FKBP5 rs4713916: A Potential Genetic Predictor of Interindividual Different Response to Inhaled Corticosteroids in Patients with Chronic Obstructive Pulmonary Disease in a Real-Life Setting.

Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and manageable lung disease characterized by large heterogeneity in disease presentation and grades impairment. Inhaled corticosteroids (ICS) are commonly used to manage COPD/COPD-exacerbation. The patient's response is characterized by interindividual variability without disease progression/survival modification. Objectives: We hypothesize that a therapeutic intervention may be more effective if single nucleotide polymorphisms (SNPs) are investigated. Methods: In 71 COPD patients under pulmonary rehabilitation, a small number of powerful SNPs, selected according to current literature, were analyzed; namely the glucocorticoid receptor gene NR3C1 (rs6190/rs6189/rs41423247), the glucocorticoid-induced transcript 1 gene (GLCCI1 rs37972), and the related co-chaperone FKBP5 gene (rs4713916). MDR1 rs2032582 was also evaluated. Lung function outcomes were assessed. Results: A significant association with functional outcomes, namely FEV1 (forced expiration volume/one second) and 6MWD (six-minutes walking distance), was found for rs4713916 and weakly for rs37972. The genotype rs4713916(GA) and, in a lesser extent, the genotype rs37972(TT), were more favorable than the wild-type. Conclusions: Our study supports a possible picture of pharmacogenomic control for COPD intervention. rs4713916 and, possibly, rs37972 may be useful predictors of clinical outcome. These results may help to tailor an optimal dose for individual COPD patients based on their genetic makeup.

Pharmacological Management of Chronic Obstructive Lung Disease (COPD). Focus on Mutations - Part 1.

BACKGROUND: We report a comprehensive overview of current Chronic Obstructive Lung Disease (COPD) therapies and discuss the development of possible new pharmacological approaches based on "new" knowledge. Specifically, sensitivity/resistance to corticosteroids is evaluated with a special focus on the role of gene mutations in drug response. OBJECTIVE: Critically review the opportunities and the challenges occurring in the treatment of COPD. CONCLUSION: Findings from "omics" trials should be used to learn more about biological targeted drugs, and to select more specific drugs matching patient's distinctive molecular profile. Specific markers of inflammation such as the percentage of eosinophils are important in determining sensitivity/resistance to corticosteroids. Specific gene variations (Single nucleotide polymorphisms: SNPs) may influence drug sensitivity or resistance. Clinicians working in a real-world need to have a suitable interpretation of molecular results together with a guideline for the treatment and recommendations. Far more translational research is required before new results from omics techniques can be applied in personalized medicine in realworld settings.

Pharmacological Management of Chronic Obstructive Lung Disease (COPD). Evidence from a Real-World Perspective - Part 2.

BACKGROUND: We report a comprehensive overview of current COPD therapies from a real-world experience. OBJECTIVE: Critically review the opportunities and the challenges occurring in the real-world treatment of COPD. METHODS: This is a review that also report results from COPD patients treated with standardized therapy including pulmonary rehabilitation (Real World Data - RWD). CONCLUSION: Comprehensive assessment of COPD management requires strategies able to evaluate efficacy and usefulness in a real-world population, that take into account the interaction between experience and academic training, research, adherence to guidelines and judgments in order to plan the appropriate and optimum use of available strategies.

Gene and protein expression of CXCR4 in adult and elderly patients with chronic rhinitis, pharyngitis or sinusitis undergoing thermal water nasal inhalations.

BACKGROUND: Chronic rhinitis, pharyngitis and sinusitis are common health problems with a significant impact on public health, and are suspected to be influenced by ageing factors. Nasal inhalation with thermal water may be used to reduce symptoms, inflammation and drug intake. A pre-post clinical study was conducted in 183 consecutive adult and elderly patients with chronic rhinitis, pharyngitis or sinusitis, to evaluate whether thermal water nasal inhalations could improve their symptoms, clinical signs and rhinomanometry measurements, and influence inflammatory biomarkers levels in nasal epithelial cells. RESULTS: Participants profile revealed that they were aged on average (mean age and SD 60.6 ± 15.2 years, median 65, range 20-86, 86 aged ≤ 65 years (47%), 96 aged > 65 years (53%)) and extremely concerned about wellbeing. Older age was associated with better compliance to inhalation treatment. Total symptom and clinical evaluation scores were significantly ameliorated after treatment (p < 0.001), with no substantial difference according to age, while rhinomanometry results were inconsistent. Persistence of symptom improvement was confirmed at phone follow up 1 year later (n = 74). The training set of 48 inflammatory genes (40 patients) revealed a strong increase of CXCR4 gene expression after nasal inhalations, confirmed both in the validation set (143 patients; 1.2 ± 0.68 vs 3.3 ± 1.2; p < 0.0001) and by evaluation of CXCR4 protein expression (40 patients; 1.0 ± 0.39 vs 2.6 ± 0.66; p < 0.0001). CXCR4 expression was consistently changed in patients with rhinitis, pharyngitis or sinusitis. The increase was smaller in current smokers compared to non-smokers. Results were substantially unchanged when comparing aged subjects (≥ 65 years) or the eldest quartile (≥ 71 years) to the others. Other genes showed weaker variations (e.g. FLT1 was reduced only in patients with sinusitis). CONCLUSIONS: These results confirm the clinical impact of thermal water nasal inhalations on upper respiratory diseases both in adults and elders, and emphasize the role of genes activating tissue repair and inflammatory pathways. Future studies should evaluate CXCR4 as possible therapeutic target or response predictor in patients with chronic rhinitis, pharyngitis or sinusitis. TRIAL REGISTRATION: Communication to Italian Ministry of Health - ICPOM 000461. Registered 10/11/2014.

WITHDRAWN: Action plans and coping strategies in elderly COPD patients influence the result of pulmonary rehabilitation: an observational study.

Ahead of Print article withdrawn by publisher.

Metabolic Disorder in Chronic Obstructive Pulmonary Disease (COPD) Patients: Towards a Personalized Approach Using Marine Drug Derivatives.

Metabolic disorder has been frequently observed in chronic obstructive pulmonary disease (COPD) patients. However, the exact correlation between obesity, which is a complex metabolic disorder, and COPD remains controversial. The current study summarizes a variety of drugs from marine sources that have anti-obesity effects and proposed potential mechanisms by which lung function can be modulated with the anti-obesity activity. Considering the similar mechanism, such as inflammation, shared between obesity and COPD, the study suggests that marine derivatives that act on the adipose tissues to reduce inflammation may provide beneficial therapeutic effects in COPD subjects with high body mass index (BMI).

Effect of Genetic Polymorphisms (SNPs) in CHRNA7 Gene on Response to Acetylcholinesterase Inhibitors (AChEI) in Patients with Alzheimer's Disease.

BACKGROUND: Cholinergic transmission loss is one of the major features in Alzheimer&#039;s Disease (AD). Acetylcholinesterase inhibitors (AChEI) are moderately active in AD. α7nAChR (alpha-7 nicotinic acetylcholine receptor), encoded by CHRNA7 (Nicotinic Cholinergic Receptor Alpha-7 gene), is involved in the cholinergic neurotransmission and AD pathogenesis. α7nAChR is a putative receptor of amyloid beta (Aß). The complex α7nAChR-Aß is found in neuritic plaques and AD cortical neurons. In normal physiologic conditions, α7nAChR-Aß interaction leads to receptor activation. Genetic polymorphisms (SNPs) of CHRNA7 and/or CHRFAM7A (fusion gene containing CHRNA7 partial duplication) may be a possible susceptibility trait to dementia, potentially useful to identify high risk or responder individuals. CHRFAM7A-2-bp deletion or CHRNA7 SNPs (rs1514246, rs2337506, rs8027814) seem protective factors in different forms of dementia including AD. OBJECTIVE: Correlation between(SNPs) of CHRNA7 and/or CHRFAM7A and cholinesterase inhibitors in AD. METHODS: Literature review. RESULTS: Among the leading AD therapeutics, Donepezil (DP) and galantamine (AChEI) induce upregulation of α7nAChR protein levels, protecting neurons from degeneration. Patients carrying rs8024987 (C/G) or rs6494223 (C/T) respond better to AChEI. In the caucasic population rs6494223 TT subjects are 7-15% of the total. α7nAChR upregulation induced by DP is higher in lymphocytes from TT subjects than in CC or CT as well as calcium uptake. CONCLUSION: The correlation between genetic and functionality data may have an impact on several aspects of disease presentation and therapy, helping in prediction pattern of AD presentation and treatment efficacy. As a consequence it may lead to better patients quality of life and longer periods of self- sufficiency. Moreover, it may contribute to clarify AChEI mechanisms of action.

Visual and auditory cortical evoked potentials in interictal episodic migraine: An audit on 624 patients from three centres.

Background Many studies report a habituation deficit of visual evoked potentials (VEP) and/or increased intensity dependence of auditory evoked cortical potentials (IDAP) in episodic migraine patients between attacks. These findings have a pathophysiological interest, but their diagnostic utility is not known. Aims To perform an audit on a large database of interictal VEP and IDAP recordings in episodic migraine patients and evaluate their diagnostic accuracy. Methods We pooled data for VEP habituation and IDAP measured in 624 episodic migraineurs (EM) and 360 healthy volunteers (HV) from three centers. Thresholds were calculated by Receiver Operating Curve analysis and used to calculate sensitivity, specificity, positive and negative likelihood ratios (LR+ and LR-) and the accuracy of each test, using ICHD diagnostic criteria as the gold standard. Results In EM, VEP habituation was significantly lower than in HV, and IDAP slopes were significantly steeper. VEP (five blocks of 50 responses), VEP (six blocks of 100 responses) and IDAP had respectively 61.0%, 61.4% and 45.7% sensitivity, and 77.9%, 77.9% and 87.2% specificity. Their positive (LR+) and negative (LR-) likelihood ratios were respectively 2.760, 2.778, 3.570 and 0.500, 0.495, 0.623, with diagnostic accuracies of 65.3%, 69.0% and 54.3%. In combined VEP + IDAP recordings, an abnormality of at least one test had 83.4% sensitivity, 66.7% specificity, 2.504 LR+, 0.249 LR- and 81.1% accuracy. Conclusions In this large database, VEP habituation is significantly reduced and IDAP increased in episodic migraine patients between attacks. Taken alone, neither VEP nor IDAP has sufficient diagnostic accuracy. However, when both tests are performed in the same patient, an abnormality of at least one of them is highly predictive of interictal episodic migraine.

Correlation between habituation of visual-evoked potentials and magnetophosphene thresholds in migraine: A case-control study.

INTRODUCTION: In migraine most studies report an interictal deficit of habituation of visual-evoked potentials (VEP-hab) and reduced thresholds for phosphene induction (PT) by transcranial magnetic stimulation (TMS). We searched for a possible correlation between VEP-hab and PT in migraine patients and healthy controls to test whether they reflect the same pathophysiological abnormality. METHODS: We assessed PT and VEP-hab measured as the percentage change of N1/P1 amplitude over six blocks of 100 responses in 15 healthy volunteers (HV) and in 13 episodic migraineurs without aura (MO) between attacks. Results were compared using Mann-Whitney U test. Interrelationships were examined using Spearman's correlation. RESULTS: In MO patients VEP-hab was reduced compared to HV (p = 0.001), while PT were not significantly different between HV and MO. There was no correlation between PT and VEP-hab in either group of participants. CONCLUSIONS: We confirm that in interictal migraine VEP habituation is deficient, but magnetophosphene threshold normal. VEP-hab and PT were not correlated with each other in healthy controls or in migraineurs. This finding suggests that they index different facets of cortical excitability in migraine, i.e. a punctual normal measure of the cortical activation threshold for PT and a dynamic response pattern to repeated stimuli for VEP habituation.

New Drugs from Marine Organisms in Alzheimer's Disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder. Current approved drugs may only ameliorate symptoms in a restricted number of patients and for a restricted period of time. Currently, there is a translational research challenge into identifying the new effective drugs and their respective new therapeutic targets in AD and other neurodegenerative disorders. In this review, selected examples of marine-derived compounds in neurodegeneration, specifically in AD field are reported. The emphasis has been done on compounds and their possible relevant biological activities. The proposed drug development paradigm and current hypotheses should be accurately investigated in the future of AD therapy directions although taking into account successful examples of such approach represented by Cytarabine, Trabectedin, Eribulin and Ziconotide. We review a complexity of the translational research for such a development of new therapies for AD. Bryostatin is a prominent candidate for the therapy of AD and other types of dementia in humans.

Effect of Smoking on Blood Pressure and Resting Heart Rate: A Mendelian Randomization Meta-Analysis in the CARTA Consortium.

BACKGROUND: Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood. METHODS AND RESULTS: Data on 141 317 participants (62 666 never, 40 669 former, 37 982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day. CONCLUSIONS: This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.

Stratification by smoking status reveals an association of CHRNA5-A3-B4 genotype with body mass index in never smokers.

We previously used a single nucleotide polymorphism (SNP) in the CHRNA5-A3-B4 gene cluster associated with heaviness of smoking within smokers to confirm the causal effect of smoking in reducing body mass index (BMI) in a Mendelian randomisation analysis. While seeking to extend these findings in a larger sample we found that this SNP is associated with 0.74% lower body mass index (BMI) per minor allele in current smokers (95% CI -0.97 to -0.51, P = 2.00 × 10(-10)), but also unexpectedly found that it was associated with 0.35% higher BMI in never smokers (95% CI +0.18 to +0.52, P = 6.38 × 10(-5)). An interaction test confirmed that these estimates differed from each other (P = 4.95 × 10(-13)). This difference in effects suggests the variant influences BMI both via pathways unrelated to smoking, and via the weight-reducing effects of smoking. It would therefore be essentially undetectable in an unstratified genome-wide association study of BMI, given the opposite association with BMI in never and current smokers. This demonstrates that novel associations may be obscured by hidden population sub-structure. Stratification on well-characterized environmental factors known to impact on health outcomes may therefore reveal novel genetic associations.

Risk factors and acute ischemic stroke subtypes.

BACKGROUND: Acute ischemic stroke (AIS) is influenced by gender, age, and the brain site affected. Better characterization of AIS is necessary for improving guidelines, prevention, and destination of resources. METHODS: Demographics, prestroke conditions, etiology, subtypes, specific hospital outcome, clinical and laboratory parameters, and mortality rates were prospectively registered in 105 southern Italian patients. RESULTS: AIS became more frequent in women than in men after age 65 years. Cryptogenic AIS decreased with age independently of sex and lesion site. Cerebellum-brainstem stroke was more prevalent in men, whereas anterior AIS was more frequent in women. There were no overall differences in 6- and 12-month survival rates based on site or sex; however, mortality rates were high after age 80 years. Chronic kidney disease was more frequent in patients with cerebellum-brainstem stroke, and its prevalence increased significantly with age independently of sex. Association of AIS with arterial hypertension, diabetes, and previous myocardial infarction increased with age, whereas that with active smoking decreased with age, independently of sex and site. CONCLUSION: Specific AIS etiology and blood characteristics associated independently to the youngest and oldest AIS patients, respectively. Chronic kidney disease was a specific predictor of cerebellum-brainstem AIS. AIS mortality showed peculiar association with the oldest patients.

Blood biomarkers role in acute ischemic stroke patients: higher is worse or better?

BACKGROUND: Thrombolytic therapy (TT) for acute ischemic stroke (AIS) can provoke bleeding's complication depending on the ischemic lesion (IL) dimension. Inflammation involved in the setting of acute ischaemic stroke, is associated with infarct size. We aimed to study the independent correlation and association between clinical panel of routinely identified biomarkers, including inflammatory parameters, and cerebral IL dimension and site. RESULTS: We evaluated eleven biomarkers in 105 unrelated patients during their hospitalization after acute stroke event. Our data indicate a significant association of: a) confluent IL size with 4th quartile of Erythrocyte Sedimentation Rate (ESR) (OR = 5.250; 95% CI, 1.002 to 27.514) and an independent correlation with sex; b) confluent IL size with 3rd quartile of fibrinogen (OR = 5.5; 95% CI, 1.027 to 29.451); c) confluent IL size with 3rd quartile of platelets (OR= 0.059; 95% CI, 0.003 to 1.175) and independent correlation with sex; d) smaller IL size (OR = 5.25; 95% CI, 1.351 to 20.396) with 3rd quartile of albumin levels and nodular and parenchimal IL size with 2nd (OR = 0.227; 95% CI, 0.053 to 0.981), 3rd (OR = 0.164; 95% CI, 0.038 to 0.711) and 4th (OR = 0.205; 95% CI, 0.048 to 0.870) quartiles albumin levels; e) smaller IL size with 3rd quartile triglycerides (TG) levels (OR = 9; 95% CI, 2.487 to 32.567) and an independent correlation with anterior location. Smaller IL size, anterior AIS turned out to be independently correlated with high serum albumin levels. Finally, high INR and PTT values were associated with worse NIHSS clinical outcomes in contrast to that observed with higher albumin level. CONCLUSIONS: We provide evidence of routine biomarkers levels correlation with acute IL size, independently of age and sex. In addition, we highlight the importance of differentiation of biomarkers normal interval levels for further improvement not only of the clinical decision making but also in post-acute clinical outcome management.

The JAK2 46/1 haplotype predisposes to MPL-mutated myeloproliferative neoplasms.

The 46/1 JAK2 haplotype predisposes to V617F-positive myeloproliferative neoplasms, but the underlying mechanism is obscure. We analyzed essential thrombocythemia patients entered into the PT-1 studies and, as expected, found that 46/1 was overrepresented in V617F-positive cases (n = 404) versus controls (n = 1492, P = 3.9 x 10(-11)). The 46/1 haplotype was also overrepresented in cases without V617F (n = 347, P = .009), with an excess seen for both MPL exon 10 mutated and V617F, MPL exon 10 nonmutated cases. Analysis of further MPL-positive, V617F-negative cases confirmed an excess of 46/1 (n = 176, P = .002), but no association between MPL mutations and MPL haplotype was seen. An excess of 46/1 was also seen in JAK2 exon 12 mutated cases (n = 69, P = .002), and these mutations preferentially arose on the 46/1 chromosome (P = .029). No association between 46/1 and clinical or laboratory features was seen in the PT-1 cohort either with or without V617F. The excess of 46/1 in JAK2 exon 12 cases is compatible with both the "hypermutability" and "fertile ground" hypotheses, but the excess in MPL-mutated cases argues against the former. No difference in sequence, splicing, or expression of JAK2 was found on 46/1 compared with other haplotypes, suggesting that any functional difference of JAK2 on 46/1, if it exists, must be relatively subtle.

Genome-wide association study of plasma polyunsaturated fatty acids in the InCHIANTI Study.

Polyunsaturated fatty acids (PUFA) have a role in many physiological processes, including energy production, modulation of inflammation, and maintenance of cell membrane integrity. High plasma PUFA concentrations have been shown to have beneficial effects on cardiovascular disease and mortality. To identify genetic contributors of plasma PUFA concentrations, we conducted a genome-wide association study of plasma levels of six omega-3 and omega-6 fatty acids in 1,075 participants in the InCHIANTI study on aging. The strongest evidence for association was observed in a region of chromosome 11 that encodes three fatty acid desaturases (FADS1, FADS2, FADS3). The SNP with the most significant association was rs174537 near FADS1 in the analysis of arachidonic acid (AA; p = 5.95 x 10(-46)). Minor allele homozygotes had lower AA compared to the major allele homozygotes and rs174537 accounted for 18.6% of the additive variance in AA concentrations. This SNP was also associated with levels of eicosadienoic acid (EDA; p = 6.78 x 10(-9)) and eicosapentanoic acid (EPA; p = 1.07 x 10(-14)). Participants carrying the allele associated with higher AA, EDA, and EPA also had higher low-density lipoprotein (LDL-C) and total cholesterol levels. Outside the FADS gene cluster, the strongest region of association mapped to chromosome 6 in the region encoding an elongase of very long fatty acids 2 (ELOVL2). In this region, association was observed with EPA (rs953413; p = 1.1 x 10(-6)). The effects of rs174537 were confirmed in an independent sample of 1,076 subjects participating in the GOLDN study. The ELOVL2 SNP was associated with docosapentanoic and DHA but not with EPA in GOLDN. These findings show that polymorphisms of genes encoding enzymes in the metabolism of PUFA contribute to plasma concentrations of fatty acids.

Evidence of major genes effects on serum homocysteine and fibrinogen levels, and premature ischemic heart disease in Italian extended families.

OBJECTIVES: The purpose of the present study was to investigate the effect of novel genetic factors on plasma levels of total homocysteine (tHcy) and fibrinogen (FIB). As tHcy and FIB have been consistently associated to increased risk of ischemic heart disease (IHD) and acute myocardial infarction (MI) also genes-trait-MI mediational effects were tested. METHODS: A complex segregation analysis, and a mediation analysis of a highly selected group of 44 extended families (302 subjects), each including at least one member with fatal premature (<50 years) IHD were carried out. RESULTS: tHcy and FIB levels turned out to be influenced by at least two major genes. A significant tHcy latent class-MI association (OR = 3.24; 95% CI, 1.37 to 7.68), and a non-significant tHcy plasma level-MI association (OR = 1.65 per 1 = log 10 mumol/l, 95% CI, 0.56 to 4.81) were estimated, suggesting a direct influence of the homocysteine major gene as suppressor of plasma tHcy levels effect. In contrast, FIB latent class-MI association (OR = 0.97; 95% CI, 0.31 to 3.05) and FIB level-MI association (OR = 1.32 per 1 = 70 g/l; 95% CI, 0.88 to 2.00) were not statistically significant. CONCLUSION: These data provide evidence for a major latent gene effect influencing variation in tHcy plasma levels, which is independent on C677T MTHFR polymorphism, and significantly affecting the risk of MI.