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1.  Application of a Fuzzy Neural Network Model in Predicting Polycyclic Aromatic Hydrocarbon- Mediated Perturbations of the Cyp1b1 Transcriptional Regulatory Network in Mouse Skin 
Toxicology and applied pharmacology  2012;267(2):192-199.
Polycyclic aromatic hydrocarbons (PAHs) are present in the environment as complex mixtures with components that have diverse carcinogenic potencies and mostly unknown interactive effects. Non-additive PAH interactions have been observed in regulation of cytochrome P450 (CYP) gene expression in the CYP1 family. To better understand and predict biological effects of complex mixtures, such as environmental PAHs, an 11 gene input-1 gene output fuzzy neural network (FNN) was developed for predicting PAH-mediated perturbations of dermal Cyp1b1 transcription in mice. Input values were generalized using fuzzy logic into low, medium, and high fuzzy subsets, and sorted using k-means clustering to create Mamdani logic functions for predicting Cyp1b1 mRNA expression. Model testing was performed with data from microarray analysis of skin samples from FVB/N mice treated with toluene (vehicle control), dibenzo[def,p]chrysene (DBC), benzo[a]pyrene (BaP), or 1 of 3 combinations of diesel particulate extract (DPE), coal tar extract (CTE) and cigarette smoke condensate (CSC) using leave one out cross-validation. Predictions were within 1 log2 fold change unit of microarray data, with the exception of the DBC treatment group, where the unexpected down-regulation of Cyp1b1 expression was predicted but did not reach statistical significance on the microarrays. Adding CTE to DPE was predicted to increase Cyp1b1 expression, whereas adding CSC to CTE and DPE was predicted to have no effect, in agreement with microarray results. The aryl hydrocarbon receptor repressor (Ahrr) was determined to be the most significant input variable for model predictions using back-propagation and normalization of FNN weights.
PMCID: PMC3626406  PMID: 23274566
PAHs; modeling; mixtures; Cyp1b1; skin Ahrr
2.  Identification of an Interaction between VWF rs7965413 and Platelet Count as a Novel Risk Marker for Metabolic Syndrome: An Extensive Search of Candidate Polymorphisms in a Case-Control Study 
PLoS ONE  2015;10(2):e0117591.
Although many single nucleotide polymorphisms (SNPs) have been identified to be associated with metabolic syndrome (MetS), there was only a slight improvement in the ability to predict future MetS by the simply addition of SNPs to clinical risk markers. To improve the ability to predict future MetS, combinational effects, such as SNP—SNP interaction, SNP—environment interaction, and SNP—clinical parameter (SNP × CP) interaction should be also considered. We performed a case-control study to explore novel SNP × CP interactions as risk markers for MetS based on health check-up data of Japanese male employees. We selected 99 SNPs that were previously reported to be associated with MetS and components of MetS; subsequently, we genotyped these SNPs from 360 cases and 1983 control subjects. First, we performed logistic regression analyses to assess the association of each SNP with MetS. Of these SNPs, five SNPs were significantly associated with MetS (P < 0.05): LRP2 rs2544390, rs1800592 between UCP1 and TBC1D9, APOA5 rs662799, VWF rs7965413, and rs1411766 between MYO16 and IRS2. Furthermore, we performed multiple logistic regression analyses, including an SNP term, a CP term, and an SNP × CP interaction term for each CP and SNP that was significantly associated with MetS. We identified a novel SNP × CP interaction between rs7965413 and platelet count that was significantly associated with MetS [SNP term: odds ratio (OR) = 0.78, P = 0.004; SNP × CP interaction term: OR = 1.33, P = 0.001]. This association of the SNP × CP interaction with MetS remained nominally significant in multiple logistic regression analysis after adjustment for either the number of MetS components or MetS components excluding obesity. Our results reveal new insight into platelet count as a risk marker for MetS.
PMCID: PMC4315519  PMID: 25646961
3.  White Blood Cell Counts as Risk Markers of Developing Metabolic Syndrome and Its Components in the Predimed Study 
PLoS ONE  2013;8(3):e58354.
The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities that includes hyperglucemia, hypertension, dyslipidemia and central obesity, conferring an increased risk of cardiovascular disease. The white blood cell (WBC) count has been proposed as a marker for predicting cardiovascular risk. However, few prospective studies have evaluated the relationship between WBC subtypes and risk of MetS.
Participants were recruited from seven PREDIMED study centers. Both a baseline cross-sectional (n = 4,377) and a prospective assessment (n = 1,637) were performed. Participants with MetS at baseline were excluded from the longitudinal analysis. The median follow-up was 3.9 years. Anthropometric measurements, blood pressure, fasting glucose, lipid profile and WBC counts were assessed at baseline and yearly during the follow-up. Participants were categorized by baseline WBC and its subtype count quartiles. Adjusted logistic regression models were fitted to assess the risk of MetS and its components.
Of the 4,377 participants, 62.6% had MetS at baseline. Compared to the participants in the lowest baseline sex-adjusted quartile of WBC counts, those in the upper quartile showed an increased risk of having MetS (OR, 2.47; 95%CI, 2.03–2.99; P-trend<0.001). This association was also observed for all WBC subtypes, except for basophils. Compared to participants in the lowest quartile, those in the top quartile of leukocyte, neutrophil and lymphocyte count had an increased risk of MetS incidence. Leukocyte and neutrophil count were found to be strongly associated with the MetS components hypertriglyceridemia and low HDL-cholesterol. Likewise, lymphocyte counts were found to be associated with the incidence of the MetS components low HDL-cholesterol and high fasting glucose. An increase in the total WBC during the follow-up was also associated with an increased risk of MetS.
Total WBC counts, and some subtypes, were positively associated with MetS as well as hypertriglyceridemia, low HDL-cholesterol and high fasting glucose, all components of MetS.
Trial registration
PMCID: PMC3602299  PMID: 23526980
4.  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
5.  Low-Grade Inflammation, Metabolic Syndrome and the Risk of Chronic Kidney Disease: the 2005 Korean National Health and Nutrition Examination Survey 
Journal of Korean Medical Science  2012;27(6):630-635.
Either chronic inflammation or metabolic syndrome (MetS) is associated with renal impairment. This cross-sectional study was designed to investigate the relationship between elevated white blood cell (WBC) counts and chronic kidney disease (CKD) stage 3 or more according to the presence of MetS in adult Koreans. In total, 5,291 subjects (≥ 20 yr-old) participating in the 2005 Korean National Health and Nutrition Examination were included. CKD stage 3 or more was defined as having an estimated glomerular filtration rate below 60 mL/min/1.73 m2, as calculated using the formula from the Modification of Diet in Renal Disease study. The odds ratio (95% confidence interval) for CKD stage 3 or more in the highest WBC quartile (≥ 7,200 cells/µL) was 1.70 (1.17-2.39) after adjusting for MetS and other covariates, compared with the lowest WBC quartile (< 5,100 cells/µL). In subjects with MetS, the prevalence risk for CKD stage 3 or more in the highest WBC quartile was 2.25 (1.28-3.95) even after fully adjusting for confounding variables. In contrast, this positive association between WBC quartile and CKD stage 3 or more disappeared in subjects without MetS. Low-grade inflammation is significantly associated with CKD stage 3 or more in subjects with MetS but not in those without MetS.
PMCID: PMC3369449  PMID: 22690094
Kidney Failure, Chronic; Inflammation; Metabolic Syndrome; Leukocytes
6.  Association of Hematological Parameters with Clustered Components of Metabolic Syndrome among Professional and Office Workers in Bangkok, Thailand 
Diabetes & metabolic syndrome  2007;1(3):143-149.
Accumulating evidence documents associations between alterations in hematological parameters, indicative of prothrombotic and proinflammatory states, and risk of metabolic syndrome (MetS). We investigated associations of hematological parameters with MetS and individual criteria of the syndrome among Thai professional and office workers.
Study subjects were 1,314 patients (531 men and 783 women) who participated in annual health examinations during the period of August through December 2001. MetS was defined using the modified ATP III criteria. Multivariable logistic regression procedures were used to estimate odds ratios (OR) and 95% confidence intervals (95%CI) of MetS risk according to quartiles of each hematological parameter with the lowest quartile specified as the referent group.
WBC counts increased with increasing numbers of MetS components in both men and women. Among women, platelet counts, hemoglobin and hematocrit concentrations increased with increasing numbers of MetS components (p<0.05). No similar trends were observed for men. Of the hematological parameters studied, elevated platelet and WBC were statistically significantly associated with MetS among men (OR=1.86, 95% CI: 1.03–3.36; OR=2.26, 95% CI: 1.27–4.02), respectively. Among women, MetS risk increased across successive quartiles of hemoglobin (1.00, 2.63, 3.59 and 4.36; p for trend = 0.002), hematocrit (1.00, 2.35, 3.04 and 5.70; p-for trend <0.001), platelet (1.00, 2.37, 2.83 and 3.11; p-for trend = 0.014) and WBC counts (1.00, 2.97, 4.09 and 5.41; p-for trend < 0.001).
Our data are consistent with an emerging literature demonstrating altered hematological status in patients at high risk of MetS.
PMCID: PMC2699274  PMID: 19543435
Metabolic Syndrome; Hematological Parameters; Thailand
7.  Black-White Divergence in the Relation of White Blood Cell Count to Metabolic Syndrome in Preadolescents, Adolescents, and Young Adults: The Bogalusa Heart Study 
Diabetes Care  2010;33(11):2474-2476.
To examine the association between white blood cell (WBC) count and metabolic syndrome (MetS) by growth periods in black versus white individuals in the general population.
The study cohort consisted of 4,184 black and white preadolescents, adolescents, and adults. In this cohort, 743 adults were followed for 8.1–20.8 years longitudinally.
White versus black subjects had a significantly higher WBC count in all age-groups. WBC count was associated with more MetS components in whites than in blacks. Mean values of WBC increased significantly with increasing number of MetS components with adverse levels in adolescents and adults, with a stronger trend in whites. WBC count was longitudinally associated with MetS in whites only (P < 0.001).
The findings on the association between higher WBC count and MetS beginning in childhood, particularly in whites, underscore a potentially mechanistic link between systemic inflammation, MetS, and cardiovascular risk.
PMCID: PMC2963517  PMID: 20798336
8.  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
9.  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
10.  Cross-sectional and longitudinal study of association between circulating thiobarbituric acid-reacting substance levels and clinicobiochemical parameters in 1,178 middle-aged Japanese men - the Amagasaki Visceral Fat Study 
Circulating thiobarbituric acid-reacting substance (TBARS) levels, a marker of systemic oxidative stress, are predictive of cardiovascular events. However, they has not been evaluated in Japanese, especially with regard to the factors that contribute to the changes in circulating TBARS levels. We investigated the cross-sectional and longitudinal relationships between circulating TBARS levels and various clinicobiochemical parameters in middle-aged men.
In this population-based study (The Amagasaki Visceral Fat Study), 1,178 Japanese male urban workers who had undergone health check-ups in 2006, 2007 and 2008 and were not on medications for metabolic disorders during the follow-up period, were enrolled. Serum TBARS levels were measured by the method of Yagi. The estimated visceral fat area (eVFA) by bioelectrical impedance was measured annually. After health check-ups, subjects received health education with lifestyle modification by medical personnel.
The number of cardiovascular risk factors (hypertension, hyperglycemia, low HDL-C, hypertriglyceridemia, hyperuricemia, hyper-LDL-C and impaired renal function) augmented with the increases in log-eVFA (p < 0.0001) and log-TBARS (p < 0.0001). The combination of TBARS and eVFA had a multiplicative effect on risk factor accumulation (F value = 79.1, p = 0.0065). Stepwise multiple regression analysis identified log-eVFA, as well as age, log-body mass index (BMI), LDL-C, log-adiponectin, γ-glutamyl transpeptidase (γ-GTP) and uric acid as significant determinants of log-TBARS. Stepwise multiple regression analysis identified one-year changes in eVFA as well as BMI, γ-GTP and estimated glomerular filtration rate (eGFR) as significant determinants of one-year change in TBARS, and biennial changes in eVFA as well as BMI and γ-GTP, eGFR as significant determinants of biennial change in TBARS.
The present study showed a significant cross-sectional and longitudinal correlation between TBARS and eVFA, as well as BMI and γ- GTP, eGFR. Visceral fat reduction may independently associate with the improvement in systemic ROS in middle-aged Japanese men.
Trial Registration
The Amagasaki Visceral Fat Study UMIN000002391.
PMCID: PMC3286396  PMID: 22108213
visceral fat accumulation; systemic reactive oxidative stress; visceral fat reduction
11.  Number of Components of the Metabolic Syndrome; Smoking and Inflammatory Markers 
The association between inflammatory markers and the combination of the smoking status plus a number of components of the metabolic syndrome was not fully evaluated in male Japanese subjects.
To demonstrate the association between inflammatory markers and the number of components of the metabolic syndrome by considering smoking status.
Patients and Methods
A total of 3,017 male subjects (1,047 current smokers, 1,970 non-smokers) were included. Metabolic syndrome (MetS) was defined by the criteria of the National Cholesterol Education Program Adult Treatment Panel III. The smoking status was categorized in a binary manner into current smokers or non-smokers.
The geometric mean value of the serum CRP increased linearly as the number of components of MetS increased (P < 0.05). In contrast, the mean values of the total WBC, neutrophil, lymphocyte and monocyte counts showed peak values when the number of MetS components was 3 or 4. The log-transformed serum CRP levels and the WBC counts were significantly correlated with one another (P < 0.001), but Pearson’s correlation coefficient was under 0.3 for current smokers.
Among several inflammatory markers, the serum CRP predominantly changed linearly as the number of MetS increased regardless of smoking status.
PMCID: PMC3693652  PMID: 23853616
Metabolic Syndrome; Inflammation; Smoking
12.  The Risk of Metabolic Syndrome According to the White Blood Cell Count in Apparently Healthy Korean Adults 
Yonsei Medical Journal  2013;54(3):615-620.
Considerable amount of interest has been focused on the positive relationship between inflammation and the metabolic syndrome (MS). However, few studies have been performed to evaluate the relationship between baseline white blood cell (WBC) count and future risk for developing MS. Therefore, we investigated whether the baseline plasma levels of WBC count could be associated with future risk for MS in apparently healthy Korean.
Materials and Methods
A total of 1135 subjects (781 men and 354 women with a mean age of 49 years), who underwent health examinations at Kangbuk Samsung Hospital in both 2002 and 2005 were enrolled. The presence of MS was defined using the modified criteria of the National Cholesterol Education Program Adult Treatment Panel III using BMI instead of waist circumference.
The baseline levels of WBC count were significantly higher among incident MS cases than among subjects without MS. The relative risks of incident MS were 1.4, 3.2 and 2.7 for WBC quartiles 2, 3, and 4, respectively, when compared with the first quartile (p-value for trend <0.001). These positive associations persisted after adjustment for baseline body mass index, blood pressure, fasting glucose, high density lipoprotein-cholesterol, triglyceride and homeostatic model assessment-insulin resistance; adjusted relative risk of incident MS for the 2nd, 3rd and 4th quartile groups vs. the lowest quartile were 1.2, 2.4 and 1.7, respectively (p-value for trend =0.011).
This retrospective cohort study suggests that an elevated WBC count could be associated with incident MS, suggesting that baseline inflammation mirrored by WBC level can impact future MS development.
PMCID: PMC3635622  PMID: 23549805
White blood cell count; metabolic syndrome; inflammation
13.  Multiple Loci Are Associated with White Blood Cell Phenotypes 
Nalls, Michael A. | Couper, David J. | Tanaka, Toshiko | van Rooij, Frank J. A. | Chen, Ming-Huei | Smith, Albert V. | Toniolo, Daniela | Zakai, Neil A. | Yang, Qiong | Greinacher, Andreas | Wood, Andrew R. | Garcia, Melissa | Gasparini, Paolo | Liu, Yongmei | Lumley, Thomas | Folsom, Aaron R. | Reiner, Alex P. | Gieger, Christian | Lagou, Vasiliki | Felix, Janine F. | Völzke, Henry | Gouskova, Natalia A. | Biffi, Alessandro | Döring, Angela | Völker, Uwe | Chong, Sean | Wiggins, Kerri L. | Rendon, Augusto | Dehghan, Abbas | Moore, Matt | Taylor, Kent | Wilson, James G. | Lettre, Guillaume | Hofman, Albert | Bis, Joshua C. | Pirastu, Nicola | Fox, Caroline S. | Meisinger, Christa | Sambrook, Jennifer | Arepalli, Sampath | Nauck, Matthias | Prokisch, Holger | Stephens, Jonathan | Glazer, Nicole L. | Cupples, L. Adrienne | Okada, Yukinori | Takahashi, Atsushi | Kamatani, Yoichiro | Matsuda, Koichi | Tsunoda, Tatsuhiko | Tanaka, Toshihiro | Kubo, Michiaki | Nakamura, Yusuke | Yamamoto, Kazuhiko | Kamatani, Naoyuki | Stumvoll, Michael | Tönjes, Anke | Prokopenko, Inga | Illig, Thomas | Patel, Kushang V. | Garner, Stephen F. | Kuhnel, Brigitte | Mangino, Massimo | Oostra, Ben A. | Thein, Swee Lay | Coresh, Josef | Wichmann, H.-Erich | Menzel, Stephan | Lin, JingPing | Pistis, Giorgio | Uitterlinden, André G. | Spector, Tim D. | Teumer, Alexander | Eiriksdottir, Gudny | Gudnason, Vilmundur | Bandinelli, Stefania | Frayling, Timothy M. | Chakravarti, Aravinda | van Duijn, Cornelia M. | Melzer, David | Ouwehand, Willem H. | Levy, Daniel | Boerwinkle, Eric | Singleton, Andrew B. | Hernandez, Dena G. | Longo, Dan L. | Soranzo, Nicole | Witteman, Jacqueline C. M. | Psaty, Bruce M. | Ferrucci, Luigi | Harris, Tamara B. | O'Donnell, Christopher J. | Ganesh, Santhi K.
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
Epidemiological studies have linked environmental arsenic (As) exposure to increased type 2 diabetes risk. Periconceptional hyperglycemia is a significant risk factor for neural tube defects (NTDs), the second most common structural birth defect. A suspected teratogen, arsenic (As) induces NTDs in laboratory animals.
We investigated whether maternal glucose homeostasis disruption was responsible for arsenate-induced NTDs in a well-established dosing regimen used in studies of arsenic’s teratogenicity in early neurodevelopment.
We evaluated maternal intraperitoneal (I.P.) exposure to As 9.6 mg/kg (as sodium arsenate) in LM/Bc/Fnn mice for teratogenicity and disruption of maternal plasma glucose and insulin levels. Selected compounds (insulin pellet, sodium selenate (SS), N-acetyl cysteine (NAC), L-methionine (L-Met), N-tert-Butyl-α-phenylnitrone (PBN)) were investigated for their potential to mitigate arsenate’s effects.
Arsenate caused significant glucose elevation during an I.P. glucose tolerance test (IPGTT). Insulin levels were not different between arsenate and control dams before (arsenate, 0.55 ng/dl; control, 0.48 ng/dl) or after glucose challenge (arsenate, 1.09 ng/dl; control, 0.81 ng/dl). HOMA-IR index was higher for arsenate (3.9) vs control (2.5) dams (p=0.0260). Arsenate caused NTDs (100%, p<0.0001). Insulin pellet and NAC were the most successful rescue agents, reducing NTD rates to 45% and 35%.
IPGTT, insulin assay, and HOMA-IR results suggest a modest failure of glucose stimulated insulin secretion and insulin resistance characteristic of glucose intolerance. Insulin’s success in preventing arsenate-induced NTDs provides evidence that these arsenate-induced NTDs are secondary to elevated maternal glucose. The NAC rescue, which did not restore maternal glucose or insulin levels, suggests oxidative disruption plays a role.
PMCID: PMC3998373  PMID: 19446573
arsenate; arsenic; glucose intolerance; insulin resistance; mouse; neural tube defect; oxidative stress; teratogen
15.  Elevated White Blood Cell Count Is Associated with Higher Risk of Glucose Metabolism Disorders in Middle-Aged and Elderly Chinese People 
White blood cell (WBC) count has been associated with diabetic risk, but whether the correlation is independent of other risk factors has hardly been studied. Moreover, very few such studies with large sample sizes have been conducted in Chinese. Therefore, we investigated the relationship between WBC count and glucose metabolism in china. We also examined the relevant variables of WBC count. A total of 9,697 subjects (mean age, 58.0 ± 9.1 years) were recruited. The subjects were classified into four groups, including subjects with normal glucose tolerance, isolated impaired fasting glucose, impaired glucose tolerance and type 2 diabetes mellitus (T2DM). We found that WBC count increased as glucose metabolism disorders exacerbated. WBC count was also positively correlated with waist hip ratio, body mass index, smoking, triglycerides, glycosylated haemoglobin A1c (HbA1c) and 2-h postprandial glucose. In addition, high density lipoprotein and the female gender were inversely correlated with WBC levels. In patients with previously diagnosed T2DM, the course of T2DM was not correlated with WBC count. Our findings indicate that elevated WBC count is independently associated with worsening of glucose metabolism in middle-aged and elderly Chinese. In addition, loss of weight, smoking cessation, lipid-modifying therapies, and control of postprandial plasma glucose and HbA1c may ameliorate the chronic low-grade inflammation.
PMCID: PMC4053882  PMID: 24852600
white blood cell; diabetes mellitus, type 2; glucose metabolism disorders; inflammation; glycosylated hemoglobin A1c
16.  Systemic inflammation in 222.841 healthy employed smokers and nonsmokers: white blood cell count and relationship to spirometry 
Tobacco Induced Diseases  2012;10(1):7.
Smoking has been linked to low-grade systemic inflammation, a known risk factor for disease. This state is reflected in elevated white blood cell (WBC) count.
We analyzed the relationship between WBC count and smoking in healthy men and women across several age ranges who underwent preventive medical check-ups in the workplace. We also analysed the relationship between smoking and lung function.
Cross-sectional descriptive study in 163 459 men and 59 382 women aged between 16 and 70 years. Data analysed were smoking status, WBC count, and spirometry readings.
Total WBC showed higher counts in both male and female smokers, around 1000 to 1300 cell/ml (t test, P < 0.001). Forced expiratory volume in 1 second (FEV1%) was higher in nonsmokers for both sexes between 25 to 54 years (t test, P < 0.001). Analysis of covariance showed a multiple variable effect of age, sex, smoking status, body mass index on WBC count. The relationship between WBC blood count and smoking status was confirmed after the sample was stratified for these variables. Smokers with airway obstruction measured by FEV1% were found to have higher WBC counts, in comparison to smokers with a normal FEV1% among similar age and BMI groups.
Smoking increases WBC count and affects lung function. The effects are evident across a wide age range, underlining the importance of initiating preventive measures as soon as an individual begins to smoke.
PMCID: PMC3419079  PMID: 22613769
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.  A routine biomarker-based risk prediction model for metabolic syndrome in urban Han Chinese population 
BMC Public Health  2015;15:64.
Many MetS related biomarkers had been discovered, which provided the possibility for building the MetS prediction model. In this paper we aimed to develop a novel routine biomarker-based risk prediction model for MetS in urban Han Chinese population.
Exploring Factor analysis (EFA) was firstly conducted in MetS positive 13,345 males and 3,212 females respectively for extracting synthetic latent predictors (SLPs) from 11 routine biomarkers. Then, depending on the cohort with 5 years follow-up in 1,565 subjects (male 1,020 and female 545), a Cox model for predicting 5 years MetS was built by using SLPs as predictor; Area under the ROC curves (AUC) with 10 fold cross validation was used to evaluate its power. Absolute risk (AR) and relative absolute risk (RAR) were calculated to develop a risk matrix for visualization of risk assessment.
Six SLPs were extracted by EFA from 11 routine health check-up biomarkers. Each of them reflected the specific pathogenesis of MetS, with inflammatory factor (IF) contributed by WBC & LC & NGC, erythrocyte parameter factor (EPF) by Hb & HCT, blood pressure factor (BPF) by SBP & DBP, lipid metabolism factor (LMF) by TG & HDL-C, obesity condition factor (OCF) by BMI, and glucose metabolism factor (GMF) by FBG with the total contribution of 81.55% and 79.65% for males and females respectively. The proposed metabolic syndrome synthetic predictor (MSP) based predict model demonstrated good performance for predicting 5 years MetS with the AUC of 0.802 (95% CI 0.776-0.826) in males and 0.902 (95% CI 0.874-0.925) in females respectively, even after 10 fold cross validation, AUC was still enough high with 0.796 (95% CI 0.770-0.821) in males and 0.897 (95% CI 0.868-0.921) in females. More importantly, the MSP based risk matrix with a series of risk warning index provided a feasible and practical tool for visualization of risk assessment in the prediction of MetS.
MetS could be explained by six SLPs in Chinese urban Han population. The proposed MSP based predict model demonstrated good performance for predicting 5 years MetS, and the MetS-based matrix provided a feasible and practical tool.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1424-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4320489  PMID: 25637138
Metabolic Syndrome (MetS); Routine biomarkers; Predictor model; Risk matrix
19.  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
20.  Worksite health screening programs for predicting the development of Metabolic Syndrome in middle-aged employees: a five-year follow-up study 
BMC Public Health  2010;10:747.
Metabolic syndrome (MetS) management programs conventionally focus on the adults having MetS. However, risk assessment for MetS development is also important for many adults potentially at risk but do not yet fulfill MetS criteria at screening. Therefore, we conducted this follow-up study to explore whether initial screening records can be efficiently applied on the prediction of the MetS occurrence in healthy middle-aged employees.
Utilizing health examination data, a five-year follow-up observational study was conducted for 1384 middle-aged Taiwanese employees not fulfilling MetS criteria. Data analyzed included: gender, age, MetS components, uric acid, insulin, liver enzymes, sonographic fatty liver, hepatovirus infections and lifestyle factors. Multivariate logistic regression was used to estimate the adjusted odds ratios (OR) and 95% confidence interval (CI) of risk for MetS development. The synergistic index (SI) values and their confidence intervals of risk factor combinations were calculated; and were used to estimate the interacting effects of coupling MetS components on MetS development.
Within five years, 13% (175 out of 1384) participants fulfilled MetS criteria. The ORs for MetS development among adults initially having one or two MetS components were 2.8 and 7.3, respectively (both p < 0.01), versus the adults having zero MetS component count at screening. Central obesity carried an OR of 7.5 (p < 0.01), which far exceeded other risk factors (all ORs < 2.7). Synergistic effects on MetS development existed between coupling MetS components: 1. High blood pressure plus low-HDL demonstrated an OR of 11.7 (p < 0.01) for MetS development and an SI of 4.7 (95% CI, 2.1-10.9). 2. High blood pressure plus hyperglycemia had an OR of 7.9 (p < 0.01), and an SI of 2.7 (95% CI, 1.2-6.4).
MetS component count and combination can be used in predicting MetS development for participants potentially at risk. Worksite MetS screening programs simultaneously allow for finding out cases and for assessing risk of MetS development.
PMCID: PMC3003648  PMID: 21126351
21.  White Blood Cell Count Measured Prior to Cancer Development Is Associated with Future Risk of Venous Thromboembolism – The Tromsø Study 
PLoS ONE  2013;8(9):e73447.
Elevated white blood cell (WBC) count is associated with risk of venous thromboembolism (VTE) in cancer patients initiating chemotherapy. It is not known whether the risk of VTE by WBC count in cancer patients is causal or merely a consequence of the malignant disease. To address this question, we studied the association between WBC count, measured prior to cancer development, and risk of VTE in subjects who did and did not develop cancer during follow-up in a prospective population-based study.
Baseline characteristics, including WBC and neutrophil counts, were measured in 24304 initially cancer-free subjects who participated in the Tromsø Study in 1994-1995. Incident cancer diagnosis and VTE events were registered up to September 1, 2007. In the cancer cohort, WBC and neutrophil counts were measured in average 7.1 years before cancer development. Cox-regression models were used to calculate hazard ratios (HRs) for VTE by WBC and neutrophil counts as categorized variables (<40th, 40-80th, and >80th percentile) with 95% confidence intervals (CIs).
During follow-up, 1720 subjects developed cancer and there were 388 VTE events, of which 116 occurred in the cancer-group (6.9 per 1000 person-years) and 272 in the cancer-free group (1.1 per 1000 person-years). In those who developed cancer, WBC count above the 80th percentile (≥8.6x109 cells/L) was associated with a 2.4-fold higher risk (HR 2.36, 95% CI: 1.44-3.87) of VTE compared to WBC count below the 40th percentile (<6.4x109 cells/L). No association was found between WBC count and VTE in those who stayed cancer-free (HR 0.94, 95% CI 0.65-1.36). Similar findings were observed for neutrophils.
Pre-cancer WBC count was associated with risk of VTE in cancer patients, but not in cancer-free subjects. Our findings suggest that leukocytes may play a causal role in cancer-related VTE rather than only reflecting the low-grade inflammation associated with cancer.
PMCID: PMC3762748  PMID: 24023876
22.  Total and Differential White Blood Cell Counts Predict Eight-Year Incident Stoke in Elderly Japanese-American Men: The Honolulu Heart Program 
Previous studies have found that a higher white blood cell (WBC) count is associated with incident stroke. There have been few studies examining differential WBC counts in elderly or Asian populations. We studied the association between total and differential WBC counts and incident stroke in an older Asian population.
The Honolulu Heart Program is a prospective population-based study of cardiovascular diseases in Japanese-American men that started in 1965. At exam 4 (1991–93), 3,741 men ages 71–93 years participated, and total and differential WBC counts were measured in 3,569 men using a Coulter counter machine. Data on incident stroke (all strokes [ALL-CVA], thromboembolic [TE-CVA] and hemorrhagic [HEM-CVA]) were available through December 1999 (8 years follow-up) from a comprehensive hospital surveillance system. After excluding 227 subjects with prevalent stroke, 3,342 subjects were divided into quartiles of total WBC, neutrophil (segmented and band), granulocyte (neutrophil, eosinophil and basophil), lymphocyte, and monocyte counts for separate analyses.
Age-adjusted incident ALL-CVA rates increased significantly with total WBC quartiles (7.68, 9.04, 9.26, 14.1, per 1,000 person years follow-up, respectively, P = .0014). Relative risks for ALL-CVA for each quartile of total and differential WBC counts were obtained using Cox proportional hazards, using the lowest quartile as the reference group. After full adjustment including age, cardiovascular risk factors, fibrinogen, prevalent CHD, cancer or COPD, and aspirin/NSAID use, the relative risks in the highest quartiles of total WBC, neutrophil, and granulocyte counts were 1.63 (95%CI = 1.05–2.54, P = .03), 2.19 (95%CI = 1.41–3.39, P < .001) and 1.91 (95%CI = 1.25–2.92, P = .003), respectively. These significant associations were also seen for TE-CVA, but not for HEM-CVA. No significant associations were found between lymphocyte or monocyte counts and incident stroke or subtypes.
In elderly Japanese-American men, higher total WBC, neutrophil, and granulocyte counts were independent predictors of overall stroke, as well as thromboembolic stroke. Further studies are needed to establish cut-points and treatment options.
PMCID: PMC4175930
23.  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
24.  Insulin-Related Biomarkers to Predict the Risk of Metabolic Syndrome 
The predictive ability of insulin resistance or insulin sensitivity, in combination with traditional cardiovascular risk factors for metabolic syndrome (MetS), has not yet been clearly evaluated in Japanese male subjects.
A one-year follow-up study was conducted to determine the ability of the insulin-related biomarkers to predict the risk of MetS development.
Patients and Methods:
A total of 2642 male workers of a Japanese company free from MetS at the baseline were monitored. The homeostasis model assessment for insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index (QUICKI) were selected as the insulin-related markers.
The incidence of metabolic syndrome after one year was 8.8%. A multiple logistic regression analysis identified regular physical activity, age (≥ 45 years old), serum uric acid (≥ 7 mg/dL), serum alanine aminotransferase (≥ 45 IU/L), serum C-reactive protein (≥ 0.1 mg/L) and HOMA-IR (≥ 2.5) as significant risk factors for the development of MetS, with odds ratios (95% confidence intervals) of 0.68 (0.50 – 0.92), 2.0 (1.5 – 2.6), 2.2 (1.6 – 3.0), 1.5 (1.02 – 2.2), 1.4 (1.01 – 2.0), and 2.3 (1.6 – 3.3), respectively. When QUICKI was used instead of HOMA-IR, age (≥ 45 years old), serum uric acid (≥ 7 mg/dL), serum gamma-glutamyl transferase (≥ 50 IU/L), and QUICKI (≤ 0.33) were identified as significant contributors to the risk of MetS, with odds ratios (95% confidence intervals) of 0.68 (0.51 – 0.93), 2.0 (1.5 – 2.6), 2.2 (1.6 – 3.0), 1.4 (1.01 – 2.0), and 2.5 (1.7 – 3.6), respectively.
The mathematical meaning of the two insulin-related biomarkers examined was the same, and the odds ratios of the two biomarkers were almost the same after adjustments for other independent variables.
PMCID: PMC3969000  PMID: 24719625
Insulin Resistance; Biomarkers; Metabolic Syndrome X; Aging
25.  Association of chronic periodontitis with white blood cell and platelet count – A Case Control Study 
Objectives:The objective of the study was to determine whether plasma levels of white blood corpuscles (WBCs) and platelets were altered in patients with chronic periodontitis compared to healthy controls. Study Design:A total of 120 subjects, 60 with chronic periodontitis and 60 with healthy periodontium of age group 30-50 years were selected for the study. Oral hygiene status and pocket probing depth were measured. During clinical evaluation, venous blood samples were taken to analyze the WBC and platelet counts. Statistical analysis was utilized to compare differences across various groups. Results:The WBC count was higher in patients with chronic periodontitis when compared with controls whereas the platelet count was lower in the case group. Conclusions:Elevated WBC count plays a key role in chronic periodontitis and in turn a risk factor for cardiovascular diseases. However, there is no significant role of platelets in periodontal infection even though it has a major role in atherogenesis.
Key words:Periodontitis, white blood cells, platelets, cardiovascular diseases.
PMCID: PMC4134847  PMID: 25136419

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