IL6 and CRP haplotypes are associated with COPD risk and systemic inflammation: a case-control study

<p>Abstract</p> <p>Background</p> <p>Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.</p> <p>The aim of this study was to examine the association between haplotypes of <it>CRP</it>, <it>IL6 </it>and <it>FGB </it>genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).</p> <p>Methods</p> <p>Eighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.</p> <p>Results</p> <p>Raised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of <it>CRP </it>gene and CRP plasma levels (P = 0.0004) and <it>IL6 </it>gene and COPD (P = 0.003). Subsequent analysis has shown that <it>IL6 </it>haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.</p> <p>Conclusion</p> <p>Our findings suggest that common genetic variation in <it>CRP </it>and <it>IL6 </it>genes may contribute to heterogeneity of COPD population associated with systemic inflammation.</p

Ассоциация полиморфных вариантов генов ферментов матриксных металлопротеаз и антипротеаз с развитием и тяжестью течения хронической обструктивной болезни легких

To evaluate a role of polymorphic variants of metalloproteinase and protease genes for hereditary susceptibility to COPD and its severity, we analyzed polymorphic loci of MMP1, MMP9, MMP12, PI, and AACT genes in COPD patients (n = 318) and healthy persons (n = 319) living at the Bashkortostan Republic. Results showed that frequency of genotypes and alleles of G(-1607)GG gene MMP1, С(-1562)T gene MMP9, A(-82)G gene MMP12, and Ala 15 Thr gene ААСТ did not differ in COPD patients and healthy subjects. The Zand S-mutations of the PI gene were also similar in both the groups. The heterozygous GA genotype of G1237A locus in the 3'-non-translated region of PI gene was associated with COPD occurrence (OR = 2.09; 95 % CI: 1.15–3.81). To determine polymorphic variants associated with severity of clinical course and age of the disease manifestation, a comparative analysis of rates of genotypes and alleles was performed in patients with different COPD stages and of different age. The stage IV COPD patients significantly more often carried rare T allele in С(-1562)T locus of the MMP9 gene (15.89 % vs 8.38 %; χ2 = 7.804; df = 1; p = 0.005; OR = 2.06; 95 % CI: 1.22–3.49). Individuals with rare TT genotype of MMP9 gene were found only among the stage IV COPD patients (3.97 % vs 0 %; χ2 = 4.78; p = 0.029; pcor = 0.058). Moreover, analysis of this locus in patients with early manifestation of COPD (younger the 55 yrs) revealed significantly more frequent rate of T allele in patients with stage IV COPD compared to patients of the same age but less severe COPD (χ2 = 5.26; df = 1; p = 0.022).С целью оценки роли полиморфных вариантов генов матриксных металлопротеаз и антипротеаз в формировании наследственной предрасположенности к развитию ХОБЛ и тяжести течения заболевания был проведен анализ полиморфных локусов генов MMP1, MMP9, MMP12, PI и AACT в группах больных ХОБЛ (n = 318) и здоровых индивидов (n = 319), проживающих в Республике Башкортостан. Анализ полученных результатов показал, что частоты генотипов и аллелей локусов G(-1607)GG гена MMP1, С(-1562)T гена MMP9, A(-82)G гена MMP12, Ala 15 Thr гена ААСТ статистически достоверно не различаются в группах больных ХОБЛ и здоровых индивидов. Частоты Z и S мутаций гена PI также сходны в обеих группах. Выявлена ассоциация гетерозиготного генотипа GA локуса G1237A в 3'-нетранслируемой области гена PI с развитием ХОБЛ (отношение риска (ОР) = 2,09, 95%-ный доверительный интервал (ДИ) – 1,15–3,81). С целью выявления полиморфных вариантов, ассоциированных с тяжестью клинического течения и возрастом манифестации заболевания был проведен сравнительный анализ частот генотипов и аллелей изученных локусов у больных с разными стадиями ХОБЛ и в разных возрастных группах. Показано, что среди больных с 4-й стадией ХОБЛ достоверно чаще встречаются носители редкого аллеля T локуса С(-1562)T гена MMP9 (15,89 % против 8,38 %; χ2 = 7,804; df = 1; p = 0,005; ОР = 2,06; 95%-ный ДИ – 1,22–3,49). Только среди больных с 4-й стадией ХОБЛ были выявлены индивиды с редким генотипом TT гена MMP9 (3,97 % против 0 %; χ2 = 4,78; p = 0,029; pcor = 0,058). Кроме того, анализ данного локуса у больных с ранней манифестацией ХОБЛ (до 55 лет) показал статистически достоверное увеличение частоты аллеля T в группе пациентов с тяжелой 4-й стадией ХОБЛ по сравнению с больными в той же возрастной группе, но с более легкими стадиями ХОБЛ (χ2 = 5,26; df = 1; p = 0,022)

Полиморфные варианты генов провоспалительных цитокинов как маркеры предрасположенности к хронической обструктивной болезни легких

The distribution of pro-inflammatory cytokine gene variants (tumour necrosis factor α-TNF, lymphotoxin — LTA, interleukin-1β — IL-1β) was studied in 139 patients with chronic obstructive lung disease (COPD) and in healthy individuals (n = 210). Analysis of -308G/A locus of TNF gene did not reveal significant difference between patients and controls (p &gt; 0.05). It was observed that LTA genotypes were associated with COPD severity. Marked prevalence of AG heterozygous genotype was noted in patients with II and III COPD stages (59.7 % and 55.0 % accordingly), but IV stage COPD patients had increased frequency of GG homozygous mutant genotype up to 11.5 %. The GG genotype of the LTA gene in smokers strongly associated with more severe COPD (OR = 5.21,95%CI: 1.48-18.52). Among patients with -511C/T locus of IL-1β gene, 90.4 % had III and IV COPD stages. Thus, the T/T mutant homozygous patients had a 4.4-fold increased risk for very severe COPD development. TNF/LTA genotype combinations were determined for various COPD stages.Изучено распределение вариантов генов, кодирующих провоспалительные цитокины: фактор некроза опухоли-α — TNF-α, лимфотоксин-α — LTA, интерлейкин-1β— IL-1β, у 139 пациентов с хронической обструктивной болезнью легких (ХОБЛ) различной степени тяжести и у здоровых индивидов (n = 210). При анализе полиморфизма -308G/A гена TNF различий между исследуемыми группами не обнаружено. По локусу +252A/G гена LTA выявлены генотипы, ассоциированные с тяжестью течения ХОБЛ: у больных со II и III стадиями ХОБЛ отмечено преобладание гетерозиготного генотипа AG (59,7 % и 55,0 % соответственно), тогда как у больных с IV стадией ХОБЛ увеличена частота генотипа GG до 11,5 %. Генотип GG в гене LTA в сочетании с таким фактором риска как курение значительно отягощает прогноз тяжести течения заболевания (OR = 5,21, 95%CI 1,48-18,52). Среди всех больных с генотипом ТТ гена IL-1β (полиморфизм -511С/Т) 90,4 % приходилось на пациентов III и IV стадий ХОБЛ. Соответственно, при наличии генотипа ТТ риск развития крайне тяжелой формы ХОБЛ (стадия IV) оказался повышен в 4,4 раза (OR = 4,4, 95%CI 0,92-29,13). По генам TNF и LTA определены комбинации генотипов, маркирующие тяжесть клинического течения ХОБЛ

Association of smoking with amyotrophic lateral sclerosis risk and survival in men and women: a prospective study

<p>Abstract</p> <p>Background</p> <p>Previous epidemiologic studies have examined the association of smoking with amyotrophic lateral sclerosis (ALS) incidence, but their results have been inconsistent. Moreover, limited information exists on the association between smoking and survival in ALS patients. We evaluated the association of smoking with ALS incidence and survival in a population-based cohort.</p> <p>Methods</p> <p>We conducted a case-control study nested in the General Practice Research Database, a computerized clinical database in the United Kingdom. Cases were 1143 individuals with a diagnosis of ALS; 11,371 matched controls were selected among GPRD participants free of ALS. Predictors of survival were determined in the ALS cases. Smoking information was obtained from the computer database.</p> <p>Results</p> <p>Smoking was not associated with the risk of ALS in this population. The rate ratio (RR) of ALS comparing ever versus never smokers was 1.04, 95% confidence interval (CI) 0.80-1.34. In analysis stratified by gender, however, ever smoking was associated with ALS in women (RR 1.53, 95% CI 1.04-2.23) but not in men (RR 0.75, 95% CI 0.53-1.06). Mortality was 71% after 2.1 average years of follow-up. Old age and female sex were associated with lower survival. Smoking was a predictor of mortality only in women. Comparing ever versus never smokers, RR (95% CI) of death was 1.31 (1.04-1.65) in women, and 0.90 (0.72-1.11) in men.</p> <p>Conclusion</p> <p>In this large population-based study, smoking was associated with ALS risk and worse survival in women but not in men.</p

Pleiotropic Benefit of Monomeric and Oligomeric Flavanols on Vascular Health - A Randomized Controlled Clinical Pilot Study

BACKGROUND: Cardiovascular diseases are expanding to a major social-economic burden in the Western World and undermine man's deep desire for healthy ageing. Epidemiological studies suggest that flavanol-rich foods (e.g. grapes, wine, chocolate) sustain cardiovascular health. For an evidenced-based application, however, sound clinical data on their efficacy are strongly demanded. METHODS: In a double-blind, randomized, placebo-controlled intervention study we supplemented 28 male smokers with 200 mg per day of monomeric and oligomeric flavanols (MOF) from grape seeds. At baseline, after 4 and 8 weeks we measured macro- and microvascular function and a cluster of systemic biomarkers for major pathological processes occurring in the vasculature: disturbances in lipid metabolism and cellular redox balance, and activation of inflammatory cells and platelets. RESULTS: In the MOF group serum total cholesterol and LDL decreased significantly (P ≤ 0.05) by 5% (n = 11) and 7% (n = 9), respectively in volunteers with elevated baseline levels. Additionally, after 8 weeks the ratio of glutathione to glutathione disulphide in erythrocytes rose from baseline by 22% (n = 15, P<0.05) in MOF supplemented subjects. We also observed that MOF supplementation exerts anti-inflammatory effects in blood towards ex vivo added bacterial endotoxin and significantly reduces expression of inflammatory genes in leukocytes. Conversely, alterations in macro- and microvascular function, platelet aggregation, plasma levels of nitric oxide surrogates, endothelin-1, C-reactive protein, fibrinogen, prostaglandin F2alpha, plasma antioxidant capacity and gene expression levels of antioxidant defense enzymes did not reach statistical significance after 8 weeks MOF supplementation. However, integrating all measured effects into a global, so-called vascular health index revealed a significant improvement of overall vascular health by MOF compared to placebo (P ≤ 0.05). CONCLUSION: Our integrative multi-biomarker approach unveiled the pleiotropic vascular health benefit of an 8 weeks supplementation with 200 mg/d MOF in humans. TRIAL REGISTRATION: ClinicalTrials.gov NCT00742287

Polymorphisms of −174G>C and −572G>C in the Interleukin 6 (IL-6) Gene and Coronary Heart Disease Risk: A Meta-Analysis of 27 Research Studies

OBJECTIVE: Elevated serum IL-6 level is a risk factor for coronary heart disease (CHD). The -174 G>C and -572 G>C polymorphisms in the IL-6 gene have previously been shown to modulate IL-6 levels. But the association between the -174 G>C and -572 G>C polymorphisms and the risk of CHD is still unclear. A meta-analysis of all eligible studies was carried out to clarify the role of IL-6 gene polymorphisms in CHD. METHODS AND RESULTS: PubMed, EMBASE, Vip, CNKI and CBM-disc were searched for eligible articles in English and Chinese that were published before October 2010. 27 studies involving 11580 patients with CHD and 17103 controls were included. A meta-analysis was performed for the included articles using the RevMan 5.0 and Stata 10.0 softwares. Overall, the -174 C allele was not significantly associated with CHD risk (ORs = 1.04, 95%CI = 0.98 to 1.10) when compared with the -174 G allele in the additive model, and meta-analysis under other genetic models (dominant, recessive, CC versus GG, and GC versus GG) also did not reveal any significant association. On the contrary, the -572 C allele was associated with a decreased risk of CHD when compared with the -572 G allele (ORs = 0.79, 95%CI = 0.68 to 0.93). Furthermore, analyses under the recessive model (ORs = 0.69, 95% = 0.59 to 0.80) and the allele contrast model (genotype of CC versus GG, ORs = 0.49, 95% = 0.35 to 0.70) yielded similar results. However, statistical significance was not found when the meta-analysis was restricted to studies focusing on European populations, studies with large sample size, and cohort studies by using subgroup analysis. CONCLUSIONS: The -174 G>C polymorphism in the IL-6 gene is not significantly associated with increased risks of CHD. However, The -572 G>C polymorphism may contribute to CHD development. Future investigations with better study design and large number of subjects are needed

Systemic Biomarkers of Neutrophilic Inflammation, Tissue Injury and Repair in COPD Patients with Differing Levels of Disease Severity

The identification and validation of biomarkers to support the assessment of novel therapeutics for COPD continues to be an important area of research. The aim of the current study was to identify systemic protein biomarkers correlated with measures of COPD severity, as well as specific protein signatures associated with comorbidities such as metabolic syndrome. 142 protein analytes were measured in serum of 140 patients with stable COPD, 15 smokers without COPD and 30 non-smoking controls. Seven analytes (sRAGE, EN-RAGE, NGAL, Fibrinogen, MPO, TGF-α and HB-EGF) showed significant differences between severe/very severe COPD, mild/moderate COPD, smoking and non-smoking control groups. Within the COPD subjects, univariate and multivariate analyses identified analytes significantly associated with FEV1, FEV1/FVC and DLCO. Most notably, a set of 5 analytes (HB-EGF, Fibrinogen, MCP-4, sRAGE and Sortilin) predicted 21% of the variability in DLCO values. To determine common functions/pathways, analytes were clustered in a correlation network by similarity of expression profile. While analytes related to neutrophil function (EN-RAGE, NGAL, MPO) grouped together to form a cluster associated with FEV1 related parameters, analytes related to the EGFR pathway (HB-EGF, TGF-α) formed another cluster associated with both DLCO and FEV1 related parameters. Associations of Fibrinogen with DLCO and MPO with FEV1/FVC were stronger in patients without metabolic syndrome (r  =  −0.52, p  = 0.005 and r  =  −0.61, p  = 0.023, respectively) compared to patients with coexisting metabolic syndrome (r  =  −0.25, p  = 0.47 and r  =  −0.15, p  = 0.96, respectively), and may be driving overall associations in the general cohort. In summary, our study has identified known and novel serum protein biomarkers and has demonstrated specific associations with COPD disease severity, FEV1, FEV1/FVC and DLCO. These data highlight systemic inflammatory pathways, neutrophil activation and epithelial tissue injury/repair processes as key pathways associated with COPD