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1.  Candidate Genes for Respiratory Disease Associated with Markers of Inflammation and Endothelial Dysfunction in Elderly Men 
Atherosclerosis  2009;206(2):480-485.
Background
Inflammation and endothelial dysfunction are important risk factors for cardiovascular disease (CVD). We hypothesized that candidate genes selected for a study of asthma and chronic obstructive pulmonary disorder (COPD) are associated with markers of systemic inflammation and endothelial dysfunction in an aging population.
Methods
Plasma levels of circulating C-reactive protein (CRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were obtained from 679 elderly male participants in the Normative Aging Study. Blood samples were analyzed for 202 SNPs in 25 candidate genes and included both haplotype tagSNPs and functional SNPs based on literature review. Data were stratified into discovery and replication cohorts for 2-stage analysis. In the discovery cohort, the relationship between biomarker level and genotype was analyzed using linear mixed effects with random intercepts for each subject and models were adjusted for age and BMI. A positive outcome in the discovery cohort was defined as a p-value <0.1 for the SNP. SNPs that met this criterion were analyzed in the replication cohort and confirmed for those which met a criterion of significance (p<0.025).
Results
In our analyses, SNPs in the CRHR1, ITPR2, and VDR genes met criteria of significant effects.
Conclusions
Our results suggest that genes thought to play a role in the pathogenesis of asthma and COPD may influence levels of serum markers of inflammation and endothelial dysfunction via novel SNP associations which have not previously been associated with cardiovascular disease.
doi:10.1016/j.atherosclerosis.2009.03.004
PMCID: PMC2882878  PMID: 19409562
biomarkers; cardiovascular disease; SNPs; inflammation; endothelial dysfunction
2.  C‐reactive protein in patients with COPD, control smokers and non‐smokers 
Thorax  2005;61(1):23-28.
Background
Patients with chronic obstructive pulmonary disease (COPD) have raised serum levels of C reactive protein (CRP). This may be related directly to COPD and its associated systemic inflammation or secondary to other factors such as concomitant ischaemic heart disease (IHD) or smoking status. The aim of this study was to evaluate IHD and smoking as potential causes of raised CRP levels in COPD and to test the association between inhaled corticosteroid (ICS) use and serum CRP levels.
Methods
Cross sectional analyses comparing cohorts of 88 patients with COPD, 33 smokers (S), and 38 non‐smoker (NS) controls were performed. Clinical assessments included a complete medical history, pulmonary function, 6 minute walk test (6MWT), cardiopulmonary exercise test, and high sensitivity serum CRP measurements.
Results
Serum CRP levels were significantly higher in patients with COPD (5.03 (1.51) mg/l) than in controls (adjusted odds ratio 9.51; 95% confidence interval 2.97 to 30.45) but were similar in the two control groups (S: 2.02 (1.04) mg/l; NS: 2.24 (1.04) mg/l). There was no clinical or exercise evidence of unstable IHD in any of the subjects. CRP levels were lower in COPD patients treated with ICS than in those not treated (3.7 (3.0) mg/l v 6.3 (3.6) mg/l); this association was confirmed in an adjusted regression model (p<0.05).
Conclusion
CRP levels are raised in COPD patients without clinically relevant IHD and independent of cigarette smoking, and reduced in patients with COPD using ICS. CRP may be a systemic marker of the inflammatory process that occurs in patients with COPD.
doi:10.1136/thx.2005.042200
PMCID: PMC2080714  PMID: 16143583
C‐reactive protein; chronic obstructive pulmonary disease; ischaemic heart disease; smoking; inhaled corticosteroids; systemic inflammation; exercise capacity
3.  Raised CRP levels mark metabolic and functional impairment in advanced COPD 
Thorax  2005;61(1):17-22.
Background
C‐reactive protein (CRP) is often used as a clinical marker of acute systemic inflammation. Since low grade inflammation is evident in chronic diseases such as chronic obstructive pulmonary disease (COPD), new methods have been developed to enhance the sensitivity of CRP assays in the lower range. A study was undertaken to investigate the discriminative value of high sensitivity CRP in COPD with respect to markers of local and systemic impairment, disability, and handicap.
Methods
Plasma CRP levels, interleukin 6 (IL‐6) levels, body composition, resting energy expenditure (REE), exercise capacity, health status, and lung function were determined in 102 patients with clinically stable COPD (GOLD stage II–IV). The cut off point for normal versus raised CRP levels was 4.21 mg/l.
Results
CRP levels were raised in 48 of 102 patients. In these patients, IL‐6 (p<0.001) and REE (adjusted for fat‐free mass, p = 0.002) were higher while maximal (p = 0.040) and submaximal exercise capacity (p = 0.017) and 6 minute walking distance (p = 0.014) were lower. The SGRQ symptom score (p = 0.003) was lower in patients with raised CRP levels, as were post‐bronchodilator FEV1 (p = 0.031) and reversibility (p = 0.001). Regression analysis also showed that, when adjusted for FEV1, age and sex, CRP was a significant predictor for body mass index (p = 0.044) and fat mass index (p = 0.016).
Conclusions
High sensitivity CRP is a marker for impaired energy metabolism, functional capacity, and distress due to respiratory symptoms in COPD.
doi:10.1136/thx.2005.041996
PMCID: PMC2080712  PMID: 16055618
C‐reactive protein; chronic obstructive pulmonary disease; systemic inflammation; exercise capacity; health status; interleukin 6
4.  Chronic airflow obstruction and markers of systemic inflammation: Results from the BOLD study in Iceland 
Respiratory medicine  2009;103(10):1548-1553.
Summary
Background
Chronic obstructive pulmonary disease (COPD) is characterized by an irreversible chronic airflow obstruction and by an accelerated decline in lung function. Elevated circulating levels of C-reactive protein (CRP) and interleukin-6 (IL-6), both markers of systemic inflammation, have been found in COPD. Their possible associations with chronic airflow obstruction have mostly been evaluated in highly selected patient samples. Our objective was to evaluate the association between postbronchodilator lung function CRP and IL-6 in a randomly selected sample of the Icelandic population, 40 years and older, while adjusting for gender, age, smoking, and body weight.
Methods
Serum CRP and IL-6 values were measured among participants in the Burden of Obstructive Lung Disease (BOLD) study.
Results
Of the 938 subjects invited a total of 403 men and 355 women participated (response rate 81%) in the study. Their mean age (±SD) was 57.7 (±12.7) years. Both CRP and IL-6 were independently related to lower FEV1 and FVC values. Individuals in the highest quartiles of CRP and IL-6 had a 7.5% and 3.9%, respectively, lower FEV1% than predicted after adjustment for smoking, age, and body weight. High CRP levels were more strongly related to lower FEV1 levels in men (−11.4%) than in women ( −0.4%).
Conclusions
In a random population-based sample both CRP and IL-6 were significantly related to lower spirometric values. The association with CRP was stronger in men than in women. This finding underscores the possible importance of systemic inflammation in irreversible airflow limitation.
doi:10.1016/j.rmed.2009.04.005
PMCID: PMC3334275  PMID: 19427181
Airflow obstruction; Systemic inflammation; Cytokines; C-reactive protein; IL-6
5.  Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis 
Thorax  2004;59(7):574-580.
Background: Individuals with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular diseases, osteoporosis, and muscle wasting. Systemic inflammation may be involved in the pathogenesis of these disorders. A study was undertaken to determine whether systemic inflammation is present in stable COPD.
Methods: A systematic review was conducted of studies which reported on the relationship between COPD, forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC), and levels of various systemic inflammatory markers: C-reactive protein (CRP), fibrinogen, leucocytes, tumour necrosis factor-α (TNF-α), and interleukins 6 and 8. Where possible the results were pooled together to produce a summary estimate using a random or fixed effects model.
Results: Fourteen original studies were identified. Overall, the standardised mean difference in the CRP level between COPD and control subjects was 0.53 units (95% confidence interval (CI) 0.34 to 0.72). The standardised mean difference in the fibrinogen level was 0.47 units (95% CI 0.29 to 0.65). Circulating leucocytes were also higher in COPD than in control subjects (standardised mean difference 0.44 units (95% CI 0.20 to 0.67)), as were serum TNF-α levels (standardised mean difference 0.59 units (95% CI 0.29 to 0.89)).
Conclusions: Reduced lung function is associated with increased levels of systemic inflammatory markers which may have important pathophysiological and therapeutic implications for subjects with stable COPD.
doi:10.1136/thx.2003.019588
PMCID: PMC1747070  PMID: 15223864
6.  Inflammation, Insulin Resistance, and Diabetes—Mendelian Randomization Using CRP Haplotypes Points Upstream 
PLoS Medicine  2008;5(8):e155.
Background
Raised C-reactive protein (CRP) is a risk factor for type 2 diabetes. According to the Mendelian randomization method, the association is likely to be causal if genetic variants that affect CRP level are associated with markers of diabetes development and diabetes. Our objective was to examine the nature of the association between CRP phenotype and diabetes development using CRP haplotypes as instrumental variables.
Methods and Findings
We genotyped three tagging SNPs (CRP + 2302G > A; CRP + 1444T > C; CRP + 4899T > G) in the CRP gene and measured serum CRP in 5,274 men and women at mean ages 49 and 61 y (Whitehall II Study). Homeostasis model assessment-insulin resistance (HOMA-IR) and hemoglobin A1c (HbA1c) were measured at age 61 y. Diabetes was ascertained by glucose tolerance test and self-report. Common major haplotypes were strongly associated with serum CRP levels, but unrelated to obesity, blood pressure, and socioeconomic position, which may confound the association between CRP and diabetes risk. Serum CRP was associated with these potential confounding factors. After adjustment for age and sex, baseline serum CRP was associated with incident diabetes (hazard ratio = 1.39 [95% confidence interval 1.29–1.51], HOMA-IR, and HbA1c, but the associations were considerably attenuated on adjustment for potential confounding factors. In contrast, CRP haplotypes were not associated with HOMA-IR or HbA1c (p = 0.52–0.92). The associations of CRP with HOMA-IR and HbA1c were all null when examined using instrumental variables analysis, with genetic variants as the instrument for serum CRP. Instrumental variables estimates differed from the directly observed associations (p = 0.007–0.11). Pooled analysis of CRP haplotypes and diabetes in Whitehall II and Northwick Park Heart Study II produced null findings (p = 0.25–0.88). Analyses based on the Wellcome Trust Case Control Consortium (1,923 diabetes cases, 2,932 controls) using three SNPs in tight linkage disequilibrium with our tagging SNPs also demonstrated null associations.
Conclusions
Observed associations between serum CRP and insulin resistance, glycemia, and diabetes are likely to be noncausal. Inflammation may play a causal role via upstream effectors rather than the downstream marker CRP.
Using a Mendelian randomization approach, Eric Brunner and colleagues show that the associations between serum C-reactive protein and insulin resistance, glycemia, and diabetes are likely to be noncausal.
Editors' Summary
Background.
Diabetes—a common, long-term (chronic) disease that causes heart, kidney, nerve, and eye problems and shortens life expectancy—is characterized by high levels of sugar (glucose) in the blood. In people without diabetes, blood sugar levels are controlled by the hormone insulin. Insulin is released by the pancreas after eating and “instructs” insulin-responsive muscle and fat cells to take up the glucose from the bloodstream that is produced by the digestion of food. In the early stages of type 2 diabetes (the commonest type of diabetes), the muscle and fat cells become nonresponsive to insulin (a condition called insulin resistance), and blood sugar levels increase. The pancreas responds by making more insulin—people with insulin resistance have high blood levels of both insulin and glucose. Eventually, however, the insulin-producing cells in the pancreas start to malfunction, insulin secretion decreases, and frank diabetes develops.
Why Was This Study Done?
Globally, about 200 million people have diabetes, but experts believe this number will double by 2030. Ways to prevent or delay the onset of diabetes are, therefore, urgently needed. One major risk factor for insulin resistance and diabetes is being overweight. According to one theory, increased body fat causes mild, chronic tissue inflammation, which leads to insulin resistance. Consistent with this idea, people with higher than normal amounts of the inflammatory protein C-reactive protein (CRP) in their blood have a high risk of developing diabetes. If inflammation does cause diabetes, then drugs that inhibit CRP might prevent diabetes. However, simply measuring CRP and determining whether the people with high levels develop diabetes cannot prove that CRP causes diabetes. Those people with high blood levels of CRP might have other unknown factors in common (confounding factors) that are the real causes of diabetes. In this study, the researchers use “Mendelian randomization” to examine whether increased blood CRP causes diabetes. Some variants of CRP (the gene that encodes CRP) increase the amount of CRP in the blood. Because these variants are inherited randomly, there is no likelihood of confounding factors, and an association between these variants and the development of insulin resistance and diabetes indicates, therefore, that increased CRP levels cause diabetes.
What Did the Researchers Do and Find?
The researchers measured blood CRP levels in more than 5,000 people enrolled in the Whitehall II study, which is investigating factors that affect disease development. They also used the “homeostasis model assessment-insulin resistance” (HOMA-IR) method to estimate insulin sensitivity from blood glucose and insulin measurements, and measured levels of hemoglobin A1c (HbA1c, hemoglobin with sugar attached—a measure of long-term blood sugar control) in these people. Finally, they looked at three “single polynucleotide polymorphisms” (SNPs, single nucleotide changes in a gene's DNA sequence; combinations of SNPs that are inherited as a block are called haplotypes) in CRP in each study participant. Common haplotypes of CRP were related to blood serum CRP levels and, as previously reported, increased blood CRP levels were associated with diabetes and with HOMA-IR and HbA1c values indicative of insulin resistance and poor blood sugar control, respectively. By contrast, CRP haplotypes were not related to HOMA-IR or HbA1c values. Similarly, pooled analysis of CRP haplotypes and diabetes in Whitehall II and another large study on health determinants (the Northwick Park Heart Study II) showed no association between CRP variants and diabetes risk. Finally, data from the Wellcome Trust Case Control Consortium also showed no association between CRP haplotypes and diabetes risk.
What Do These Findings Mean?
Together, these findings suggest that increased blood CRP levels are not responsible for the development of insulin resistance or diabetes, at least in European populations. It may be that there is a causal relationship between CRP levels and diabetes risk in other ethnic populations—further Mendelian randomization studies are needed to discover whether this is the case. For now, though, these findings suggest that drugs targeted against CRP are unlikely to prevent or delay the onset of diabetes. However, they do not discount the possibility that proteins involved earlier in the inflammatory process might cause diabetes and might thus represent good drug targets for diabetes prevention.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050155.
This study is further discussed in a PLoS Medicine Perspective by Bernard Keavney
The MedlinePlus encyclopedia provides information about diabetes and about C-reactive protein (in English and Spanish)
US National Institute of Diabetes and Digestive and Kidney Diseases provides patient information on all aspects of diabetes, including information on insulin resistance (in English and Spanish)
The International Diabetes Federation provides information about diabetes, including information on the global diabetes epidemic
The US Centers for Disease Control and Prevention provides information for the public and professionals on all aspects of diabetes (in English and Spanish)
Wikipedia has a page on Mendelian randomization (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.0050155
PMCID: PMC2504484  PMID: 18700811
7.  Plasma C-Reactive Protein and Endothelin-1 Level in Patients with Chronic Obstructive Pulmonary Disease and Pulmonary Hypertension 
Journal of Korean Medical Science  2010;25(10):1487-1491.
Pulmonary hypertension is a frequent complication of chronic obstructive pulmonary disease (COPD) and associated with a worse survival and increased risk of hospitalization for exacerbation of COPD. However, little information exists regarding the potential role of systemic inflammation in pulmonary hypertension of COPD. The purpose of the present study was to investigate the degree of C-reactive protein (CRP) and endothelin-1 (ET-1) levels in COPD patient with and without pulmonary hypertension. The levels of CRP and ET-1 were investigated in 58 COPD patient with pulmonary hypertension and 50 patients without pulmonary hypertension. Pulmonary hypertension was defined as a systolic pulmonary artery pressure (Ppa) ≥35 mmHg assessed by Doppler echocardiography. Plasma CRP and ET-1 levels were significantly higher in patients with pulmonary hypertension than in patients without hypertension. There were significant positive correlations between the plasma ET-1 level and CRP level in the whole study groups. For COPD patients, systolic Ppa correlated significantly with plasma CRP levels and plasma ET-1 levels. These findings support a possibility that CRP and ET-1 correlate to pulmonary hypertension in COPD patients.
doi:10.3346/jkms.2010.25.10.1487
PMCID: PMC2946660  PMID: 20890431
Chronic Obstructive Pulmonary Disease; Pulmonary Hypertension; C-Reactive Protein; Endothelin-1
8.  Persistent Systemic Inflammation is Associated with Poor Clinical Outcomes in COPD: A Novel Phenotype 
PLoS ONE  2012;7(5):e37483.
Background
Because chronic obstructive pulmonary disease (COPD) is a heterogeneous condition, the identification of specific clinical phenotypes is key to developing more effective therapies. To explore if the persistence of systemic inflammation is associated with poor clinical outcomes in COPD we assessed patients recruited to the well-characterized ECLIPSE cohort (NCT00292552).
Methods and Findings
Six inflammatory biomarkers in peripheral blood (white blood cells (WBC) count and CRP, IL-6, IL-8, fibrinogen and TNF-α levels) were quantified in 1,755 COPD patients, 297 smokers with normal spirometry and 202 non-smoker controls that were followed-up for three years. We found that, at baseline, 30% of COPD patients did not show evidence of systemic inflammation whereas 16% had persistent systemic inflammation. Even though pulmonary abnormalities were similar in these two groups, persistently inflamed patients during follow-up had significantly increased all-cause mortality (13% vs. 2%, p<0.001) and exacerbation frequency (1.5 (1.5) vs. 0.9 (1.1) per year, p<0.001) compared to non-inflamed ones. As a descriptive study our results show associations but do not prove causality. Besides this, the inflammatory response is complex and we studied only a limited panel of biomarkers, albeit they are those investigated by the majority of previous studies and are often and easily measured in clinical practice.
Conclusions
Overall, these results identify a novel systemic inflammatory COPD phenotype that may be the target of specific research and treatment.
doi:10.1371/journal.pone.0037483
PMCID: PMC3356313  PMID: 22624038
9.  Association of MMP - 12 polymorphisms with severe and very severe COPD: A case control study of MMPs - 1, 9 and 12 in a European population 
BMC Medical Genetics  2010;11:7.
Background
Genetic factors play a role in chronic obstructive pulmonary disease (COPD) but are poorly understood. A number of candidate genes have been proposed on the basis of the pathogenesis of COPD. These include the matrix metalloproteinase (MMP) genes which play a role in tissue remodelling and fit in with the protease - antiprotease imbalance theory for the cause of COPD. Previous genetic studies of MMPs in COPD have had inadequate coverage of the genes, and have reported conflicting associations of both single nucleotide polymorphisms (SNPs) and SNP haplotypes, plausibly due to under-powered studies.
Methods
To address these issues we genotyped 26 SNPs, providing comprehensive coverage of reported SNP variation, in MMPs- 1, 9 and 12 from 977 COPD patients and 876 non-diseased smokers of European descent and evaluated their association with disease singly and in haplotype combinations. We used logistic regression to adjust for age, gender, centre and smoking history.
Results
Haplotypes of two SNPs in MMP-12 (rs652438 and rs2276109), showed an association with severe/very severe disease, corresponding to GOLD Stages III and IV.
Conclusions
Those with the common A-A haplotype for these two SNPs were at greater risk of developing severe/very severe disease (p = 0.0039) while possession of the minor G variants at either SNP locus had a protective effect (adjusted odds ratio of 0.76; 95% CI 0.61 - 0.94). The A-A haplotype was also associated with significantly lower predicted FEV1 (42.62% versus 44.79%; p = 0.0129). This implicates haplotypes of MMP-12 as modifiers of disease severity.
doi:10.1186/1471-2350-11-7
PMCID: PMC2820470  PMID: 20078883
10.  C-reactive protein as a prognostic marker in chronic obstructive pulmonary disease 
The present study aimed to evaluate whether circulating C-reactive protein (CRP) levels are a biomarker of systemic inflammation and a significant predictor of future chronic obstructive pulmonary disease (COPD) outcome. During the study, 116 patients with stable COPD and 35 age- and gender-matched healthy subjects with normal pulmonary function were observed. Patient follow-up was also performed to evaluate the strength of the associations between CRP levels and future outcomes. The observations from the present study showed that serum CRP levels were significantly higher in stable COPD patients than in control subjects (4.48±0.83 vs. 1.01±0.27 mg/l, respectively; P<0.05). In addition, it was identified that a serum CRP concentration of >3 mg/l is a poor prognostic variable of COPD compared with a CRP concentration of ≤3 mg/l [hazard ratio (HR), 2.71; 95% confidence interval (CI), 1.05–6.99; P<0.05]. A quantitative synthesis of four studies including 1,750 COPD patients was performed and statistically similar results were obtained (HR, 1.54; 95% CI, 1.14–2.07; P<0.01). The present study showed that circulating CRP levels are higher in stable COPD patients and, therefore, may be used as a long-term predictor of future outcomes. These observations highlight the importance of high sensitivity CRP assays in patients with stable COPD.
doi:10.3892/etm.2013.1441
PMCID: PMC3881036  PMID: 24396422
C-reactive protein; chronic obstructive pulmonary disease; survival
11.  Does High C-reactive Protein Concentration Increase Atherosclerosis? The Whitehall II Study 
PLoS ONE  2008;3(8):e3013.
Background
C-reactive protein (CRP), a marker of systemic inflammation, is associated with risk of coronary events and sub-clinical measures of atherosclerosis. Evidence in support of this link being causal would include an association robust to adjustments for confounders (multivariable standard regression analysis) and the association of CRP gene polymorphisms with atherosclerosis (Mendelian randomization analysis).
Methodology/Principal Findings
We genotyped 3 tag single nucleotide polymorphisms (SNPs) [+1444T>C (rs1130864); +2303G>A (rs1205) and +4899T>G (rs 3093077)] in the CRP gene and assessed CRP and carotid intima-media thickness (CIMT), a structural marker of atherosclerosis, in 4941 men and women aged 50–74 (mean 61) years (the Whitehall II Study). The 4 major haplotypes from the SNPs were consistently associated with CRP level, but not with other risk factors that might confound the association between CRP and CIMT. CRP, assessed both at mean age 49 and at mean age 61, was associated both with CIMT in age and sex adjusted standard regression analyses and with potential confounding factors. However, the association of CRP with CIMT attenuated to the null with adjustment for confounding factors in both prospective and cross-sectional analyses. When examined using genetic variants as the instrument for serum CRP, there was no inferred association between CRP and CIMT.
Conclusions/Significance
Both multivariable standard regression analysis and Mendelian randomization analysis suggest that the association of CRP with carotid atheroma indexed by CIMT may not be causal.
doi:10.1371/journal.pone.0003013
PMCID: PMC2507732  PMID: 18714381
12.  TNFA-863 polymorphism is associated with a reduced risk of Chronic Obstructive Pulmonary Disease: A replication study 
BMC Medical Genetics  2011;12:132.
Background
TNF-α mediated inflammation is thought to play a key role in the respiratory and systemic features of Chronic Obstructive Pulmonary Disease. The aim of the present study was to replicate and extend recent findings in Taiwanese and Caucasian populations of associations between COPD susceptibility and variants of the TNFA gene in a Spanish cohort.
Methods
The 3 reported SNPs were complemented with nine tag single nucleotide polymorphisms (SNP) of the TNFA and LTA genes and genotyped in 724 individuals (202 COPD patients, 90 smokers without COPD and 432 healthy controls). Pulmonary function parameters and serum inflammatory markers were also measured in COPD patients.
Results
The TNFA rs1800630 (-863C/A) SNP was associated with a lower COPD susceptibility (ORadj = 0.50, 95% CI = 0.33-0.77, p = 0.001). The -863A allele was also associated with less severe forms of the disease (GOLD stages I and II) (ORadj = 0.303, 95%CI = 0.14-0.65, p = 0.014) and with lower scores of the BODE index (< 2) (ORadj = 0.40, 95%CI = 0.17-0.94, p = 0.037). Moreover, the -863A carrier genotype was associated with a better FEV1 percent predicted (p = 0.004) and a lower BODE index (p = 0.003) over a 2 yrs follow-up period. None of the TNFA or LTA gene variants correlated with the serum inflammatory markers in COPD patients (p > 0.05).
Conclusions
We replicated the previously reported association between the TNFA -863 SNP and COPD. TNFA -863A allele may confer a protective effect to the susceptibility to the disease in the Spanish population.
doi:10.1186/1471-2350-12-132
PMCID: PMC3209447  PMID: 21985478
13.  Systemic inflammation in COPD in relation to smoking status 
Background and aims
Smoking is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) that has been recently defined as a systemic pulmonary inflammatory disease. However, the impact of smoking itself on systemic inflammation in COPD patients has not yet been well established. The aim of our study was to investigate the association between inflammatory markers and smoking status.
Materials and methods
We compared 202 current smokers, 61 ex-smokers and 57 never-smokers, all COPD patients. Assessments included medical history, spirometry, alpha-1 antitrypsin (AAT) genotyping, serum AAT, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and soluble tumor necrosis factor receptor (sTNFR)-1 and sTNFR-2 concentrations.
Results
AAT and CRP concentrations in smokers (1.75 ± 0.51 g/L and 14.4 [9.5-20.5] mg/L) and ex-smokers (1.69 ± 0.43 g/L and 12.3 [8.7-16.3] mg/L) were higher than in never-smokers (1.49 ± 0.38 g/L and 5.1 [2.5-8.7] mg/L; p < 0.05). sTNFR-1 level was higher in smokers than ex-smokers or never-smokers (241.2 pg/mL [145.3-349.4] vs. 213.7 pg/mL [147.1-280.3] and 205.2 pg/mL [125-275]; p < 0.05).
Conclusions
Our data confirm that smoking is associated with increased levels of AAT, CRP, and sTNFR-1 in COPD patients, an array of systemic inflammation markers that continue to be active even after smoking cessation.
doi:10.1186/2049-6958-6-4-214
PMCID: PMC3463080  PMID: 22958407
Alpha-1 antitrypsin; COPD; inflammatory markers
14.  Smoking status and tumor necrosis factor-alpha mediated systemic inflammation in COPD patients 
Background
Smoking cause airway and systemic inflammation and COPD patients present low grade inflammation in peripheral blood. However, data on the influence of smoking itself on systemic inflammation in COPD patients are scarce. This study investigated the association between inflammation, smoking status, and disease.
Methods
A cross-sectional analysis comparing 53 COPD ex-smokers, 24 COPD current smokers, 24 current smoker controls and 34 never-smoker controls was performed. Assessments included medical history, body composition, spirometry, and plasma concentration of tumor necrosis factor-alpha (TNF-α), interleukins (IL)-6, IL-8, and C-reactive protein (CRP).
Results
Our exploratory analysis showed that serum TNF-α was higher in COPD current smokers [4.8(4.2-5.8)pg/mL] and in current smoker controls [4.8 (4.2-6.1) pg/mL] when compared to COPD ex-smokers [4.3 (3.9-4.9)pg/mL; p = 0.02] and to never-smoker controls [3.7 (3.4-4.0)pg/mL; p < 0.001]. Multiple regression results with and without adjustment for covariates were consistent with the hypothesis that TNF-α levels were associated with smoking status in both models (p < 0.001 and p < 0.001). IL-6 and CRP were significantly higher in COPD patients when compared to smoker and never-smoker controls and the multiple regression analysis confirmed the association of these mediators with disease, but not with smoking status (p < 0.001 and p < 0.001). IL-8 had only a borderline association with disease in both models (p = 0.069 and p = 0.053). No influence of disease severity, inhaled corticosteroid, fat-free mass (FFM) depletion and long term oxygen therapy (LTOT) use on systemic inflammation was found.
Conclusion
Smoking may influence TNF-α mediated systemic inflammation, which, in turn, may account for some of the benefits observed in patients with COPD who stop smoking.
doi:10.1186/1476-9255-7-29
PMCID: PMC2891738  PMID: 20534161
15.  Changes of HMGB1 and sRAGE during the recovery of COPD exacerbation 
Journal of Thoracic Disease  2014;6(6):734-741.
Background
Acute exacerbation of chronic obstructive pulmonary disease is associated with increased airway and systemic inflammation. However, the correlation between acute exacerbation/convalescence of chronic obstructive pulmonary disease (COPD) and simultaneous changes of high mobility group protein B1 (HMGB1) and soluble RAGE (sRAGE) levels has not been clearly clarified. The aim of this study was to assess these issues.
Methods
A total of 44 COPD patients were recruited. Following a structured interview, plasma levels of HMGB1, sRAGE, fibrinogen and serum level of high-sensitivity C-reactive protein (hsCRP) were measured in patients with acute exacerbation of COPD (AECOPD) within 24 h of hospitalization and pre-discharge (convalescence). All patients were examined with spirometry in convalescence of COPD.
Results
There was a significant decline in plasma HMGB1 (P<0.01), sRAGE (P<0.05), fibrinogen (P<0.01) and serum hsCRP (P<0.01) levels from acute exacerbation to convalescence phase of COPD. Changes of sRAGE was significantly correlated with changes of HMGB1 (r=0.4, P=0.007). COPD disease status correlated with the ratio of HMGB1/sRAGE, but not gender, age, course of disease, smoking history and FEV1% pred. Levels of HMGB1 and sRAGE were the highest in the current smoker group, and significantly decreased in ex-smoker group in both acute exacerbation and convalescence phase of COPD, however, their levels in never smoker group were higher than ex-smoker group in either phase of COPD.
Conclusions
HMGB1 and sRAGE levels were dynamically changed between exacerbation and convalescence phase of COPD, HMGB1 and sRAGE were likely not only a potential marker in COPD exacerbation but also a therapeutic target for COPD treatment.
doi:10.3978/j.issn.2072-1439.2014.04.31
PMCID: PMC4073385  PMID: 24976997
Chronic obstructive pulmonary disease (COPD); high mobility group protein B1 (HMGB1); soluble RAGE (sRAGE); biomarker; exacerbation; convalescence
16.  Biomarkers of inflammation and MRI-defined small vessel disease of the brain: the Cardiovascular Health Study 
Background
To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the CRP and IL6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.
Methods and Results
Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known CVD risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (N=532) and Whites (N=2,905). Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the −174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: (1.02; 1.28)). The common haplotype tagged by the −572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: (1.15; 2.14)). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.
Conclusions
This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.
doi:10.1161/STROKEAHA.107.508135
PMCID: PMC2888487  PMID: 18436879
17.  Mechanisms of atherothrombosis in chronic obstructive pulmonary disease 
Patients affected by chronic obstructive pulmonary disease (COPD) have an increased risk of atherothrombotic acute events, independent of smoking and other cardiovascular risk factors. As a consequence, myocardial ischemia is a relevant cause of death in these patients. We reviewed studies concerning the potential mechanisms of atherothrombosis in COPD. Bronchial inflammation spreads to the systemic circulation and is known to play a key role in plaque formation and rupture. In fact, C-reactive protein blood levels increase in COPD and provide independent prognostic information. Systemic inflammation is the first cause of the hypercoagulable state commonly observed in COPD. Furthermore, hypoxia is supposed to activate platelets, thus accounting for the increased urinary excretion of platelet-derived thromboxane in COPD. The potential metabolic risk in COPD is still debated, in that recent studies do not support an association between COPD and diabetes mellitus. Finally, oxidative stress contributes to the pathogenesis of COPD and may promote oxidation of low-density-lipoproteins with foam cells formation. Retrospective observations suggest that inhaled corticosteroids may reduce atherothrombotic mortality by attenuating systemic inflammation, but this benefit needs confirmation in ongoing randomized controlled trials. Physicians approaching COPD patients should always be aware of the systemic vascular implications of this disease.
PMCID: PMC2528208  PMID: 18488431
COPD; atherothrombosis; cardiovascular risk; mortality
18.  TNF-α is associated with loss of lean body mass only in already cachectic COPD patients 
Respiratory Research  2012;13(1):48.
Background
Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years.
Methods
The patients, aged 40–76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models.
Results
At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry.
Conclusion
This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.
doi:10.1186/1465-9921-13-48
PMCID: PMC3487870  PMID: 22708547
Inflammation; TNF-α; COPD; Cachexia
19.  Genetic Variations in ADIPOQ Gene Are Associated with Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(11):e50848.
Background
Adiponectin is reported to be related to the development of chronic obstructive pulmonary disease (COPD). Genetic variants in the gene encoding adiponectin (ADIPOQ) have been reported to be associated with adiponectin level in several genome–wide linkage and association studies. However, relatively little is known about the effects of ADIPOQ gene variants on COPD susceptibility. We determined the frequencies of single-nucleotide polymorphisms (SNPs) in ADIPOQ in a Chinese Han population and their possible association with COPD susceptibility.
Methods
We conducted a case–control study of 279 COPD patients and 367 age- and gender-distribution-matched control subjects. Seven tagging SNPs in ADIPOQ, including rs710445, rs16861205, rs822396, rs7627128, rs1501299, rs3821799 and rs1063537 were genotyped by SNaPshot. Association analysis of genotypes/alleles and haplotypes constructed from these loci with COPD was conducted under different genetic models.
Results
The alleles or genotypes of rs1501299 distributed significantly differently in COPD patients and controls (allele: P = 0.002, OR = 1.43 and 95%CI = 1.14–1.79; genotype: P = 0.008). The allele A at rs1501299 was potentially associated with an increased risk of COPD in all dominant model analysis (P = 0.009; OR: 1.54; 95%CI: 1.11–2.13), recessive model analyses (P = 0.015; OR: 1.75; 95% CI: 1.11–2.75) and additive model analyses (P = 0.003; OR: 2.11; 95% CI: 1.29–3.47). In haplotype analysis, we observed haplotypes AAAAACT and GGACCTC had protective effects, while haplotypes AGAACTC, AGGCCTC, GGAACTC, GGACACT and GGGCCTC were significantly associated with the increased risk of COPD.
Conclusions
We conducted the first investigation of the association between the SNPs in ADIPOQ and COPD risk. Our current findings suggest that ADIPOQ may be a potential risk gene for COPD. Further studies in larger groups are warranted to confirm our results.
doi:10.1371/journal.pone.0050848
PMCID: PMC3508992  PMID: 23209832
20.  Systemic inflammation, depression and obstructive pulmonary function: a population-based study 
Respiratory Research  2013;14(1):53.
Background
Levels of Interleukin-6 (IL-6) and C-creative protein (CRP) indicating systemic inflammation are known to be elevated in chronic diseases including chronic obstructive pulmonary disease (COPD) and depression. Comorbid depression is common in patients with COPD, but no studies have investigated whether proinflammatory cytokines mediate the association between pulmonary function and depressive symptoms in healthy individuals with no known history of obstructive pulmonary diseases.
Methods
In a population-based sample (n = 2077) of individuals aged 55 and above with no known history of obstructive pulmonary disease in the Singapore Longitudinal Ageing Study (SLAS), we analyzed the relationships between IL-6 and CRP, depressive symptoms (GDS-15 ≥5) and obstructive pulmonary function (FEV1% predicted and FEV1/FVC% predicted).
Results
High serum levels of IL-6 and CRP were associated with greater prevalence of depressive symptoms (p < 0.05). High IL-6, high CRP and depressive symptoms were independently associated with decreased FEV1% predicted and FEV1/FVC% predicted after adjusting for smoking status, BMI and number of chronic inflammatory diseases. Increasing grades of combination of inflammatory markers and/or depressive symptoms was associated with progressive increases in pulmonary obstruction. In hierarchical models, the significant association of depressive symptoms with pulmonary obstruction was reduced by the presence of IL-6 and CRP.
Conclusions
This study found for the first time an association of depressive symptoms and pulmonary function in older adults which appeared to be partly mediated by proinflammatory cytokines. Further studies should be conducted to investigate proinflammatory immune markers and depressive symptoms as potential phenotypic indicators for chronic obstructive airway disorders in older adults.
doi:10.1186/1465-9921-14-53
PMCID: PMC3656806  PMID: 23676005
Depressive symptoms; Pulmonary function; Healthy individuals; Common neurobiological process; Inverse association
21.  Genome-Wide Association Analysis of Blood Biomarkers in Chronic Obstructive Pulmonary Disease 
Rationale: A genome-wide association study (GWAS) for circulating chronic obstructive pulmonary disease (COPD) biomarkers could identify genetic determinants of biomarker levels and COPD susceptibility.
Objectives: To identify genetic variants of circulating protein biomarkers and novel genetic determinants of COPD.
Methods: GWAS was performed for two pneumoproteins, Clara cell secretory protein (CC16) and surfactant protein D (SP-D), and five systemic inflammatory markers (C-reactive protein, fibrinogen, IL-6, IL-8, and tumor necrosis factor-α) in 1,951 subjects with COPD. For genome-wide significant single nucleotide polymorphisms (SNPs) (P < 1 × 10−8), association with COPD susceptibility was tested in 2,939 cases with COPD and 1,380 smoking control subjects. The association of candidate SNPs with mRNA expression in induced sputum was also elucidated.
Measurements and Main Results: Genome-wide significant susceptibility loci affecting biomarker levels were found only for the two pneumoproteins. Two discrete loci affecting CC16, one region near the CC16 coding gene (SCGB1A1) on chromosome 11 and another locus approximately 25 Mb away from SCGB1A1, were identified, whereas multiple SNPs on chromosomes 6 and 16, in addition to SNPs near SFTPD, had genome-wide significant associations with SP-D levels. Several SNPs affecting circulating CC16 levels were significantly associated with sputum mRNA expression of SCGB1A1 (P = 0.009–0.03). Several SNPs highly associated with CC16 or SP-D levels were nominally associated with COPD in a collaborative GWAS (P = 0.001–0.049), although these COPD associations were not replicated in two additional cohorts.
Conclusions: Distant genetic loci and biomarker-coding genes affect circulating levels of COPD-related pneumoproteins. A subset of these protein quantitative trait loci may influence their gene expression in the lung and/or COPD susceptibility.
Clinical trial registered with www.clinicaltrials.gov (NCT 00292552).
doi:10.1164/rccm.201206-1013OC
PMCID: PMC3622441  PMID: 23144326
biomarker; chronic obstructive pulmonary disease; genome-wide association study
22.  Effects of rehabilitative exercise on peripheral muscle TNFα, IL‐6, IGF‐I and MyoD expression in patients with COPD 
Thorax  2007;62(11):950-956.
Background
Skeletal muscle wasting commonly occurs in patients with chronic obstructive pulmonary disease (COPD) and has been associated with the presence of systemic inflammation. This study investigated whether rehabilitative exercise training decreases the levels of systemic or local muscle inflammation or reverses the abnormalities associated with muscle deconditioning.
Methods
Fifteen patients with COPD (mean (SE) forced expiratory volume in 1 s 36 (4)% predicted) undertook high‐intensity exercise training 3 days/week for 10 weeks. Before and after the training programme the concentration of tumour necrosis factor α (TNFα), interleukin‐6 (IL‐6) and C‐reactive protein (CRP) in plasma was determined by ELISA, and vastus lateralis mRNA expression of TNFα, IL‐6, total insulin‐like growth factor‐I (IGF‐I) and its isoform mechanogrowth factor (MGF) and myogenic differentiation factor D (MyoD) were assessed by real‐time PCR. Protein levels of TNFα, IGF‐I and MyoD were measured by Western blotting.
Results
Rehabilitation improved peak exercise work rate by 10 (2%) (p = 0.004) and mean fibre cross‐sectional area from 4061 (254) μm2 to 4581 (241) μm2 (p = 0.001). Plasma inflammatory mediators and vastus lateralis expression of TNFα and IL‐6 were not significantly modified by training. In contrast, there was a significant increase in mRNA expression of IGF‐I (by 67 (22)%; p = 0.044), MGF (by 67 (15)%; p = 0.002) and MyoD (by 116 (30)%; p = 0.001). The increase observed at the mRNA level was also seen at the protein level for IGF‐I (by 72 (36)%; p = 0.046) and MyoD (by 67 (21)%; p = 0.012).
Conclusions
Pulmonary rehabilitation can induce peripheral muscle adaptations and modifications in factors regulating skeletal muscle hypertrophy and regeneration without decreasing the levels of systemic or local muscle inflammation.
doi:10.1136/thx.2006.069310
PMCID: PMC2117139  PMID: 17573449
23.  C-reactive protein levels are raised in stable Chronic obstructive pulmonary disease patients independent of smoking behavior and biomass exposure 
Journal of Thoracic Disease  2013;5(4):414-421.
Background
The aim of this case control study is to assess the relationship between serum C-reactive protein (CRP) levels and well-known clinical parameters in Chronic obstructive pulmonary disease (COPD) considering the impact of smoking behavior, biomass exposure and accompanying clinical entities, namely pulmonary hypertension, systemic hypertension and diabetes mellitus.
Methods
Spirometry, echocardiography, arterial oxygen saturation (SpO2) measurements, BODE scores and serum CRP levels were investigated in stable COPD patients. Associations between CRP levels and clinical parameters were evaluated.
Results
CRP levels are significantly higher in COPD patients than in healthy controls. CRP levels were not significantly different between COPD patients treated with inhaled corticosteroids and those not treated. CRP levels significantly correlated with age, FEV1% predicted, FVC% predicted, SpO2, MMRC, 6 minute walk distance, BODE scores and haemoglobin levels. In multivariate analysis BODE scores and concomitant systemic hypertension manifested the strongest association with CRP levels. CRP levels in COPD patients with and without pulmonary hypertension were significantly different. CRP levels did not differ significantly according to smoking status or biomass exposure, moreover COPD cases due to biomass exposure who never smoked also had higher CRP levels compared to healthy controls.
Conclusions
Systemic inflammation is inherent to COPD independent of ever-smoking status and correlates with disease severity, concomitant systemic hypertension and pulmonary hypertension.
doi:10.3978/j.issn.2072-1439.2013.06.27
PMCID: PMC3755654  PMID: 23991296
Biomass; C-reactive protein (CRP); chronic obstructive pulmonary disease (COPD); pulmonary artery pressure; smoking behaviour
24.  The Role of Circulating Serotonin in the Development of Chronic Obstructive Pulmonary Disease 
PLoS ONE  2012;7(2):e31617.
Background
Cigarette smoking is a major risk factor in the development of age-related chronic obstructive pulmonary disease (COPD). The serotonin transporter (SERT) gene polymorphism has been reported to be associated with COPD, and the degree of cigarette smoking has been shown to be a significant mediator in this relationship. The interrelation between circulating serotonin (5-hydroxytyptamine, 5-HT), cigarette smoking and COPD is however largely unknown. The current study aimed at investigating the mediation effects of plasma 5-HT on cigarette smoking-induced COPD and the relation between plasma 5-HT levels and age.
Methods
The association between plasma 5-HT, age and COPD was analyzed in a total of 62 COPD patients (ever-smokers) and 117 control subjects (healthy non-smokers and ever-smokers). Plasma 5-HT levels were measured by enzyme-linked immuno assay (EIA).
Results
The elevated plasma 5-HT levels were significantly associated with increased odds for COPD (OR = 1.221, 95% CI = 1.123 to 1.319, p<0.0001). The effect remained significant after being adjusted for age and pack-years smoked (OR = 1.271, 95% CI = 1.134 to 1.408, p = 0.0003). Furthermore, plasma 5-HT was found to mediate the relation between pack-years smoked and COPD. A positive correlation (r = 0.303, p = 0.017) was found between plasma 5-HT levels and age in COPD, but not in the control subjects (r = −0.149, p = 0.108).
Conclusion
Our results suggest that cigarette smoke-induced COPD is partially mediated by the plasma levels of 5-HT, and that these become elevated with increased age in COPD. The elevated plasma 5-HT levels in COPD might contribute to the pathogenesis of this disease.
doi:10.1371/journal.pone.0031617
PMCID: PMC3272036  PMID: 22319639
25.  Echocardiography, Spirometry, and Systemic Acute-Phase Inflammatory Proteins in Smokers with COPD or CHF: An Observational Study 
PLoS ONE  2013;8(11):e80166.
Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1β (IL-1 β), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged ≥50 years and with ≥10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 β, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 β, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.
doi:10.1371/journal.pone.0080166
PMCID: PMC3823838  PMID: 24244639

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