Receptor for Chemokines” on red blood cells, perhaps altering the concentrations and distribution of chemokines that regulate neutrophil production or migration.
PMCID: PMC2628742  PMID: 19180233
11.  Diagnostic value of urine sTREM-1 for sepsis and relevant acute kidney injuries: a prospective study 
Critical Care  2011;15(5):R250.
We explored the diagnostic value of a urine soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) for early sepsis identification, severity and prognosis assessment, and for secondary acute kidney injury (AKI). We compared this with white blood cell (WBC) counts, serum C-reactive protein (CRP), serum procalcitonin (PCT), urine output, creatinine clearance (CCr), serum creatinine (SCr), and blood urea nitrogen (BUN).
We enrolled 104 subjects admitted to the ICU: 16 cases with systemic inflammatory response syndrome (SIRS); 35 with sepsis and 53 with severe sepsis. Results for urine sTREM-1, WBC, serum CRP and serum PCT were recorded on days 1, 3, 5, 7, 10, and 14. For 17 sepsis cases diagnosed with secondary AKI, comparisons between their urine sTREM-1, urine output, CCr, SCr and BUN at diagnosis and 48 h before diagnosis were made.
On the day of admission to the ICU, and compared with the SIRS group, the sepsis group exhibited higher levels of urine sTREM-1 and Acute Physiologic Assessment and Chronic Health Evaluation II (APACHE II) scores (P < 0.05). Areas under the curve (AUC) shaped by the scores were 0.797 (95% CI 0.711 to 0.884) and 0.722 (95% CI 0.586 to 0.858), respectively. On days 1, 3, 5, 7, 10, and 14, urine sTREM-1, serum PCT and WBC levels registered higher in the severe sepsis group in contrast to the sepsis group (P < 0.05). Urine sTREM-1 and serum PCT levels continuously increased among non-survivors, while WBC and serum CRP levels in both groups declined. For 17 patients with AKI, urine sTREM-1, SCr and BUN levels at 48 h before AKI diagnosis were higher, and CCr level was lower than those for non-AKI subjects (P < 0.05). AUC for urine sTREM-1 was 0.922 (95% CI 0.850 to 0.995), the sensitivity was 0.941, and the specificity was 0.76 (based on a cut-off point of 69.04 pg/ml). Logistic regression analysis showed that urine sTREM-1 and severity were risk factors related to AKI occurrence.
Besides being non-invasive, urine sTREM-1 testing is more sensitive than testing WBC, serum CRP, and serum PCT for the early diagnosis of sepsis, as well as for dynamic assessments of severity and prognosis. It can also provide an early warning of possible secondary AKI in sepsis patients.
Trial Registration identifier NCT01333657
PMCID: PMC3334801  PMID: 22023777
urine; soluble triggering receptor expressed on myeloid cells-1(sTREM-1); sepsis; severity; prognosis; acute kidney injury (AKI); sensitivity; specificity
12.  Is the absence of JAK2V617F mutation a risk factor for bleeding in essential thrombocythemia? An analysis of 106 patients 
Blood Transfusion  2010;8(1):21-27.
JAK2V617F mutation has been recognized as a possible thrombotic risk factor in essential thrombocythaemia (ET). It’s role is probably due to an increased myeloid proliferation and white blood cells (WBC) activation. Only few data are available about the effect of JAK2V617F on hemorrhagic risk. The aim of our study was to evaluate the influence of the mutational status on hemorrhagic complication.
We retrospectively analysed laboratory and clinical findings of 106 consecutive patients with ET to evaluate possible relationships between thrombosis, abnormal bleeding, peripheral blood count, overexpression of PRV1 and JAK2V617F mutational status.
On univariate analysis we found: an association between JAK2V617F mutation and thrombotic events before or at diagnosis (p<0.003, OR=4.44, 95% CI=1.74–12.4); no statistical correlation between the median value of JAK2V617F burden and an increased risk of thrombosis (p=0.4, 95% CI= −22.8–10.4); significant relationships between mutated status and higher haematocrit, high WBC count and low platelet count; and a strong correlation between JAK2V617F and PRV1 overexpression (p<0.0001). Moreover, the presence of the JAK2V617F mutation and a WBC count greater than 8.4 × 109/L were found to be independent factors related to thrombotic complications in multivariable analysis (p<0.006, OR=3.85, 95% CI=1.3–11.9; and p<0.002, OR=2.8, 95% CI=1.08–7.03, respectively). The prognostic impact of JAK2 mutation status and WBC count on thrombosis was evaluated in the whole cohort. Only new cases occurring in patients without previous thrombotic events were recorded for the analysis. The multivariable analysis showed a statistical correlation between the presence of the mutation and a WBC count greater than 8.12 × 106/L and an increased risk of thrombosis if no cytoreductive treatment was started at diagnosis (JAK2V617F p=0.02; WBC p=0.02; OR=4.97; 95% CI=1.04–23.8). Finally, wild-type JAK2 was associated with a higher haemorrhagic risk (p=0.02) in univariate analysis but only a platelet count greater than 1,022 × 109/L was associated with an increased risk of bleeding in the multivariable analysis.
Our data confirm the role of both JAK2V617F as factor associated with an increased risk of thrombosis at the diagnosis and during follow-up in no treated patients. Moreover a WBC count over 8.4×109/L1 was also strictly associated to an increased risk of thrombosis. Regarding bleedings, our statistical analysis allows to exclude the mutation protective role on haemorrhage.
PMCID: PMC2809508  PMID: 20104275
essential thrombocythaemia; JAK2V617F; myeloproliferative disorders; thrombosis; bleeding
13.  Effects of fluoxetine and escitalopram on C-reactive protein in patients of depression 
To study the anti-inflammatory activity of fluoxetine and escitalopram in newly diagnosed patients of depression and also to evaluate the association between depression and inflammation.
Materials and Methods:
Ninety-eight newly diagnosed patients of depression were recruited as cases. From these, 48 had started treatment with fluoxetine (20 mg/day) and 50 had started treatment with escitalopram (20 mg/day). After 2 months of treatment of these patients, Hamilton rating scale for depression (HRSD scale), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and white blood cell (WBC) count were measured and compared to their respective baseline values before starting treatment. One hundred healthy volunteers were recruited as controls and their baseline of CRP, ESR and WBC count were measured and compared with their respective baseline values of cases. Severity of depression was measured by HRSD scale and anti-inflammatory activity was measured by reduction CRP, ESR and WBC count.
On baseline comparison between cases and controls, there were significant increases in the levels of CRP (P = 0.014), ESR (P = 0.023) and WBC count (P = 0.020) in cases. In fluoxetine (20 mg/day) treatment group, there was a significant reduction in the levels of CRP (P = 0.046), ESR (P = 0.043) and WBC count (P = 0.021) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.190). Similarly, in escitalopram treatment group, there was a significant reduction in CRP (P = 0.041), ESR (P = 0.030) and WBC count (P = 0.017) after 2 months of treatment but no significant reduction in HRSD scale (P = 0.169).
In newly diagnosed patients of depression, inflammatory markers such as CRP, ESR and WBC count were significantly raised and Selective serotonin reuptake inhibitors SSRIs such as fluoxetine and escitalopram reduced them independent of their antidepressant effect. So, SSRIs have some anti-inflammatory activity independent of their antidepressant action.
PMCID: PMC3117562  PMID: 21701640
Anti-inflammatory activity; C-reactive protein; erythrocyte sedimentation rate; Hamilton rating scale for depression; white blood cell count
14.  Impact of preprocedural white blood cell count on long term mortality after percutaneous coronary intervention: insights from the EPIC, EPILOG, and EPISTENT trials 
Heart  2003;89(10):1200-1204.
Background: Raised inflammatory markers are associated with worse outcome after percutaneous coronary interventions (PCI). An increase in the white blood cell (WBC) count is a non-specific response to inflammation. We hypothesised that a raised baseline WBC count would be a predictor of mortality in patients undergoing PCI.
Methods: The association between preprocedural WBC count and long term mortality was studied in 7179 patients enrolled in the EPIC, EPILOG, and EPISTENT trials. The end points were the incidence of myocardial infarction at one year, and one and three year mortality.
Results: There were 188 deaths and 582 myocardial infarctions at one year. While WBC count was a strong predictor of death at one year, with every increase of 1 k/μl (1×106/l) being associated with a hazard ratio (HR) of 1.109 (95% confidence interval (CI) 1.072 to 1.147, p < 0.001), there was no association with myocardial infarction at one year (HR 1.020, 95% CI 0.990 to 1.052, p = 0.195). There were a total of 406 deaths at three years with a strong association between WBC count and three year mortality (HR for every 1 k/μl increase 1.089, 95% CI 1.058 to 1.121, p < 0.001). WBC count remained a significant predictor of mortality after multivariable adjustment (HR for every 1 k/μl increase 1.100, 95% CI 1.069 to 1.131, p < 0.001). The association was significant across multiple subgroups, including diabetes, female sex, clinical presentation, and cigarette smoking.
Conclusion: A raised pre-procedural WBC count in patients undergoing PCI is associated with an increased risk of long term death. These results suggest a key role for inflammation in coronary artery disease.
PMCID: PMC1767915  PMID: 12975419
white blood cell count; percutaneous coronary intervention; inflammation; atherosclerosis
15.  Combining white blood cell count and thrombosis for predicting in-hospital outcomes after acute myocardial infraction 
Admission white blood cell (WBC) count and thrombosis in myocardial infarction (TIMI) risk score have been associated with adverse outcomes after acute myocardial infarction (AMI). This study investigated the joint effect of WBC count and TIMI risk score on predicting in-hospital outcomes in patients with AMI.
Materials and Methods:
WBC count and TIMI risk score were measured at the time of hospital admission in 70 patients with AMI. Echocardiogram was done on prior to discharge by a cardiologist and ejection fraction (EF) was determined according to the Simpson formula. Patients were stratified into tertiles (low and high) based on WBC count and TIMI risk score.
Patients with a high WBC count had a 5.0-fold increase in-hospital congestive heart failure and 2.2 increases in mortality compared with those with a low WBC count. Patients with a high TIMI risk score had a 10-fold increase in congestive heart failure presentation and mortality compared with those with a low TIMI risk score. When a combination of different strata for each variable was analyzed, a stepwise increase in mortality was seen. There were a few number of patients with a high WBC count and low TIMI risk score or with a low WBC count and high TIMI risk score. These patients had an intermediate risk, whereas those with a high WBC count and TIMI risk score had the highest risk.
These findings suggested that a simple combination of WBC count and TIMI risk score might provide further information for predicting outcomes in patients with AMI.
PMCID: PMC3162703  PMID: 21887024
Heart failure; infarction; ST elevation myocardial; white blood cell
16.  Inflammation and Cardiovascular Events in Individuals with and without Chronic Kidney Disease 
Kidney international  2008;73(12):1406-1412.
Inflammation and chronic kidney disease (CKD) predict cardiovascular events. Little is known about the interaction of inflammation and CKD. We evaluated inflammation markers (fibrinogen, albumin, white blood cell (WBC) count) in individuals with and without CKD to assess: 1) inflammation as a risk factor for adverse events; 2) synergy between inflammation and CKD; and 3) prognostic ability of these markers relative to c-reactive protein (CRP).
Using Atherosclerosis Risk in Communities and Cardiovascular Health Study data, inflammation was defined by 2 of 3 criteria: lowest albumin quartile and highest fibrinogen and race-specific WBC quartiles. CKD was defined as estimated glomerular filtration rate of 0.25-1 mL/sec/1.73m2. In Cox models, inflammation was assessed as a risk factor for a composite of cardiac events, stroke and mortality as well as components of this composite.
Among 20,413 individuals, mean WBC count was 6.2±2.0/L3, albumin 41±3 g/L, and fibrinogen 9.1±1.9 µmol/L. Inflammation was defined in 3,594 subjects and CKD in 1,649. In multivariable analyses, while both inflammation and CKD predicted all outcomes, their interaction was non-significant. In those with CRP measurements (Cardiovascular Health Study only, n=5,597), inflammation and elevated CRP had similar hazard ratios. When focusing only on worst quartile of WBC and albumin, results remained consistent.
CKD and inflammation are associated with an increased risk of adverse events but do not exhibit synergy. The composite of albumin, WBC count and fibrinogen as well as the composite of only albumin and WBC count have a similar association with adverse events as CRP.
PMCID: PMC4083694  PMID: 18401337
17.  White blood cell count and endothelin-1 vasoconstrictor tone in middle-aged and older adults 
Artery research  2012;6(2):65-70.
Higher white blood cell (WBC) count is associated with impaired endothelium-dependent vasodilation. However, the influence of higher WBC count on endothelin (ET)-1 vasoconstrictor activity is currently unknown. We tested the hypothesis that adults with elevated WBC count demonstrate enhanced ET-1 system activity.
Thirty-four healthy adults were studied: 17 with WBC count < 5.0 × 109 cells/L (lower WBC; 9M/8F; age: 53 ± 2 yr) and 17 with WBC count > 5.0 × 109 cells/L (higher WBC; 10M/7F; 54 ± 3 yr). Forearm blood flow (FBF) responses to intra-brachial infusion of ET-1 (5 pmol/min for 20 min) and selective ETA receptor blockade (BQ-123; 100 nmol/min for 60 min) were measured by venous occlusion plethysmography.
The vasoconstrictor response to ET-1 was significantly blunted (∼60%) in the higher WBC group versus the lower WBC group. The FBF responses to selective ETA receptor blockade were also significantly different (P < 0.05) between the groups. In the lower WBC group, resting FBF increased marginally (∼5%) to BQ-123, whereas the increase in FBF to BQ-123 was significantly greater (∼15%) in higher WBC group. Furthermore, there was a significant relation between WBC count and FBF response to ET-1 (r = −0.43) and BQ-123 (r = 0.41).
Relative elevations in WBC count in middle-aged and older adults, independent of adiposity and other cardiometabolic risk factors, are associated with enhanced ET-1-mediated vasoconstrictor tone. Elevated ET-1 system activity may be a mechanism linking higher WBC count with increased cardiovascular risk.
PMCID: PMC3727287  PMID: 23908675
Endothelin; Vasoconstriction; White blood cell
18.  Time-Course of Changes in Inflammatory Response after Whole-Body Cryotherapy Multi Exposures following Severe Exercise 
PLoS ONE  2011;6(7):e22748.
The objectives of the present investigation was to analyze the effect of two different recovery modalities on classical markers of exercise-induced muscle damage (EIMD) and inflammation obtained after a simulated trail running race. Endurance trained males (n = 11) completed two experimental trials separated by 1 month in a randomized crossover design; one trial involved passive recovery (PAS), the other a specific whole body cryotherapy (WBC) for 96 h post-exercise (repeated each day). For each trial, subjects performed a 48 min running treadmill exercise followed by PAS or WBC. The Interleukin (IL) -1 (IL-1), IL-6, IL-10, tumor necrosis factor alpha (TNF-α), protein C-reactive (CRP) and white blood cells count were measured at rest, immediately post-exercise, and at 24, 48, 72, 96 h in post-exercise recovery. A significant time effect was observed to characterize an inflammatory state (Pre vs. Post) following the exercise bout in all conditions (p<0.05). Indeed, IL-1β (Post 1 h) and CRP (Post 24 h) levels decreased and IL-1ra (Post 1 h) increased following WBC when compared to PAS. In WBC condition (p<0.05), TNF-α, IL-10 and IL-6 remain unchanged compared to PAS condition. Overall, the results indicated that the WBC was effective in reducing the inflammatory process. These results may be explained by vasoconstriction at muscular level, and both the decrease in cytokines activity pro-inflammatory, and increase in cytokines anti-inflammatory.
PMCID: PMC3145670  PMID: 21829501
19.  A Study on Biomarkers, Cytokines, and Growth Factors in Children With Burn Injuries 
Background. Burns are a unique injury which not only is devastating for the patients but also puts a great burden on society by consuming enormous health care resources. Despite improvements in burn wound care and treatment, understanding the role of pro-inflammatory and anti-inflammatory cytokines as well as the mechanisms responsible for the healing process remains to be clarified. Although leptin is regarded as a circulating hormone, it can exert a direct effect on T cells and monocytes, causing the release of cytokines. It may induce angiogenesis or influence angiogenic factors. The aim of the present work is to determine serum levels of leptin, tumour necrosis factor a (TNFa), interleukin-6 (IL-6), basic fibroblast growth factor (bFGF), procalcitonin (PCT), and C-reactive protein (CRP) in a group of children with thermal burns and to determine the changes in these parameters in relation to the duration of hospital stay, the presence of infection, and the total body surface area (TBSA) burned. Patients and methods. The study included 42 children with burns (22 males and 20 females; age range, 2 months to 7 years). The study also included 26 age-matched controls. Besides full clinical assessment, including assessment of TBSA burned and the presence or absence of sepsis, all the patients and controls had the following investigations performed: complete blood count, CRP, IL-6, TNFa, PCT, serum leptin, bFGF, and transforming growth factor a (TGFa). Results. The fatality rate in this study was 28.6%. Burn cases as a whole showed significantly higher values of white blood cells (WBC), CRP, PCT, TNFa, IL-6, leptin, bFGF, and TGFa than controls. Cases with sepsis showed significantly higher values of WBC, CRP, PCT, TNFa, and IL-6 than cases without sepsis. They showed significantly lower values of TGFa than cases without sepsis. Patients with larger TBSA (>30%) showed significantly higher levels of WBC, CRP, PCT, TNFa, IL-6, and leptin than cases with smaller TBSA. They showed significantly lower levels of bFGF and TGFa than patients with smaller TBSA. Non-survivors showed significantly higher levels of WBC, CRP, PCT, TNFa, and IL-6 than survivors. They showed significantly lower levels of leptin, bFGF, and TGFa than survivors. Correlation studies showed a significant positive correlation between TBSA and each of IL-6, TNFa, and leptin. Conclusions. Cytokines and leptin increased in severely burned patients, cases associated with sepsis, and in fatal cases, while bFGF and TGFa levels were lower in severe cases. This may point to impaired healing in such cases and to their poorer prognosis. Recommendations. It is highly recommended to monitor immunological parameters such as PCT and/or IL-6 for early detection of infectious complications following thermal injury. Leptin can be regarded as a novel treatment modality to diminish burn-induced inflammation, reduce post-burn immune dysfunction, and enhance burn healing.
PMCID: PMC3188064  PMID: 21991076
20.  Lipoprotein Particles, Insulin, Adiponectin, C-Reactive Protein and Risk of Coronary Heart Disease among Men with Metabolic Syndrome 
Atherosclerosis  2006;195(1):122-128.
We tested the hypotheses whether nuclear magnetic resonance (NMR) determined lipoprotein particles, insulin and adiponectin, and C-reactive protein (CRP) and white blood cell (WBC) count as markers of inflammation predicted risk of coronary heart disease (CHD) death among 428 men age 35–57 years with metabolic syndrome (MetSyn) in a matched case control study within the Multiple Risk Factor Intervention Trial.
Blood samples collected at entry into the study and stored at −60° C were obtained from central storage for blood analyte analysis. 214 men with MetSyn who died of CHD were matched with 214 men with MetSyn who did not die of CHD during 18 years of follow-up. Cases were matched to controls on age, study group, number of factors present in the MetSyn, and presence or absence of a non-fatal CVD event during the trial. Mortality follow up was determined using the National Death Index.
Higher levels of high density lipoprotein particles (HDL-P), especially medium-sized HDL-P, [hazard ratio (95% confidence interval) 0.45 (0.25–0.83, p<0.01), quartile 1 as compared to quartile 4], were associated with lower risk of CHD death. Low density lipoprotein (LDL) particles were not associated with increased risk of CHD. Elevated LDL cholesterol (LDL-C), smoking and WBC count were, but levels of adiponectin, insulin and CRP were not significantly related to CHD death. In multivariate models adjusting for smoking and LDL-C, medium HDL-P and WBC count remained independent predictors of CHD death.
Number of HDL particles, especially medium-sized HDL particles and WBC count were independent predictors of CHD death among men with MetSyn.
PMCID: PMC2098784  PMID: 17011566
Lipoproteins; metabolic syndrome; coronary heart disease; white blood cell count; C-reactive protein
21.  The Hematologic Profile of the Fetus with Systemic Inflammatory Response Syndrome 
Journal of Perinatal Medicine  2011;40(1):19-32.
The Fetal Inflammatory Response Syndrome (FIRS) is associated with the impending onset of preterm labor/delivery, microbial invasion of the amniotic cavity and increased perinatal morbidity. FIRS has been defined by an elevated fetal plasma interleukin-6 (IL-6), a cytokine with potent effects on the differentiation and proliferation of hematopoietic precursors. The objective of this study was to characterize the hematologic response of fetuses with FIRS.
Fetal blood sampling was performed in patients with preterm prelabor rupture of membranes and preterm labor with intact membranes (n=152). A fetal plasma IL-6 concentration >=11 pg/ml was used to define FIRS. Hemoglobin concentration, platelet count, total white blood cell (WBC) count, differential count and nucleated red blood cell (NRBC) count were obtained. Since blood cell count varies with gestational age, the observed values were corrected for fetal age by calculating a ratio between the observed and expected mean value for gestational age.
1) The prevalence of FIRS was 28.9% (44/152); 2) fetuses with FIRS had a higher median corrected WBC and corrected neutrophil count than those without FIRS (WBC median 1.4; range 0.3–5.6 vs. median 1.1; range 0.4–2.9 p=0.001; neutrophils median 3.6; range 0.1–57.5 vs. median 1.8; range 0.2–13.9 p<0.001); 3) neutrophilia (defined as a neutrophil count >95th centile of gestational age) was significantly more common in fetuses with FIRS than in those without FIRS [71% (30/42) vs. 35% (37/105); p<0 001]; 4) more than two thirds of fetuses with FIRS had neutrophilia, while neutropenia was present in only 4.8% (2/42); 5) FIRS was not associated with detectable changes in hemoglobin concentration, platelet, lymphocyte, monocyte, basophil or eosinophil counts and; 6) fetuses with FIRS had a median corrected NRBC count higher than those without FIRS. However, the difference did not reach statistical significance (NRBC median 0.07; range 0–1.3 vs. median 0.04; range 0–2.3 p=0.06);
The hematological response of the human fetus with FIRS is characterized by significant changes in the total white blood cell and neutrophil counts. The NRBC count in fetuses with FIRS tends to be higher than fetuses without FIRS.
PMCID: PMC3380620  PMID: 21957997
FIRS; preterm labor; preterm PROM; cordocentesis; neutrophil; nucleated red blood cells; infection; hypoxia; neutrophilia; neutropenia; white blood cell count
22.  Uric acid and inflammatory markers 
European heart journal  2006;27(10):1174-1181.
The role of uric acid (UA) in the process of atherosclerosis and atherotrombosis is controversial. Epidemiological studies have recently shown that UA may be a risk factor for cardiovascular diseases and a negative prognostic marker for mortality in subjects with pre-existing heart failure.
Methods and results
We evaluate a relationship between UA levels and several inflammatory markers in 957 subjects, free of severe renal failure, from a representative Italian cohort of persons aged 65–95. Plasma levels of UA and white blood cell (WBC) and neutrophil count, C-reactive protein, interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), soluble IL-6 receptor (sIL-6r), interleukin-18 (IL-18), and tumor necrosis factor-α (TNF-α) were measured. Complete information on potential confounders was collected using standard methods. WBC (P = 0.0001), neutrophils (P < 0.0001), C-reactive protein (P < 0.0001), IL-1ra (P < 0.0001), IL-6 (P = 0.0004), sIL-6r (P = 0.002), IL-18 (P < 0.0001), TNF-α (P = 0.0008), and the percentage of subjects with abnormally high levels of C-reactive protein (P = 0.004) and IL-6 (P = <0.0001) were significantly higher across UA quintiles. After adjustment for age, sex, behaviour- and disease-related confounders, results were virtually unchanged. In subjects with UA within the normal range, UA was significantly and independently associated with neutrophils count, C-reactive protein, IL-6, IL-1ra, IL-18, and TNF-α, whereas non-significant trends were observed for WBC (P = 0.1) and sIL-6r (P = 0.2).
A positive and significant association between UA and several inflammatory markers was found in a large population-based sample of older persons and in a sub-sample of participants with normal UA. Accordingly, the prevalence of abnormally high levels of C-reactive protein and IL-6 increased significantly across UA quintiles.
PMCID: PMC2668163  PMID: 16611671
Metabolism; Inflammation; Comorbidity; Elderly
23.  White Blood Cell Count and the Risk for Coronary Artery Disease in Young Adults 
PLoS ONE  2012;7(10):e47183.
The association between white blood cell (WBC) count and coronary artery disease (CAD) is unknown in young adults. Our objective was to assess the association between WBC count and its changes over time with CAD incidence in the Metabolic, Life-style and Nutrition Assessment in Young adults (MELANY) study, a cohort of Israeli army personnel.
Methods and Findings
29,120 apparently healthy young men (mean age; 31.2±5.5 years) with a normal baseline WBC count (3,000–12,000 cells/mm3) were followed during a mean follow up of 7.5±3.8 years for incidence of CAD. Participants were screened every 3–5 years using a stress test, and CAD was confirmed by coronary angiography. In a multivariate model adjusted for age, body mass index (BMI), LDL- and HDL-cholesterol, blood pressure, family history of CAD, physical activity, diabetes, triglycerides and smoking status, WBC levels (divided to quintiles) above 6,900 cells/mm3 (quintile 4) were associated with a 2.17-fold increase (95%CI = 1.18–3.97) in the risk for CAD as compared with men in quintile 1 (WBC≤5,400 cells/mm3). When modeled as a continuous variable, a WBC increment of 1000 cells/mm3 was associated with a 17.4% increase in CAD risk (HR 1.174; 95%CI = 1.067–1.290, p = 0.001). A decrease in the WBC level (within the normal range) during the follow-up period was associated with increased physical activity and decreased triglyceride levels as well as with reduced incidence of CAD.
WBC count is an independent risk factor for CAD in young adults at values well within the normal range. WBC count may assist in detecting subgroups of young men at either low or high risk for progression to CAD.
PMCID: PMC3470580  PMID: 23077568
24.  Correlation of Circulating MMP-9 with White Blood Cell Count in Humans: Effect of Smoking 
PLoS ONE  2013;8(6):e66277.
Matrix metalloproteinase-9 (MMP-9) is an emerging biomarker for several disease conditions, where white blood cell (WBC) count is also elevated. In this study, we examined the relationship between MMP-9 and WBC levels in apparently healthy smoking and non-smoking human subjects.
We conducted a cross-sectional study to assess the relationship of serum MMP-9 with WBC in 383 men and 356 women. Next, we divided the male population (women do not smoke in this population) into three groups: never (n = 243), current (n = 76) and former (n = 64) smokers and compared the group differences in MMP-9 and WBC levels and their correlations within each group.
Circulating MMP-9 and WBC count are significantly correlated in men (R2 = 0.13, p<0.001) and women (R2 = 0.19, p<0.001). After stratification by smoking status, MMP-9 level was significantly higher in current smokers (mean ± SE; 663.3±43.4 ng/ml), compared to never (529.7±20.6) and former smokers (568±39.3). WBC count was changed in a similar pattern. Meanwhile, the relationship became stronger in current smokers with increased correlation coefficient of r = 0.45 or R2 = 0.21 (p<0.001) and steeper slope of ß = 1.16±0.30 (p<0.001) in current smokers, compared to r = 0.26 or R2 = 0.07 (p<0.001) and ß = 0.34±0.10 (p<0.001) in never smokers.
WBC count accounts for 13% and 19% of MMP-9 variance in men and women, respectively. In non-smoking men, WBC count accounts for 7% of MMP-9 variance, but in smoking subjects, it accounts for up to 21% of MMP-9 variance. Thus, we have discovered a previously unrecognized correlation between the circulating MMP-9 and WBC levels in humans.
PMCID: PMC3692499  PMID: 23825535
25.  White Blood Cells Count and Incidence of Type 2 Diabetes in Young Men 
Diabetes Care  2013;36(2):276-282.
Association between white blood cell (WBC) count and diabetes risk has been recently suggested. We assessed whether WBC count is an independent risk factor for diabetes incidence among young healthy adults.
WBC count was measured in 24,897 young (mean age 30.8 ± 5.36 years), normoglycemic men with WBC range of 3,000 to 12,000 cells/mm3. Participants were periodically screened for diabetes during a mean follow-up of 7.5 years.
During 185,354 person-years of follow-up, diabetes was diagnosed in 447 subjects. A multivariate model adjusted for age, BMI, family history of diabetes, physical activity, and fasting glucose and triglyceride levels revealed a 7.6% increase in incident diabetes for every increment of 1,000 cells/mm3 (P = 0.046). When grouped in quintiles, a baseline WBC count above 6,900 cells/mm3 had an independent 52% increase in diabetes risk (hazard ratio 1.52 [95% CI 1.06–2.18]) compared with the lowest quintile (WBC <5,400 cells/mm3). Men at the lowest WBC quintile were protected from diabetes incidence even in the presence of overweight, family history of diabetes, or elevated triglyceride levels. After simultaneous control for risk factors, BMI was the primary contributor of the variation in multivariate models (P < 0.001), followed by age and WBC count (P < 0.001), and family history of diabetes and triglyceride levels (P = 0.12).
WBC count, a commonly used and widely available test, is an independent risk factor for diabetes in young men at values well within the normal range.
PMCID: PMC3554323  PMID: 22961572

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