Inflammation, kidney function and albuminuria in the Framingham Offspring cohort.

BACKGROUND: Inflammation and chronic kidney disease (CKD) are both associated with cardiovascular disease (CVD). Whether inflammatory biomarkers are associated with kidney function and albuminuria after accounting for traditional CVD risk factors is not completely understood. METHODS: The sample comprised Framingham Offspring cohort participants (n = 3294, mean age 61, 53% women) who attended the seventh examination cycle (1998-2001). Inflammatory biomarkers [C-reactive protein (CRP), tumour necrosis factor (TNF)-alpha, interleukin-6, TNF receptor 2 (TNFR2), intercellular adhesion molecule-1 (ICAM-1), monocyte chemoattractant protein-1 (MCP-1), P-selectin, CD-40 ligand, osteoprotegerin, urinary isoprostanes, myeloperoxidase and fibrinogen] were measured on fasting blood samples. Serum creatinine-based estimated glomerular filtration rate (eGFR) and serum cystatin C concentration were used to assess kidney function. Urinary albumin-to-creatinine ratio (UACR) was used to assess albuminuria. Linear or logistic regression was used to test associations between biomarkers and kidney measures. RESULTS: Chronic kidney disease (CKD), defined as eGFR < 59/64 mL/min/1.73 m(2) in women/men, was present in 8.8% (n = 291) of participants. TNF-alpha, interleukin-6, TNFR2, MCP-1, osteoprotegerin, myeloperoxidase and fibrinogen were higher among individuals with CKD; all biomarkers except for urinary isoprostanes were elevated in higher cystatin C quartiles; and TNF-alpha, interleukin-6, TNFR2, ICAM-1 and osteoprotegerin were elevated in higher UACR quartiles-all assessed after multivariable adjustment. Almost 6% and 17% of variability in TNFR2 were explained by CKD status and higher cystatin C quartiles, respectively. CONCLUSIONS: Biomarkers of inflammation are associated with kidney function and albuminuria. In particular, substantial variability in soluble TNFR2 is explained by CKD and cystatin C.

Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality.

OBJECTIVE: Experimental evidence identified the osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB (RANK)/RANK ligand (RANKL) pathway as a candidate system modulating vascular remodeling and cardiovascular disease (CVD). METHODS AND RESULTS: Serum concentrations of OPG and RANKL were measured in 3250 Framingham Study participants (54% women, 61+/-9 years). During a mean follow-up of 4.6 years, 143 (of 3084 free of CVD at baseline) participants developed a first CVD event, and 235 died. In multivariable models, OPG was associated with increased hazards for incident CVD and mortality (hazard ratio, 1.27; 95% CI, 1.04 to 1.54; and hazard ratio, 1.25; 95% CI, 1.07 to 1.47, per 1-SD increment in log-OPG, respectively). Log-OPG was positively related to multiple CVD risk factors, including age, smoking, diabetes, systolic blood pressure, and prevalent CVD. In a subsample (n=1264), the prevalence of coronary artery calcification, measured by computed tomography, increased nonsignificantly with OPG quartiles. RANKL concentrations displayed inverse associations with multiple CVD risk factors, including smoking, diabetes, and antihypertensive treatment, and were not related to coronary artery calcification or incident CVD or mortality. CONCLUSIONS: Our prospective data reinforce OPG as marker for CVD risk factor burden and predictor for CVD and mortality in the community.

Visceral and subcutaneous adipose tissue volumes are cross-sectionally related to markers of inflammation and oxidative stress: the Framingham Heart Study.

BACKGROUND: Excess adiposity is associated with greater systemic inflammation. Whether visceral adiposity is more proinflammatory than subcutaneous abdominal adiposity is unclear. METHODS AND RESULTS: We examined the relations of abdominal subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), assessed by multidetector computerized tomography, to circulating inflammatory and oxidative stress biomarkers in 1250 Framingham Heart Study participants (52% women; age 60+/-9 years). Biomarkers were examined in relation to increments of SAT and VAT after adjustment for age, sex, smoking, physical activity, menopause, hormone replacement therapy, alcohol, and aspirin use; additional models included body mass index and waist circumference. SAT and VAT were positively and similarly (with respect to strength of association) related to C-reactive protein, fibrinogen, intercellular adhesion molecule-1, interleukin-6, P-selectin, and tumor necrosis factor receptor-2 (multivariable model R2 0.06 to 0.28 [SAT] and 0.07 to 0.29 [VAT]). However, compared with SAT, VAT was more highly associated with urinary isoprostanes and monocyte chemoattractant protein-1 (SAT versus VAT comparison: isoprostanes, R2 0.07 versus 0.10, P=0.002; monocyte chemoattractant protein-1, R2 0.07 versus 0.08, P=0.04). When body mass index and waist circumference were added to the models, VAT remained significantly associated with only C-reactive protein (P=0.0003 for women; P=0.006 for men), interleukin-6 (P=0.01), isoprostanes (P=0.0002), and monocyte chemoattractant protein-1 (P=0.008); SAT only remained associated with fibrinogen (P=0.01). CONCLUSIONS: The present cross-sectional data support an association between both SAT and VAT with inflammation and oxidative stress. The data suggest that the contribution of visceral fat to inflammation may not be completely accounted for by clinical measures of obesity (body mass index and waist circumference).

Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample.

CONTEXT: The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown. OBJECTIVE: The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample. DESIGN, SETTING, AND PARTICIPANTS: We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort. MAIN OUTCOME MEASURES: Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured. RESULTS: Ghrelin and leptin concentrations were significantly higher in women (P < 0.0001). In multivariable models, ghrelin was inversely associated with age and systolic blood pressure, and leptin was positively related to body mass index and WC. sOB-R was positively associated with age, total cholesterol, and fasting glucose and inversely with WC and high-density lipoprotein cholesterol. Ghrelin and sOB-R concentrations were significantly lower with number of MetS components (P for trend = 0.022 and < 0.0001, respectively), whereas leptin concentrations were higher (P for trend = 0.0001). Relating all adipokines to MetS conjointly, higher ghrelin and leptin concentrations were associated with decreased and increased odds of MetS (odds ratio 0.55, P < 0.0001; odds ratio 4.44, P = 0.0002, per 1 sd increase of respective log adipokine). CONCLUSIONS: In our community-based sample, we observed a sexual dimorphism in circulating ghrelin and leptin concentrations. Ghrelin, leptin, and sOB-R were associated with number of MetS components cross-sectionally, consistent with the hypothesis that these adipokines may have a central role in cardiometabolic risk.

Clinical correlates, heritability, and genetic linkage of circulating CD40 ligand in the Framingham Offspring Study.

BACKGROUND: The CD40 receptor and its ligand (CD40L) are known to modulate both inflammation and thrombosis-2 processes important for the development and clinical expression of atherosclerosis. Circulating soluble CD40L (sCD40L) concentration predicts cardiovascular risk in selected patient samples. The purpose of this study was to determine the predictors of sCD40L in a large, community-based sample. METHODS: We determined both serum and plasma sCD40L concentration in 3,259 participants (54% women) from the Framingham Offspring Study. RESULTS: In multivariable models, advancing age was the only consistent (inverse) correlate of both serum and plasma sCD40L concentration. Overall, the variability explained by clinical covariates was very low for both measurements of sCD40L; with values of only 1.4% and 2.7% for serum and plasma, respectively. We observed that genetic factors accounted for a modest (12% serum; 14% plasma) amount of the adjusted variability in sCD40L. CONCLUSIONS: Circulating sCD40L concentration was poorly associated with known cardiovascular disease (CVD) risk factors and was modestly heritable. Determining if either serum or plasma sCD40L are predictive of CVD risk in the community will require longitudinal follow-up.

Systemic inflammation and COPD: the Framingham Heart Study.

BACKGROUND: The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking. METHODS: Using data from the Framingham Heart Study, we examined cross-sectional associations of systemic inflammatory biomarkers (CD40 ligand [CD40L], intercellular adhesion molecule [ICAM]-1, interleukin [IL]-6, monocyte chemoattractant protein-1, P-selectin, and myeloperoxidase, in addition to C-reactive protein) to impaired lung function. RESULTS: IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], - 61 to - 20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, - 37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories. CONCLUSIONS: Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.

Association of multiple inflammatory markers with carotid intimal medial thickness and stenosis (from the Framingham Heart Study).

Inflammatory markers, particularly C-reactive protein (CRP), predict incident cardiovascular disease and are associated with the presence of subclinical atherosclerosis. The relations between multiple inflammatory markers and direct measures of atherosclerosis are less well established. Participants in the Offspring Cohort of the Framingham Heart Study (n = 2,885, 53% women, mean age 59 years) received routine assessments of common carotid artery intima-media thickness (CCA-IMT), internal carotid artery intima-media thickness (ICA-IMT), and the presence or absence of > or =25% carotid stenosis by ultrasonography. Circulating inflammatory markers assessed from an examination 4 years later included CRP, interleukin-6 (IL-6), intercellular adhesion molecule-1, monocyte chemoattractant protein-1, P-selectin, and CD40 ligand. Assessed as a group, inflammatory markers were significantly associated with ICA-IMT (p = 0.01), marginally with carotid stenosis (p = 0.08), but not with CCA-IMT. Individually, with an increase from the 25th to 75th percentile in IL-6, there were significant increases in ICA-IMT and carotid stenosis (for ICA-IMT, estimated fold increase 1.04, 95% confidence interval 1.03 to 1.06, p = 0.0004; for carotid stenosis, odds ratio 1.25, 95% confidence interval 1.06 to 1.47, p = 0.007) after adjustment for age, gender, and established risk factors for atherosclerosis. There was a similar significant multivariate-adjusted association of CRP with ICA-IMT but not with carotid stenosis. Smoking appeared to modify the associations of ICA-IMT with CRP (p = 0.009) and with IL-6 (p = 0.006); the association was more pronounced in current (vs former or never) smokers. In conclusion, there were modest associations of inflammatory markers, particularly IL-6, with carotid atherosclerosis. This association appears more pronounced in current smokers than in former smokers and nonsmokers.

Brachial artery vasodilator function and systemic inflammation in the Framingham Offspring Study.

BACKGROUND: In experimental studies, traditional risk factors and proinflammatory processes alter the regulatory functions of the vascular endothelium to promote atherosclerosis. These alterations include expression of leukocyte adhesion molecules and decreased bioavailability of endothelium-derived nitric oxide, an important regulator of vascular homeostasis and tone. The precise relations among risk factors, inflammation, and nitric oxide bioavailability remain uncertain. METHODS AND RESULTS: To test the hypothesis that inflammation impairs endothelial function in humans, we measured brachial artery flow-mediated dilation, reactive hyperemia, and serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), soluble intracellular adhesion molecule-1 (sICAM-1), and monocyte chemotactic protein-1 (MCP-1) in 2701 participants from the Framingham Study (mean age 61 years, 53% women). There were modest unadjusted inverse correlations between flow-mediated dilation and CRP, IL-6, and sICAM-1 (P<0.001 for all) that were rendered nonsignificant after accounting for traditional coronary risk factors. For reactive hyperemia, we observed inverse correlations with markers of inflammation in unadjusted models that were attenuated 57% to 74% after accounting for risk factors. However, partial correlations of CRP, IL-6, and sICAM-1 with reactive hyperemia remained significant. CONCLUSIONS: Our observations are consistent with the hypothesis that risk factors induce a state of inflammation that impairs vascular function. For flow-mediated dilation, we found no evidence that inflammation has additional effects beyond those attributable to traditional risk factors. The incremental contribution of CRP, IL-6, and sICAM-1 to reactive hyperemia above and beyond known risk factors suggests that systemic inflammation may contribute to impaired vasomotor function in forearm microvessels.

Effects of physiological leptin administration on markers of inflammation, platelet activation, and platelet aggregation during caloric deprivation.

CONTEXT: Leptin is a nutritionally regulated adipocyte-derived cytokine. Previous studies in obese patients have demonstrated increased inflammatory markers and increased platelet aggregation in association with leptin. However, the effects of leptin administration on markers of inflammation and platelet aggregation in a human model of undernutrition have not previously been studied. OBJECTIVE: The objective of the study was to investigate markers of inflammation, platelet activation, and platelet aggregation in a model of caloric deprivation and increased leptin sensitivity. DESIGN: This study was a randomized, placebo-controlled study conducted between November 2002 and November 2003. SETTING: The study was conducted at an inpatient care setting at the General Clinical Research Center. PARTICIPANTS: Twenty healthy, young (18-35 yr old), normal-weight (body mass index, 20-26 kg/m2) women were recruited from local advertisements. No subjects withdrew due to adverse effects. INTERVENTION: The effects of physiological recombinant methionyl human leptin or identical placebo administration were investigated over a 4-d fast. MAIN OUTCOME MEASURES: The primary outcome measures for this study were C-reactive protein (CRP) and indices of platelet activity. RESULTS: Leptin administration prevented the fasting-induced decline in leptin (P < 0.05 vs. placebo at each time point). Leptin administration increased CRP (6.3 +/- 2.4 vs. 0.7 +/- 0.3 mg/liter; P = 0.04), circulating P-selectin (11.6 +/- 10.2 vs. -28.9 +/- 15.6 ng/ml; P = 0.04), and induction of platelet aggregation (5.8 +/- 2.6 vs. -2.7 +/- 2.9%, P = 0.04, percent maximum platelet aggregation) relative to placebo administration (change in leptin vs. change in placebo, respectively, for each variable). Leptin tended to increase serum amyloid A [0.1 +/- 0.2 vs. -0.3 +/- 0.1 log10 (ng/ml); P = 0.07], and the changes in serum amyloid A and CRP were highly correlated (r = 0.83; P < 0.0001). No changes in TNFalpha, IL-6, IL-10, plasminogen activator inhibitor-1, haptoglobin, intercellular adhesion molecule, or vascular cell adhesion molecule were seen between the groups. CONCLUSIONS: Our data provide evidence that physiological leptin administration stimulates inflammatory and platelet responses in humans during caloric deprivation.

Heritability and correlates of intercellular adhesion molecule-1 in the Framingham Offspring Study.

OBJECTIVES: We sought to determine the clinical factors and heritability associated with inflammation measured as circulating levels of soluble-intercellular adhesion molecule-1 (sICAM-1) in a community-based cohort. BACKGROUND: Several prospective studies indicate that circulating sICAM-1 is predictive of future cardiovascular events. However, in some studies this predictive value is lost after multivariable adjustment for traditional cardiovascular disease (CVD) risk factors. We addressed the heritability of sICAM-1 and its relation to CVD risk factors in a community-based cohort. METHODS: We examined 3,295 subjects from the Framingham Heart Study and measured sICAM-1 levels. We then used linear and stepwise multivariable regression to determine predictors or sICAM-1 levels. RESULTS: In age- and gender-adjusted regression models, increased sICAM-1 levels were positively associated with age, total/high-density lipoprotein cholesterol, systolic blood pressure, body mass index (BMI), blood glucose, diabetes, smoking, and prevalent CVD. In stepwise multivariable regression models, sICAM-1 levels remained associated with age, female gender, total/high-density lipoprotein cholesterol ratio, BMI, blood glucose, smoking, and prevalent CVD. The residual heritability of sICAM-1 was 24%. CONCLUSIONS: In addition to prevalent CVD, established CVD risk factors and non-traditional ones such as BMI were associated with systemic inflammation as determined by sICAM-1 levels. There also is significant heritability of sICAM-1, which suggests a genetic component to systemic inflammation.

Genome scan of systemic biomarkers of vascular inflammation in the Framingham Heart Study: evidence for susceptibility loci on 1q.

Vascular inflammation plays a central role in atherosclerosis and inflammatory biomarkers predict risk of cardiovascular disease (CVD). Thus, finding genes that influence systemic levels of inflammatory biomarkers may provide insights into genetic determinants of vascular inflammation and CVD. We conducted variance-component linkage analyses of blood levels of four biomarkers of vascular inflammation [C-reactive protein (CRP), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), soluble intercellular adhesion molecule-1 (sICAM-1)] in 304 extended families from the Framingham Heart Study, using data from a 10cM genome scan. We computed p-values by a permutation approach. Heritability estimates ranged from 14% (IL-6) to 44% (MCP-1) after log transforming and adjusting for covariates. Significant linkage to MCP-1 was found on chromosome 1 (LOD=4.27 at 186cM; genome-wide p=0.005), in a region containing inflammatory candidate genes such as SELE, SELP (E- and P-selectin) and CRP. Other linkage peaks with LOD scores >2 were found for MCP-1 on chromosome 1 (LOD=2.04 at 16cM; LOD=2.34 at 70cM) and chromosome 17 (LOD=2.44 at 22cM) and for sICAM-1 on chromosome 1 at 229cM (LOD=2.09) less than 5cM from the interleukin-10 (IL10) gene. Multiple genes on chromosome 1 may influence inflammatory biomarker levels and may have a potential role in development of CVD.

Effect of medical and surgical weight loss on endothelial vasomotor function in obese patients.

We prospectively examined brachial artery endothelial function using vascular ultrasound in 41 obese subjects treated with medical or surgical (gastric bypass) weight loss interventions. Surgical intervention produced greater weight loss and more pronounced improvement in endothelial function than medical treatment alone. Improved endothelial function with weight loss correlated strongly with fasting glucose but not with alteration in blood pressure, lipids, degree of weight loss, or plasma resistin concentrations. These data demonstrate that weight loss in markedly obese patients improves endothelial function and glycemic control that may represent important mechanisms of the cardiovascular benefit associated with weight reduction.

Obesity and systemic oxidative stress: clinical correlates of oxidative stress in the Framingham Study.

OBJECTIVE: To determine the clinical conditions associated with systemic oxidative stress in a community-based cohort. Information regarding cardiovascular risk factors associated with systemic oxidative stress has largely been derived from highly selected samples with advanced stages of vascular disease. Thus, it has been difficult to evaluate the relative contribution of each cardiovascular risk factor to systemic oxidative stress and to determine whether such risk factors act independently and are applicable to the general population. METHODS AND RESULTS: We examined 2828 subjects from the Framingham Heart Study and measured urinary creatinine-indexed levels of 8-epi-PGF2alpha as a marker of systemic oxidative stress. Age- and sex-adjusted multivariable regression models were used to assess clinical correlates of oxidative stress. In age- and sex-adjusted models, increased urinary creatinine-indexed 8-epi-PGF2alpha levels were positively associated with female sex, hypertension treatment, smoking, diabetes, blood glucose, body mass index, and a history of cardiovascular disease. In contrast, age and total cholesterol were negatively correlated with urinary creatinine-indexed 8-epi-PGF2alpha levels. After adjustment for several covariates, decreasing age and total/HDL cholesterol ratio, sex, smoking, body mass index, blood glucose, and cardiovascular disease remained associated with urinary 8-epi-PGF2alpha levels. CONCLUSIONS: Smoking, diabetes, and body mass index were highly associated with systemic oxidative stress as determined by creatinine-indexed urinary 8-epi-PGF2alpha levels. The effect of body mass index was minimally affected by blood glucose, and diabetes and may suggest an important role of oxidative stress in the deleterious impact of obesity on cardiovascular disease.

Association between obesity and a prothrombotic state: the Framingham Offspring Study.

Although obesity is associated with increased cardiovascular risk, the mechanism has not been fully explained. Since thrombosis is a critical component of cardiovascular disease, we examined the relationship between obesity and hemostatic factors. We studied 3230 subjects (55% females, mean age 54 years) without a history of cardiovascular disease in cycle 5 of the Framingham Offspring Study. Obesity was assessed by body mass index and waist-to-hip ratio. Fasting blood samples were obtained for fibrinogen, plasminogen activator inhibitor (PAI-1) antigen, tissue plasminogen activator (tPA) antigen, factor VII antigen, von Willebrand factor (VWF), and plasma viscosity. Body mass index was directly associated with fibrinogen, factor VII, PAI-1 and tPA antigen in both men and women (p>0.001) and with VWF and viscosity in women. Similar associations were present between waist-to-hip ratio and the hemostatic factors. With minor exceptions for VWF and viscosity, all associations persisted after controlling for age, smoking, total and HDL cholesterol, triglycerides, glucose level, blood pressure, and use of antihypertensive medication. The association between increased body mass index and waist-to-hip ratio and prothrombotic factors and impaired fibrinolysis suggests that obesity is a risk factor whose effect is mediated in part by a prothrombotic state.

Pericardial fat volume correlates with inflammatory markers: the Framingham Heart Study.

The objective of this study was to determine whether systemic inflammatory and oxidative stress marker concentrations correlate with pericardial and intrathoracic fat volumes. Participants of the Framingham Offspring Study (n = 1,175, 53% women, mean age 59 +/- 9 years) had pericardial and intrathoracic fat volumes assessed by multidetector computed tomography (MDCT) scans, and provided fasting blood and urine samples to measure concentrations of 14 inflammatory markers: C-reactive protein (CRP), interleukin-6, monocyte chemoattractant protein-1 (MCP-1), CD40 ligand, fibrinogen, intracellular adhesion molecule-1, lipoprotein-associated phospholipase A(2) activity and mass, myeloperoxidase, osteoprotegerin, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor-2, and urinary isoprostanes. Multivariable linear regression models were used to determine the association of log-transformed inflammatory marker concentrations with fat volumes, using fat volume as the dependent variable. Due to smaller sample sizes, models were rerun after adding urinary isoprostanes (n = 961) and tumor necrosis factor-alpha (n = 813) to the marker panel. Upon backward elimination, four of the biomarkers correlated positively with each fat depot: CRP (P < 0.0001 for each fat depot), interleukin-6 (P < 0.05 for each fat depot), MCP-1 (P < 0.01 for each fat depot), and urinary isoprostanes (P < 0.01 for pericardial fat; P < 0.001 for intrathoracic fat). Even after adjusting for BMI, waist circumference (WC), and abdominal visceral fat, CRP (P = 0.0001) and urinary isoprostanes (P = 0.02) demonstrated significant positive associations with intrathoracic fat, but not with pericardial fat. Multiple markers of inflammation and oxidative stress correlated with pericardial and intrathoracic fat volumes, extending the known association between regional adiposity and inflammation and oxidative stress.

The relation of genetic and environmental factors to systemic inflammatory biomarker concentrations.

BACKGROUND: Environmental and genetic correlates of inflammatory marker variability are incompletely understood. In the family-based Framingham Heart Study, we investigated heritability and candidate gene associations of systemic inflammatory biomarkers. METHODS AND RESULTS: In offspring participants (n=3710), we examined 11 inflammatory biomarkers (CD40 ligand, C-reactive protein, intercellular adhesion molecule-1, interleukin-6, urinary isoprostanes, monocyte chemoattractant protein-1, myeloperoxidase, P-selectin, tumor necrosis factor-alpha, tumor necrosis factor receptor II, fibrinogen). Heritability and bivariate genetic and environmental correlations were assessed by Sequential Oligogenic Linkage Analysis routines in 1012 family members. We examined 1943 tagging single-nucleotide polymorphisms in 233 inflammatory pathway genes with >or=5 minor allele carriers using a general genetic linear model. Clinical correlates explained 2.4% (CD40 ligand) to 28.5% (C-reactive protein) of the variability in inflammatory biomarkers. Estimated heritability ranged from 10.9% (isoprostanes) to 44.8% (P-selectin). Most correlations between biomarkers were weak although statistically significant. A total of 45 single-nucleotide polymorphism-biomarker associations met the q-value threshold of 0.25. Novel top single-nucleotide polymorphisms were observed in ICAM1 gene in relation to intercellular adhesion molecule-1 concentrations (rs1799969, P=1.32 x 10(-8)) and MPO in relation to myeloperoxidase (rs28730837, P=1.9 x 10(-5)). Lowest P values for trans-acting single-nucleotide polymorphisms were observed for APCS with monocyte chemoattractant protein-1 concentrations (rs1374486, P=1.01 x 10(-7)) and confirmed for IL6R with interleukin-6 concentrations (rs8192284, P=3.36 x 10(-5)). Novel potential candidates (APCS, MPO) need to be replicated. CONCLUSIONS: Our community-based data support the relevance of clinical and genetic factors for explaining variation in inflammatory biomarker traits.

Relation of smoking status to a panel of inflammatory markers: the framingham offspring.

AIMS: We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation. METHODS AND RESULTS: We examined the relation of smoking to 11 systemic inflammatory markers in Framingham Study participants (n=2944, mean age 60 years, 55% women, 12% ethnic minorities) examined from 1998-2001. The cohort was divided into never (n=1149), former (n=1424), and current smokers with last cigarette >6h (n=134) or < or =6h (n=237) prior to phlebotomy. In multivariable-adjusted models there were significant overall between-smoking group differences (defined as p<0.0045 to account for multiple testing) for every inflammatory marker tested, except for serum CD40 ligand (CD40L), myeloperoxidase (MPO) and tumor necrosis factor receptor-2 (TNFR2). With multivariable-adjustment, pair-wise comparisons with never smokers revealed that former smokers had significantly lower concentrations of plasma CD40L (p<0.0001) and higher concentrations of (CRP) C-reactive protein (p=0.002). CONCLUSIONS: As opposed to never smokers, those with acute cigarette smoke exposure (< or =6h) had significantly higher concentrations of all markers (p<0.0001) except serum CD40L, MPO, and TNFR2; plasma CD40L were significantly lower. Compared with never smokers, cigarette smokers have significantly elevated concentrations of most circulating inflammatory markers, consistent with the hypothesis that smoking is associated with a systemic inflammatory state.

Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection.

Inflammation causes vascular dysfunction and perpetuates proatherosclerotic processes. We hypothesized that a broad panel of inflammatory biomarkers and single nucleotide polymorphisms in inflammatory genes is associated with vascular stiffness. We assessed 12 circulating inflammatory biomarkers (C-reactive protein, fibrinogen, interleukin-6, intercellular adhesion molecule-1, lipoprotein-associated phospholipase-A2 [mass and activity], monocyte chemoattractant protein-1, myeloperoxidase, CD40 ligand, osteoprotegerin, P-selectin, and tumor necrosis factor receptor-II) in relation to tonometry variables (central pulse pressure, mean arterial pressure, forward pressure wave, reflected pressure wave, carotid-femoral pulse wave velocity, and augmentation index) measured in 2409 Framingham Heart Study participants (mean age: 60 years; 55% women; 13% ethnic/racial minorities). Single nucleotide polymorphisms (n=2195) in 240 inflammatory candidate genes were related to tonometry measures in 1036 white individuals. In multivariable analyses, biomarkers explained <1% of any tonometry measure variance. Applying backward elimination, markers related to tonometry (P<0.01) were as follows: tumor necrosis factor receptor-II (inversely) with mean arterial pressure; C-reactive protein (positively) and lipoprotein-associated phospholipase-A2 (inversely) with reflected pressure wave; and interleukin-6 and osteoprotegerin (positively) with carotid-femoral pulse wave velocity. In genetic association analyses, lowest P values (false discovery rate <0.50) were observed for rs10509561 (FAS), P=6.6x10(-5) for central pulse pressure and rs11559271 (ITGB2), P=1.1x10(-4) for mean arterial pressure. These data demonstrate that, in a community-based sample, circulating inflammatory markers tumor necrosis factor receptor-II (mean arterial pressure), C-reactive protein, lipoprotein-associated phospholipase-A2 activity (reflected pressure wave), interleukin-6, and osteoprotegerin (carotid-femoral pulse wave velocity) were significantly but modestly associated with measures of arterial stiffness and wave reflection. Additional studies are needed to determine whether variation in inflammatory marker genes is associated with tonometry measures.

Alcohol consumption and platelet activation and aggregation among women and men: the Framingham Offspring Study.

BACKGROUND: Alcohol intake has been associated with lower platelet activity; however, few large-scale studies have included women, and to our knowledge, the relationship of alcohol intake with measures of platelet activation has not been studied. METHODS: We performed a cross-sectional analysis of adults free of cardiovascular disease enrolled in the Framingham Offspring Study. Study physicians assessed alcohol consumption with a standardized questionnaire. We measured platelet activation in response to 1 and 5 microm of adenosine diphosphate (ADP) with a P-selectin assay among 1037 participants and platelet aggregability in response to ADP, epinephrine, and collagen among 2013 participants. RESULTS: Alcohol consumption was inversely associated with P-selectin expression in response to 1 microm ADP (p = 0.007) and 5 microm ADP (p = 0.02) among men but not women. Alcohol consumption was also inversely associated with platelet aggregation induced by ADP among both women (p = 0.04) and men (p trend = 0.008) and by epinephrine among men (p = 0.03) CONCLUSIONS: Alcohol consumption is inversely associated with both platelet activation and aggregation, particularly in men. Additional research is needed to determine whether these findings contribute to the contrasting associations of alcohol consumption with risk of thrombotic and hemorrhagic cardiovascular events.