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author:("Varo, nerka")
1.  Inflammatory and repair serum biomarker pattern. Association to clinical outcomes in COPD 
Respiratory Research  2012;13(1):71.
The relationship between serum biomarkers and clinical expressions of COPD is limited. We planned to further describe this association using markers of inflammation and injury and repair.
We studied lung function, comorbidities, exercise tolerance, BODE index, and quality of life in 253 COPD patients and recorded mortality over three years. Serum levels of Interleukins 6,8 and16, tumor necrosis factor alpha (TNF α) [inflammatory panel], vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) [injury and repair panel] and pulmonary and activation-regulated chemokine (PARC/CCL-18) and monocyte chemotactic protein 1 (MCP-1/CCL2) [chemoattractant panel] were measured. We related the pattern of the biomarker levels to minimal clinically important differences (MCID) using a novel visualization method [ObServed Clinical Association Results (OSCAR) plot].
Levels of the inflammatory markers IL-6, TNF α were higher and those of injury and repair lower (p < 0.01) with more advanced disease (GOLD 1 vs. 4). Using the OSCAR plot, we found that patients in the highest quartile of inflammatory and lowest quartile of injury and repair biomarkers level were more clinically compromised and had higher mortality (p < 0.05).
In COPD, serum biomarkers of inflammation and repair are distinctly associated with important clinical parameters and survival.
PMCID: PMC3493287  PMID: 22906131
Exercise; Inflammation; Phenotypes; Repair; Survival
2.  TNFA-863 polymorphism is associated with a reduced risk of Chronic Obstructive Pulmonary Disease: A replication study 
BMC Medical Genetics  2011;12:132.
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.
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.
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).
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.
PMCID: PMC3209447  PMID: 21985478
3.  Association between serum soluble CD40 ligand levels and mortality in patients with severe sepsis 
Critical Care  2011;15(2):R97.
CD40 Ligand (CD40L) and its soluble counterpart (sCD40L) are proteins that exhibit prothrombotic and proinflammatory properties on binding to their cell surface receptor CD40. The results of small clinical studies suggest that sCD40L levels could play a role in sepsis; however, there are no data on the association between sCD40L levels and mortality of septic patients. Thus, the aim of this study was to determine whether circulating sCD40L levels could be a marker of adverse outcome in a large cohort of patients with severe sepsis.
This was a multicenter, observational and prospective study carried out in six Spanish intensive care units. Serum levels of sCD40L, tumour necrosis factor-alpha and interleukin-10, and plasma levels of tissue factor were measured in 186 patients with severe sepsis at the time of diagnosis. Serum sCD40L was also measured in 50 age- and sex-matched controls. Survival at 30 days was used as the endpoint.
Circulating sCD40L levels were significantly higher in septic patients than in controls (P = 0.01), and in non-survivors (n = 62) compared to survivors (n = 124) (P = 0.04). However, the levels of CD40L were not different regarding sepsis severity. Logistic regression analysis showed that sCD40L levels >3.5 ng/mL were associated with higher mortality at 30 days (odds ratio = 2.89; 95% confidence interval = 1.37 to 6.07; P = 0.005). The area under the curve of sCD40L levels >3.5 ng/mL as predictor of mortality at 30 days was 0.58 (95% CI = 0.51 to 0.65; P = 0.03).
In conclusion, circulating sCD40L levels are increased in septic patients and are independently associated with mortality in these patients; thus, its modulation could represent an attractive therapeutic target.
PMCID: PMC3219362  PMID: 21406105
4.  Gender Differences in Plasma Biomarker Levels in a Cohort of COPD Patients: A Pilot Study 
PLoS ONE  2011;6(1):e16021.
Little is known about gender differences in plasma biomarker levels in patients with chronic obstructive pulmonary disease (COPD).
There are differences in serum biomarker levels between women and men with COPD.
Explore gender differences in plasma biomarker levels in patients with COPD and smokers without COPD.
We measured plasma levels of IL-6, IL-8, IL-16, MCP-1, MMP-9, PARC and VEGF in 80 smokers without COPD (40 males, 40 females) and 152 stable COPD patients (76 males, 76 females) with similar airflow obstruction. We determined anthropometrics, smoking history, lung function, exercise tolerance, body composition, BODE index, co-morbidities and quality of life. We then explored associations between plasma biomarkers levels and the clinical characteristics of the patients and also with the clinical and physiological variables known to predict outcome in COPD.
The plasma biomarkers level explored were similar in men and women without COPD. In contrast, in patients with COPD the median value in pg/mL of IL-6 (6.26 vs 8.0, p = 0.03), IL-16 (390 vs 321, p = 0.009) and VEGF (50 vs 87, p = 0.02) differed between women and men. Adjusted for smoking history, gender was independently associated with IL-16, PARC and VEGF levels. There were also gender differences in the associations between IL-6, IL-16 and VEGF and physiologic variables that predict outcomes.
In stable COPD patients with similar airflow obstruction, there are gender differences in plasma biomarker levels and in the association between biomarker levels and important clinical or physiological variables. Further studies should confirm our findings.
PMCID: PMC3022655  PMID: 21267454
5.  TRAF1 Deficiency Attenuates Atherosclerosis in Mice by Impairing Monocyte Recruitment to the Vessel Wall 
Circulation  2010;121(18):2033-2044.
Members of the tumor necrosis factor (TNF) superfamily, such as TNFα, potently promote atherogenesis in mice and humans. TNF receptor-associated factors (TRAFs) are cytoplasmic adaptor proteins for this group of cytokines.
Methods and Results
This study tested the hypothesis that TRAF1 modulates atherogenesis in vivo. TRAF1−/−/LDLR−/− mice consuming a high-cholesterol diet for 18 weeks developed significantly smaller atherosclerotic lesions compared with LDLR−/− (low density lipoprotein receptor) control animals. As the most prominent change in histologic composition, plaques of TRAF1-deficient animals contained significantly fewer macrophages. Bone marrow transplantations revealed that TRAF1 deficiency on both hematopoetic as well as vascular resident cells contributed to the reduction in atherogenesis observed. Mechanistic studies showed that deficiency of TRAF1 in endothelial cells and monocytes reduced adhesion of inflammatory cells to the endothelium in static and dynamic assays. Impaired adhesion coincided with reduced cell spreading, actin polymerization, and CD29 expression in macrophages, as well as decreased expression of the adhesion molecules ICAM-1 and VCAM-1 on endothelial cells. SiRNA studies on human cells verified these findings. Furthermore, TRAF1 mRNA levels were significantly elevated in blood of patients with acute coronary syndrome.
TRAF1 deficiency attenuates atherogenesis in mice, most likely due to impaired monocyte recruitment to the vessel wall. These data identify TRAF1 as a potential treatment target for atherosclerosis.
PMCID: PMC2995263  PMID: 20421522
TRAF1; inflammation; atherosclerosis; monocyte recruitment
6.  Tumor Necrosis Factor Receptor Associated Factor 6 Is Not Required for Atherogenesis in Mice and Does Not Associate with Atherosclerosis in Humans 
PLoS ONE  2010;5(7):e11589.
Tumor necrosis factor receptor-associated factors (TRAFs) are important signaling molecules for a variety of pro-atherogenic cytokines including CD40L, TNF α, and IL1β. Several lines of evidence identified TRAF6 as a pro-inflammatory signaling molecule in vitro and we previously demonstrated overexpression of TRAF6 in human and Murine atherosclerotic plaques. This study investigated the role of TRAF6-deficiency in mice developing atherosclerosis, a chronic inflammatory disease.
Methodology/Principal Findings
Lethally irradiated low density lipoprotein receptor-deficient mice (TRAF6+/+/LDLR−/−) were reconstituted with TRAF6-deficient fetal liver cells (FLC) and consumed high cholesterol diet for 18 weeks to assess the relevance of TRAF6 in hematopoietic cells for atherogenesis. Additionally, TRAF6+/−/LDLR−/− mice received TRAF6-deficient FLC to gain insight into the role of TRAF6 deficiency in resident cells. Surprisingly, atherosclerotic lesion size did not differ between the three groups in both aortic roots and abdominal aortas. Similarly, no significant differences in plaque composition could be observed as assessed by immunohistochemistry for macrophages, lipids, smooth muscle cells, T-cells, and collagen. In accord, in a small clinical study TRAF6/GAPDH total blood RNA ratios did not differ between groups of patients with stable coronary heart disease (0.034±0.0021, N = 178), acute coronary heart disease (0.029±0.0027, N = 70), and those without coronary heart disease (0.032±0.0016, N = 77) as assessed by angiography.
Our study demonstrates that TRAF6 is not required for atherogenesis in mice and does not associate with clinical disease in humans. These data suggest that pro- and anti-inflammatory features of TRAF6 signaling outweigh each other in the context of atherosclerosis.
PMCID: PMC2904388  PMID: 20644648
7.  Identification of a locus modulating serum C-reactive protein levels on chromosome 5p15 
Atherosclerosis  2007;196(2):863-870.
Individual propensity to chronic, low–grade inflammation – a determinant of atherosclerosis – is in part under the control of genetic factors. To identify genes involved in this modulation, we performed a 10 cM genome screen for linkage with plasma C-reactive protein in 38 extended families including 317 non-diabetic and 177 type 2 diabetic family members (2,547 relative pairs).
Methods and results:
In a variance component analysis, heritability of CRP values was significant (h2=0.39, p<0.0001). This effect was independent of BMI and was present in both diabetic (h2=0.42, p=0.003) and non-diabetic (h2=0.34, p=0.0015) relatives. The strongest evidence of linkage with CRP was on chromosome 5p15, where the LOD score reached genome-wide significance (LOD=3.41, genome-wide p=0.013). Both diabetic and non-diabetic family members contributed to linkage at this location. Smaller linkage peaks were detected on chromosomes 5q35 (LOD=1.35) and 17p11 (LOD=1.33). When the analysis was restricted to diabetic family members, another peak of moderate intensity (LOD=2.17) was evident at 3p21.
A major gene influencing CRP levels appears to be located on chromosome 5p15, with an effect that is independent of diabetes. Another gene on 3p21 may control CRP variation but only in the presence of a diabetic or insulin-resistant environment.
PMCID: PMC2335172  PMID: 17343862
CRP; genome-wide scan; diabetes; insulin-resistance; linkage

Results 1-7 (7)