Epigenetic responses to rhinovirus exposure in airway epithelial cells are correlated with key transcriptional pathways in chronic rhinosinusitis.

BACKGROUND: Viruses may drive immune mechanisms responsible for chronic rhinosinusitis with nasal polyposis (CRSwNP), but little is known about the underlying molecular mechanisms. OBJECTIVES: To identify epigenetic and transcriptional responses to a common upper respiratory pathogen, rhinovirus (RV), that are specific to patients with CRSwNP using a primary sinonasal epithelial cell culture model. METHODS: Airway epithelial cells were collected at surgery from patients with CRSwNP (cases) and from controls without sinus disease, cultured, and then exposed to RV or vehicle for 48 h. Differential gene expression and DNA methylation (DNAm) between cases and controls in response to RV were determined using linear mixed models. Weighted gene co-expression analysis (WGCNA) was used to identify (a) co-regulated gene expression and DNAm signatures, and (b) genes, pathways, and regulatory mechanisms specific to CRSwNP. RESULTS: We identified 5585 differential transcriptional and 261 DNAm responses (FDR <0.10) to RV between CRSwNP cases and controls. These differential responses formed three co-expression/co-methylation modules that were related to CRSwNP and three that were related to RV (Bonferroni corrected p < .01). Most (95%) of the differentially methylated CpGs (DMCs) were in modules related to CRSwNP, whereas the differentially expressed genes (DEGs) were more equally distributed between the CRSwNP- and RV-related modules. Genes in the CRSwNP-related modules were enriched in known CRS and/or viral response immune pathways. CONCLUSION: RV activates specific epigenetic programs and correlated transcriptional networks in the sinonasal epithelium of individuals with CRSwNP. These novel observations suggest epigenetic signatures specific to patients with CRSwNP modulate response to viral pathogens at the mucosal environmental interface. Determining how viral response pathways are involved in epithelial inflammation in CRSwNP could lead to therapeutic targets for this burdensome airway disorder.

Multi-omic association study identifies DNA methylation-mediated genotype and smoking exposure effects on lung function in children living in urban settings.

Impaired lung function in early life is associated with the subsequent development of chronic respiratory disease. Most genetic associations with lung function have been identified in adults of European descent and therefore may not represent those most relevant to pediatric populations and populations of different ancestries. In this study, we performed genome-wide association analyses of lung function in a multiethnic cohort of children (n = 1,035) living in low-income urban neighborhoods. We identified one novel locus at the TDRD9 gene in chromosome 14q32.33 associated with percent predicted forced expiratory volume in one second (FEV1) (p = 2.4x10-9; ßz = -0.31, 95% CI = -0.41- -0.21). Mendelian randomization and mediation analyses revealed that this genetic effect on FEV1 was partially mediated by DNA methylation levels at this locus in airway epithelial cells, which were also associated with environmental tobacco smoke exposure (p = 0.015). Promoter-enhancer interactions in airway epithelial cells revealed chromatin interaction loops between FEV1-associated variants in TDRD9 and the promoter region of the PPP1R13B gene, a stimulator of p53-mediated apoptosis. Expression of PPP1R13B in airway epithelial cells was significantly associated the FEV1 risk alleles (p = 1.3x10-5; ß = 0.12, 95% CI = 0.06-0.17). These combined results highlight a potential novel mechanism for reduced lung function in urban youth resulting from both genetics and smoking exposure.

Cardiac Implantable Electronic Devices in Different Anatomical Types of Persistent Left Superior Vena Cava: Case Series and Brief Review of the Literature.

Persistent left superior vena cava (PLSVC) is the most common congenital malformation of the thoracic venous system, being present in 0.3% to 0.5% of the general population. In the majority of the cases, PLSVC is asymptomatic, but in certain patients, it can manifest through several symptoms, such as arrhythmias and cyanosis, especially when it is associated with complex cardiac pathologies. The clinical significance of this venous anomaly depends on the anatomical variant of the drainage site. In this article, we will present the experience of our clinic, with patients with PLSVC that were diagnosed intraprocedurally, during cardiac pacemaker (CP) or cardioverter defibrillator (ICD) implantation, highlighting the technical difficulties that this anomaly poses for cardiac device implantation. Out of 4000 patients who were admitted to our clinic for CP or ICD implantation, we encountered six cases of PLSVC (four reported in this article and two previously published) corresponding to different anatomical types of this congenital anomaly. In all of these situations, we had to adapt our technique to the patient's anatomy in order to avoid certain complications, the most serious being the improper placement of the right ventricle lead at the level of the coronary sinus.

Cardiac Toxicity Associated with Immune Checkpoint Inhibitors: A Systematic Review.

Immune checkpoint inhibitors (ICIs) are an important advancement in the field of cancer treatment, significantly improving the survival of patients with a series of advanced malignancies, like melanoma, non-small cell lung cancer (NSCLC), hepatocellular carcinoma (HCC), renal cell carcinoma (RCC), and Hodgkin lymphoma. ICIs act upon T lymphocytes and antigen-presenting cells, targeting programmed cell death protein 1 (PD1), programmed cell death protein ligand 1 (PD-L1), and cytotoxic T-lymphocyte antigen 4 (CTLA-4), breaking the immune tolerance of the T cells against malignant cells and enhancing the body's own immune response. A variety of cardiac-adverse effects are associated with ICI-based treatment, including pericarditis, arrhythmias, cardiomyopathy, and acute coronary syndrome, with myocarditis being the most studied due to its often-unexpected onset and severity. Overall, Myocarditis is rare but presents an immune-related adverse event (irAE) that has a high fatality rate. Considering the rising number of oncological patients treated with ICIs and the severity of their potential adverse effects, a good understanding and continuous investigation of cardiac irAEs is of the utmost importance. This systematic review aimed to revise recent publications (between 2016-2022) on ICI-induced cardiac toxicities and highlight the therapeutical approach and evolution in the selected cases.

Fine-mapping studies distinguish genetic risks for childhood- and adult-onset asthma in the HLA region.

BACKGROUND: Genome-wide association studies of asthma have revealed robust associations with variation across the human leukocyte antigen (HLA) complex with independent associations in the HLA class I and class II regions for both childhood-onset asthma (COA) and adult-onset asthma (AOA). However, the specific variants and genes contributing to risk are unknown. METHODS: We used Bayesian approaches to perform genetic fine-mapping for COA and AOA (n=9432 and 21,556, respectively; n=318,167 shared controls) in White British individuals from the UK Biobank and to perform expression quantitative trait locus (eQTL) fine-mapping in immune (lymphoblastoid cell lines, n=398; peripheral blood mononuclear cells, n=132) and airway (nasal epithelial cells, n=188) cells from ethnically diverse individuals. We also examined putatively causal protein coding variation from protein crystal structures and conducted replication studies in independent multi-ethnic cohorts from the UK Biobank (COA n=1686; AOA n=3666; controls n=56,063). RESULTS: Genetic fine-mapping revealed both shared and distinct causal variation between COA and AOA in the class I region but only distinct causal variation in the class II region. Both gene expression levels and amino acid variation contributed to risk. Our results from eQTL fine-mapping and amino acid visualization suggested that the HLA-DQA1*03:01 allele and variation associated with expression of the nonclassical HLA-DQA2 and HLA-DQB2 genes accounted entirely for the most significant association with AOA in GWAS. Our studies also suggested a potentially prominent role for HLA-C protein coding variation in the class I region in COA. We replicated putatively causal variant associations in a multi-ethnic cohort. CONCLUSIONS: We highlight roles for both gene expression and protein coding variation in asthma risk and identified putatively causal variation and genes in the HLA region. A convergence of genomic, transcriptional, and protein coding evidence implicates the HLA-DQA2 and HLA-DQB2 genes and HLA-DQA1*03:01 allele in AOA.

Estimating and accounting for unobserved covariates in high-dimensional correlated data.

Many high dimensional and high-throughput biological datasets have complex sample correlation structures, which include longitudinal and multiple tissue data, as well as data with multiple treatment conditions or related individuals. These data, as well as nearly all high-throughput 'omic' data, are influenced by technical and biological factors unknown to the researcher, which, if unaccounted for, can severely obfuscate estimation of and inference on the effects of interest. We therefore developed CBCV and CorrConf: provably accurate and computationally efficient methods to choose the number of and estimate latent confounding factors present in high dimensional data with correlated or nonexchangeable residuals. We demonstrate each method's superior performance compared to other state of the art methods by analyzing simulated multi-tissue gene expression data and identifying sex-associated DNA methylation sites in a real, longitudinal twin study.

Implantable Cardioverter Defibrillator in Primary and Secondary Prevention of SCD-What We Still Don't Know.

Implantable cardioverter defibrillators (ICDs) are the cornerstone of primary and secondary prevention of sudden cardiac death (SCD) all around the globe. In almost 40 years of technological advances and multiple clinical trials, there has been a continuous increase in the implantation rate. The purpose of this review is to highlight the grey areas related to actual ICD recommendations, focusing specifically on the primary prevention of SCD. We will discuss the still-existing controversies strongly reflected in the differences between the international guidelines regarding ICD indication class in non-ischemic cardiomyopathy, and also address the question of early implantation after myocardial infarction in the absence of clear protocols for patients at high risk of life-threatening arrhythmias. Correlating the insufficient data in the literature for 40-day waiting times with the increased risk of SCD in the first month after myocardial infarction, we review the pros and cons of early ICD implantation.

Myocardial Infarction with Non-Obstructive Coronary Artery Disease: The Labyrinth of Investigations. Case Report and Review of the Literature.

Myocardial infarction with non-obstructive coronary artery disease (MINOCA) accounts for approximately 5-15% of acute myocardial infarctions (MI). This infarction type raises a series of questions about the underlying mechanism of myocardial damage, the diagnostic pathway, optimal therapy, and the outcomes of these patients when compared to MI associated with obstructive coronary artery disease. We present the case of a 60-year-old patient with multiple cardiovascular risk factors and comorbidities who is admitted in an emergency setting. The patient is known with a conservatively treated inferior myocardial infarction which occurred 3 months prior, with reduced left ventricular ejection fraction. Emergency coronary angiography revealed normal epicardial coronary arteries, which led to further investigations of the underlying cause. Considering the absence of epicardial and microvascular spasm, CMR (cardiac magnetic resonance) confirmation of two transmural myocardial infarctions in the territories tributary to coronary arteries, and a high index of myocardial resistance in culprit arteries, we concluded the diagnosis of MINOCA due to the microvascular endothelial dysfunction. Although the concept of MINOCA was devised almost a decade ago, and these patients are an important part of MI presentations, it still represents a diagnostic challenge with multiple explorations required to establish the precise etiology.

Multi-omics colocalization with genome-wide association studies reveals a context-specific genetic mechanism at a childhood onset asthma risk locus.

BACKGROUND: Genome-wide association studies (GWASs) have identified thousands of variants associated with asthma and other complex diseases. However, the functional effects of most of these variants are unknown. Moreover, GWASs do not provide context-specific information on cell types or environmental factors that affect specific disease risks and outcomes. To address these limitations, we used an upper airway epithelial cell (AEC) culture model to assess transcriptional and epigenetic responses to rhinovirus (RV), an asthma-promoting pathogen, and provide context-specific functional annotations to variants discovered in GWASs of asthma. METHODS: Genome-wide genetic, gene expression, and DNA methylation data in vehicle- and RV-treated upper AECs were collected from 104 individuals who had a diagnosis of airway disease (n=66) or were healthy participants (n=38). We mapped cis expression and methylation quantitative trait loci (cis-eQTLs and cis-meQTLs, respectively) in each treatment condition (RV and vehicle) in AECs from these individuals. A Bayesian test for colocalization between AEC molecular QTLs and adult onset asthma and childhood onset asthma GWAS SNPs, and a multi-ethnic GWAS of asthma, was used to assign the function to variants associated with asthma. We used Mendelian randomization to demonstrate DNA methylation effects on gene expression at asthma colocalized loci. RESULTS: Asthma and allergic disease-associated GWAS SNPs were specifically enriched among molecular QTLs in AECs, but not in GWASs from non-immune diseases, and in AEC eQTLs, but not among eQTLs from other tissues. Colocalization analyses of AEC QTLs with asthma GWAS variants revealed potential molecular mechanisms of asthma, including QTLs at the TSLP locus that were common to both the RV and vehicle treatments and to both childhood onset and adult onset asthma, as well as QTLs at the 17q12-21 asthma locus that were specific to RV exposure and childhood onset asthma, consistent with clinical and epidemiological studies of these loci. CONCLUSIONS: This study provides evidence of functional effects for asthma risk variants in AECs and insight into RV-mediated transcriptional and epigenetic response mechanisms that modulate genetic effects in the airway and risk for asthma.

Sintered and 3D-Printed Bulks of MgB2-Based Materials with Antimicrobial Properties.

Pristine high-density bulk disks of MgB2 with added hexagonal BN (10 wt.%) were prepared using spark plasma sintering. The BN-added samples are machinable by chipping them into desired geometries. Complex shapes of different sizes can also be obtained by the 3D printing of polylactic acid filaments embedded with MgB2 powder particles (10 wt.%). Our present work aims to assess antimicrobial activity quantified as viable cells (CFU/mL) vs. time of sintered and 3D-printed materials. In vitro antimicrobial tests were performed against the bacterial strains Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Staphylococcus aureus ATCC 25923, Enterococcus faecium DSM 13590, and Enterococcus faecalis ATCC 29212; and the yeast strain Candida parapsilosis ATCC 22019. The antimicrobial effects were found to depend on the tested samples and microbes, with E. faecium being the most resistant and E. coli the most susceptible.

Antimicrobial Activity of MgB2 Powders Produced via Reactive Liquid Infiltration Method.

We report for the first time on the antimicrobial activity of MgB2 powders produced via the Reactive Liquid Infiltration (RLI) process. Samples with MgB2 wt.% ranging from 2% to 99% were obtained and characterized, observing different levels of grain aggregation and of impurity phases. Their antimicrobial activity was tested against Staphylococcus aureus ATCC BAA 1026, Enterococcus faecalis ATCC 29212, Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, and Candida albicans ATCC 10231. A general correlation is observed between the antibacterial activity and the MgB2 wt.%, but the sample microstructure also appears to be very important. RLI-MgB2 powders show better performances compared to commercial powders against microbial strains in the planktonic form, and their activity against biofilms is also very similar.

Multifractality through Non-Markovian Stochastic Processes in the Scale Relativity Theory. Acute Arterial Occlusions as Scale Transitions.

By assimilating biological systems, both structural and functional, into multifractal objects, their behavior can be described in the framework of the scale relativity theory, in any of its forms (standard form in Nottale's sense and/or the form of the multifractal theory of motion). By operating in the context of the multifractal theory of motion, based on multifractalization through non-Markovian stochastic processes, the main results of Nottale's theory can be generalized (specific momentum conservation laws, both at differentiable and non-differentiable resolution scales, specific momentum conservation law associated with the differentiable-non-differentiable scale transition, etc.). In such a context, all results are explicated through analyzing biological processes, such as acute arterial occlusions as scale transitions. Thus, we show through a biophysical multifractal model that the blocking of the lumen of a healthy artery can happen as a result of the "stopping effect" associated with the differentiable-non-differentiable scale transition. We consider that blood entities move on continuous but non-differentiable (multifractal) curves. We determine the biophysical parameters that characterize the blood flow as a Bingham-type rheological fluid through a normal arterial structure assimilated with a horizontal "pipe" with circular symmetry. Our model has been validated based on experimental clinical data.

Chromosome 17q12-21 Variants Are Associated with Multiple Wheezing Phenotypes in Childhood.

Rationale: Birth cohort studies have identified several temporal patterns of wheezing, only some of which are associated with asthma. Whether 17q12-21 genetic variants, which are closely associated with asthma, are also associated with childhood wheezing phenotypes remains poorly explored.Objectives: To determine whether wheezing phenotypes, defined by latent class analysis (LCA), are associated with nine 17q12-21 SNPs and if so, whether these relationships differ by race/ancestry.Methods: Data from seven U.S. birth cohorts (n = 3,786) from the CREW (Children's Respiratory Research and Environment Workgroup) were harmonized to represent whether subjects wheezed in each year of life from birth until age 11 years. LCA was then performed to identify wheeze phenotypes. Genetic associations between SNPs and wheeze phenotypes were assessed separately in European American (EA) (n = 1,308) and, for the first time, in African American (AA) (n = 620) children.Measurements and Main Results: The LCA best supported four latent classes of wheeze: infrequent, transient, late-onset, and persistent. Odds of belonging to any of the three wheezing classes (vs. infrequent) increased with the risk alleles for multiple SNPs in EA children. Only one SNP, rs2305480, showed increased odds of belonging to any wheezing class in both AA and EA children.Conclusions: These results indicate that 17q12-21 is a "wheezing locus," and this association may reflect an early life susceptibility to respiratory viruses common to all wheezing children. Which children will have their symptoms remit or reoccur during childhood may be independent of the influence of rs2305480.

A Rare Entity-Percutaneous Lead Extraction in a Very Late Onset Pacemaker Endocarditis: Case Report and Review of Literature.

The number of infections related to cardiac implantable electronic devices (CIEDs) has increased as the number of devices implanted around the world has grown exponentially in recent years. CIED complications can sometimes be difficult to diagnose and manage, as in the case of lead-related infective endocarditis. We present the case of a 48-year-old male diagnosed with Staphylococcus aureus device-related infective endocarditis, 12 years after the implant of a single chamber pacemaker. A recent history of the patient includes two urinary catheterizations due to obstructive uropathy in the context of a prostatic adenoma, 2 months previously, both without antibiotic prophylaxis; no other possible entry sites were found and no history of other invasive procedures. After initiation of antibiotic therapy according to antibiotic susceptibility testing, we decided to remove the right ventricular passive fixation lead along with the vegetation and pacemaker generator; because of severe lead adhesions in the costoclavicular region, and especially in the right ventricle, we needed mechanical sheaths to remove the abundant fibrous tissue that encompassed the lead. After a difficult, but successful, lead extraction along with a large vegetation and 6 weeks' antibiotic therapy, the clinical and biological evolution was favorable, without reappearance of symptoms. While very late lead endocarditis is a rarity, late lead-related infective endocarditis (more than 12 months elapsed since implant) is not an exception; this is why we find that endocarditis prophylaxis should be reconsidered in certain patient categories, our patient being proof that procedures with neglectable endocarditis risk according to the guidelines can lead to bacterial endocarditis.

Longitudinal data reveal strong genetic and weak non-genetic components of ethnicity-dependent blood DNA methylation levels.

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that race-associated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life.

Implantation of a Dual-Chamber Automatic Cardioverter Defibrillator in a Patient with Persistent Left Superior Vena Cava: Case Report and Brief Literature Review.

Persistence of the left superior vena cava (PLSVC) is a congenital anomaly reported in 0.3-0.5% of patients. Due to the multiple and complex anatomical variations, transvenous lead placement can become challenging. We report the case of a 47-year-old patient diagnosed with non-ischemic dilated cardiomyopathy with reduced left ventricular ejection fraction (LVEF-27%), who was referred to our clinic for implantation of a dual-chamber cardioverter defibrillator for primary prevention of sudden cardiac death. During the procedure we encountered an abnormal guidewire trajectory and after venographic examination we established the diagnosis of persistent left superior vena cava. After difficult implantation of a 7F defibrillation lead through the coronary sinus, we managed to place the atrial lead through a narrow brachiocephalic vein into the right atrial appendage. In this paper, we aim to illustrate the medical and technical implications of implanting a cardioverter defibrillator in patients with PLSVC, highlighting the benefit of identifying and utilizing both the innominate vein, and the left superior vena cava and coronary sinus for placement of multiple leads, which would otherwise have been impossible.

Altered transcriptional and chromatin responses to rhinovirus in bronchial epithelial cells from adults with asthma.

There is a life-long relationship between rhinovirus (RV) infection and the development and clinical manifestations of asthma. In this study we demonstrate that cultured primary bronchial epithelial cells from adults with asthma (n = 9) show different transcriptional and chromatin responses to RV infection compared to those without asthma (n = 9). Both the number and magnitude of transcriptional and chromatin responses to RV were muted in cells from asthma cases compared to controls. Pathway analysis of the transcriptionally responsive genes revealed enrichments of apoptotic pathways in controls but inflammatory pathways in asthma cases. Using promoter capture Hi-C we tethered regions of RV-responsive chromatin to RV-responsive genes and showed enrichment of these regions and genes at asthma GWAS loci. Taken together, our studies indicate a delayed or prolonged inflammatory state in cells from asthma cases and highlight genes that may contribute to genetic risk for asthma.

Epigenetic landscape links upper airway microbiota in infancy with allergic rhinitis at 6 years of age.

BACKGROUND: The upper airways present a barrier to inhaled allergens and microbes, which alter immune responses and subsequent risk for diseases, such as allergic rhinitis (AR). OBJECTIVE: We tested the hypothesis that early-life microbial exposures leave a lasting signature in DNA methylation that ultimately influences the development of AR in children. METHODS: We studied upper airway microbiota at 1 week, 1 month, and 3 months of life, and measured DNA methylation and gene expression profiles in upper airway mucosal cells and assessed AR at age 6 years in children in the Copenhagen Prospective Studies on Asthma in Childhood birth cohort. RESULTS: We identified 956 AR-associated differentially methylated CpGs in upper airway mucosal cells at age 6 years, 792 of which formed 3 modules of correlated differentially methylated CpGs. The eigenvector of 1 module was correlated with the expression of genes enriched for lysosome and bacterial invasion of epithelial cell pathways. Early-life microbial diversity was lower at 1 week (richness P = .0079) in children with AR at age 6 years, and reduced diversity at 1 week was also correlated with the same module's eigenvector (ρ = -0.25; P = 3.3 × 10-5). We show that the effect of microbiota richness at 1 week on risk for AR at age 6 years was mediated in part by the epigenetic signature of this module. CONCLUSIONS: Our results suggest that upper airway microbial composition in infancy contributes to the development of AR during childhood, and this trajectory is mediated, at least in part, through altered DNA methylation patterns in upper airway mucosal cells.

Expression quantitative trait locus fine mapping of the 17q12-21 asthma locus in African American children: a genetic association and gene expression study.

BACKGROUND: African ancestry is associated with a higher prevalence and greater severity of asthma than European ancestries, yet genetic studies of the most common locus associated with childhood-onset asthma, 17q12-21, in African Americans have been inconclusive. The aim of this study was to leverage both the phenotyping of the Children's Respiratory and Environmental Workgroup (CREW) birth cohort consortium, and the reduced linkage disequilibrium in African Americans, to fine map the 17q12-21 locus. METHODS: We first did a genetic association study and meta-analysis using 17q12-21 tag single-nucleotide polymorphisms (SNPs) for childhood-onset asthma in 1613 European American and 870 African American children from the CREW consortium. Nine tag SNPs were selected based on linkage disequilibrium patterns at 17q12-21 and their association with asthma, considering the effect allele under an additive model (0, 1, or 2 effect alleles). Results were meta-analysed with publicly available summary data from the EVE consortium (on 4303 European American and 3034 African American individuals) for seven of the nine SNPs of interest. Subsequently, we tested for expression quantitative trait loci (eQTLs) among the SNPs associated with childhood-onset asthma and the expression of 17q12-21 genes in resting peripheral blood mononuclear cells (PBMCs) from 85 African American CREW children and in upper airway epithelial cells from 246 African American CREW children; and in lower airway epithelial cells from 44 European American and 72 African American adults from a case-control study of asthma genetic risk in Chicago (IL, USA). FINDINGS: 17q12-21 SNPs were broadly associated with asthma in European Americans. Only two SNPs (rs2305480 in gasdermin-B [GSDMB] and rs8076131 in ORMDL sphingolipid biosynthesis regulator 3 [ORMDL3]) were associated with asthma in African Americans, at a Bonferroni-corrected threshold of p<0·0055 (for rs2305480_G, odds ratio [OR] 1·36 [95% CI 1·12-1·65], p=0·0014; and for rs8076131_A, OR 1·37 [1·13-1·67], p=0·0010). In upper airway epithelial cells from African American children, genotype at rs2305480 was the most significant eQTL for GSDMB (eQTL effect size [ß] 1·35 [95% CI 1·25-1·46], p<0·0001), and to a lesser extent showed an eQTL effect for post-GPI attachment to proteins phospholipase 3 (ß 1·15 [1·08-1·22], p<0·0001). No SNPs were eQTLs for ORMDL3. By contrast, in PBMCs, the five core SNPs were associated only with expression of GSDMB and ORMDL3. Genotype at rs12936231 (in zona pellucida binding protein 2) showed the strongest associations across both genes (for GSDMB, eQTLß 1·24 [1·15-1·32], p<0·0001; and for ORMDL3 (ß 1·19 [1·12-1·24], p<0·0001). The eQTL effects of rs2305480 on GSDMB expression were replicated in lower airway cells from African American adults (ß 1·29 [1·15-1·44], p<0·0001). INTERPRETATION: Our study suggests that SNPs regulating GSDMB expression in airway epithelial cells have a major role in childhood-onset asthma, whereas SNPs regulating the expression levels of 17q12-21 genes in resting blood cells are not central to asthma risk. Our genetic and gene expression data in African Americans and European Americans indicated GSDMB to be the leading candidate gene at this important asthma locus. FUNDING: National Institutes of Health, Office of the Director.

On the Chameleonic Behaviour of Cholesterol through a Fractal/Multifractal Model.

An increasing number of studies are beginning to show that both low-density lipoprotein and high-density lipoprotein cholesterol can constitute risk factors for myocardial infarction. Such a behaviour has been called by experts in the field the "chameleonic effect" of cholesterol. In the present paper, a fractal/multifractal model for low-density lipoprotein and high-density lipoprotein cholesterol dynamics is proposed. In such a context, a fractal/multifractal tunneling effect for systems with spontaneous symmetry breaking is analyzed so that if the spontaneous symmetry breaking is assimilated to an inflammation (in the form of a specific scalar potential), then a coupling between two fractal/multifractal states can be observed. These two states, which have been associated to biological structures such as low-density lipoprotein and high-density lipoprotein, transfer their states through a fractal/multifractal tunneling effect. Moreover, in our opinion, the widely used notions of "good" and "bad" cholesterol must be redefined as two different states (low-density lipoprotein and high-density lipoprotein) of the same biological structure named "cholesterol." In our work, for the first time in the specialized literature, low-density lipoprotein and high-density lipoprotein have been regarded as two different states of the same biological structure (named "cholesterol"), such as in nuclear physics, the neutron and proton are two different states of the same particle named nucleon.