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Objective: To elucidate how postdiagnosis multimorbidity and lifestyle changes contribute to the excess mortality of rheumatoid arthritis (RA). Methods: We performed a matched cohort study among women in the Nurses' Health Study (1976–2018). We identified women with incident RA and matched each by age and year to 10 non‐RA comparators at the RA diagnosis index date. Specific causes of death were ascertained via death certificates and medical record review. Lifestyle and morbidity factors were reported biennially; 61 chronic conditions were combined into the Multimorbidity Weighted Index (MWI). After adjusting for baseline confounders, we used inverse probability weighting analysis to examine the mediating influence of postindex MWI scores and lifestyle factors on total, cardiovascular, and respiratory mortality, comparing women with RA to their matched comparators. Results: We identified 1,007 patients with incident RA and matched them to 10,070 non‐RA comparators. After adjusting for preindex confounders, we found that hazard ratios (HRs) and 95% confidence intervals (95% CIs) were higher for total mortality (HR 1.46 [95% CI 1.32, 1.62]), as well as cardiovascular (HR 1.54 [95% CI 1.22, 1.94]) and respiratory (HR 2.75 [95% CI 2.05, 3.71]) mortality in patients with RA compared to non‐RA comparators. Adjusting for postindex lifestyle factors (physical activity, body mass index, diet, smoking) attenuated but did not substantially account for this excess RA mortality. After additional adjustment for postindex MWI scores, patients with RA had HRs of 1.18 (95% CI 1.05, 1.32) for total, 1.19 (95% CI 0.94, 1.51) for cardiovascular, and 1.93 (95% CI 1.42, 2.62) for respiratory mortality. Conclusion: We found that MWI scores substantially accounted for the excess total and cardiovascular mortality among women with RA. This finding underscores the importance of monitoring for the total disease burden as a whole in monitoring patients with RA. [ABSTRACT FROM AUTHOR]

Background: We recently described increased NFATc1, IRF4, and NIP45 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) of asthmatic children and adults with multiple allergies. Objective: NFATc2 has been described to associate with IRF4 to induce interleukin‐4, and to be inhibited by T‐bet. Here, we analyzed the role of NFATc2 in asthmatic children and adults. Methods: PBMCs were isolated from the blood of control of asthmatics subjects. Some PBMCs were analyzed untreated and some cultured with and without phytohemagglutinin. Then, RNA was extracted from the cells and cytokines were measured in the supernatants via enzyme‐linked immunosorbent assay or multiplex analysis. RNA was then reverse‐transcribed and NFATc1, NFATC2, IRF4, and T‐bet mRNA were analyzed by real‐time polymerase chain reaction. In addition, in peripheral blood cells, NFATc2 expression was analyzed, in a population of asthmatic children and adults from the Asthma BRIDGE study. Results: In addition to NFATc1 and NIP45, also NFATc2 was found upregulated in PBMCs and peripheral blood cells from asthmatic children and adults with allergic asthma. Moreover, NFATc1 directly correlated with lymphocytes number whereas NFATc2 correlated with peripheral eosinophilia in asthma. Conclusions: In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 mRNA correlated with lymphocytes both in control and asthma, and NFATC1 and NFATc2 mRNA showed a direct correlation with eosinophils in controls but not in asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma. Clinical Significance: Targeting NFATc2 in T lymphocytes might ameliorate the allergic phenotype in asthmatic subjects. [ABSTRACT FROM AUTHOR]

Bronchoscopy is the safest procedure for lung cancer diagnosis when an invasive evaluation is required after imaging procedures. However, its sensitivity is relatively low, especially for small and peripheral lesions. We assessed benefits and costs of introducing a bronchial gene‐expression classifier (BGC) to improve the performance of bronchoscopy and the overall diagnostic process for early detection of lung cancer. We used discrete‐event simulation to compare clinical and economic outcomes of two different strategies with the standard practice in former and current smokers with indeterminate nodules: (i) location‐based strategy—integrated the BGC to the bronchoscopy indication; (ii) simplified strategy—extended use of bronchoscopy plus BGC also on small and peripheral lesions. Outcomes modeled were rate of invasive procedures, quality‐adjusted‐life‐years (QALYs), costs and incremental cost‐effectiveness ratios. Compared to the standard practice, the location‐based strategy (i) reduced absolute rate of invasive procedures by 3.3% without increasing costs at the current BGC market price. It resulted in savings when the BGC price was less than $3,000. The simplified strategy (ii) reduced absolute rate of invasive procedures by 10% and improved quality‐adjusted life expectancy, producing an incremental cost‐effectiveness ratio of $10,109 per QALY. In patients with indeterminate nodules, both BGC strategies reduced unnecessary invasive procedures at high risk of adverse events. Moreover, compared to the standard practice, the simplified use of BGC for central and peripheral lesions resulted in larger QALYs gains at acceptable cost. The location‐based is cost‐saving if the price of classifier declines. What's new? Bronchoscopy is the safest procedure for lung cancer diagnosis when an invasive evaluation is required following imaging procedures. Its sensitivity is relatively low, however. This study assesses benefits and costs of introducing a bronchial gene‐expression classifier (BGC) to improve the performance of bronchoscopy and the overall process for early detection of lung cancer. When compared with standard practice, an extended use of BGC for diagnosis of central and peripheral pulmonary lesions improves quality‐adjusted life expectancy, reduces unnecessary invasive procedures, and has an incremental cost‐effectiveness ratio of US $10,109 per quality‐adjusted life year gained, without increasing mortality. [ABSTRACT FROM AUTHOR]

Background: Response to inhaled corticosteroids is highly variable, and the association between DNA methylation and treatment response is not known. Objective: To examine the association between peripheral blood DNA methylation and inhaled corticosteroid response in children with persistent asthma. Methods: Epigenome‐wide DNA methylation was analysed in individuals on inhaled corticosteroids in three independent and ethnically diverse cohorts—Childhood Asthma Management Program (CAMP); Children, Allergy, Milieu, Stockholm, Epidemiology (BAMSE); and Genetic Epidemiology of Asthma in Costa Rica Study (GACRS). Treatment response was evaluated using two definitions, the absence of emergency department visits and/or hospitalizations and the absence oral corticosteroid use while on inhaled corticosteroid therapy. CpG sites meeting nominal significance (P < 0.05) for each outcome were combined in a three‐cohort meta‐analysis with adjustment for multiple testing. DNA methylation was correlated with gene expression using Pearson and partial correlations. Results: In 154 subjects from CAMP, 72 from BAMSE, and 168 from GACRS, relative hypomethylation of cg00066816 (171 bases upstream of IL12B) was associated with the absence of emergency department visits and/or hospitalizations (Q = 0.03) in all cohorts and lower IL12B expression (ρ = 0.34, P = 0.01) in BAMSE. Relative hypermethylation of cg04256470 (688 bases upstream of CORT) was associated with the absence of oral corticosteroid use (Q = 0.04) in all cohorts and higher CORT expression (ρ = 0.20, P = 0.045) in CAMP. Conclusion and Clinical Relevance: Differential DNA methylation of IL12B and CORT are associated with inhaled corticosteroid treatment response in persistent childhood asthmatics. Pharmaco‐methylation can identify novel markers of treatment sensitivity in asthma. [ABSTRACT FROM AUTHOR]

Objective: Asthmatic children who develop obesity through adolescence have poorer disease outcomes compared with those who do not. This study aimed to characterize the biology of childhood asthma complicated by adult obesity.Methods: Gene expression networks are powerful statistical tools for characterizing human disease that leverage the putative coregulatory relationships of genes to infer relevant biological pathways. Weighted gene coexpression network analysis of gene expression data was performed in whole blood from 514 adult asthmatic subjects. Then, module preservation and association replication analyses were performed in 418 subjects from two independent asthma cohorts (one pediatric and one adult).Results: A multivariate model was identified in which three gene coexpression network modules were associated with incident obesity in the discovery cohort (each P < 0.05). Two module memberships were enriched for genes in pathways related to platelets, integrins, extracellular matrix, smooth muscle, NF-κB signaling, and Hedgehog signaling. The network structures of each of the obesity modules were significantly preserved in both replication cohorts (permutation P = 9.999E-05). The corresponding module gene sets were significantly enriched for differential expression in subjects with obesity in both replication cohorts (each P < 0.05).Conclusions: The gene coexpression network profiles thus implicate multiple interrelated pathways in the biology of an important endotype of asthma with obesity. [ABSTRACT FROM AUTHOR]

Summary: Background: Asthma represents a significant public health burden; however, novel biological therapies targeting immunoglobulin E (IgE)‐mediated pathways have widened clinical treatment options for the disease. Objective: In this study, we sought to identify gene transcripts and gene networks involved in the determination of serum IgE levels in people with asthma that can help inform the development of novel therapeutic agents. Methods: We analysed gene expression data from a cross‐sectional study of 326 Costa Rican children with asthma, aged 6 to 12 years, from the Genetics of Asthma in Costa Rica Study and 610 young adults with asthma, aged 16 to 25 years, from the Childhood Asthma Management Program trial. We utilized differential gene expression analysis and performed weighted gene coexpression network analysis on 25 060 genes, to identify gene transcripts and network modules associated with total IgE, adjusting for age and gender. We used pathway enrichment analyses to identify key biological pathways underlying significant modules. We compared findings that replicated between both populations. Results: We identified 31 transcripts associated with total IgE that replicated between the two study cohorts. These results were notable for increased eosinophil‐related transcripts (including IL5RA, CLC, SMPD3, CCL23 and CEBPE). Pathway enrichment identified the regulation of T cell tolerance as important in the determination of total IgE levels, supporting a key role for IDO1. Conclusions and Clinical Relevance: These results provide robust evidence that biologically meaningful gene expression profiles (relating to eosinophilic and regulatory T cell pathways in particular) associated with total IgE levels can be identified in individuals diagnosed with asthma during childhood. These profiles and their constituent genes may represent novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Williams-Beuren syndrome (WBS) is a chromosomal microdeletion syndrome typically presenting with intellectual disability, a unique personality, a characteristic facial appearance, and cardiovascular disease. Several clinical features of WBS are thought to be due to haploinsufficiency of elastin (ELN), as the ELN locus is included within the WBS critical region at 7q11.23. Emphysema, a disease attributed to destruction of pulmonary elastic fibers, has been reported in patients without WBS who have pathogenic variants in ELN but only once (in one patient) in WBS. Here we report a second adult WBS patient with emphysema where the diagnosis of WBS was established subsequent to the discovery of severe bullous emphysema. Haploinsufficiency of ELN likely contributed to this pulmonary manifestation of WBS. This case emphasizes the contribution of rare genetic variation in cases of severe emphysema and provides further evidence that emphysema should be considered in patients with WBS who have respiratory symptoms, as it may be under-recognized in this patient population. [ABSTRACT FROM AUTHOR]

Introduction While whole genome prediction (WGP) methods have recently demonstrated successes in the prediction of complex genetic diseases, they have not yet been applied to asthma and related phenotypes. Longitudinal patterns of lung function differ between asthmatics, but these phenotypes have not been assessed for heritability or predictive ability. Herein, we assess the heritability and genetic predictability of asthma-related phenotypes. Methods We applied several WGP methods to a well-phenotyped cohort of 832 children with mild-to-moderate asthma from CAMP. We assessed narrow-sense heritability and predictability for airway hyperresponsiveness, serum immunoglobulin E, blood eosinophil count, pre- and post-bronchodilator forced expiratory volume in 1 sec (FEV1), bronchodilator response, steroid responsiveness, and longitudinal patterns of lung function (normal growth, reduced growth, early decline, and their combinations). Prediction accuracy was evaluated using a training/testing set split of the cohort. Results We found that longitudinal lung function phenotypes demonstrated significant narrow-sense heritability (reduced growth, 95%; normal growth with early decline, 55%). These same phenotypes also showed significant polygenic prediction (areas under the curve [AUCs] 56% to 62%). Including additional demographic covariates in the models increased prediction 4-8%, with reduced growth increasing from 62% to 66% AUC. We found that prediction with a genomic relatedness matrix was improved by filtering available SNPs based on chromatin evidence, and this result extended across cohorts. Conclusions Longitudinal reduced lung function growth displayed extremely high heritability. All phenotypes with significant heritability showed significant polygenic prediction. Using SNP-prioritization increased prediction across cohorts. WGP methods show promise in predicting asthma-related heritable traits. [ABSTRACT FROM AUTHOR]

Short-acting β agonists (e.g., albuterol) are the most commonly used medications for asthma, a disease that affects over 300 million people in the world. Metabolomic profiling of asthmatics taking β agonists presents a new and promising resource for identifying the molecular determinants of asthma control. The objective is to identify novel genetic and biochemical predictors of asthma control using an integrative 'omics' approach. We generated lipidomic data by liquid chromatography tandem mass spectrometry (LC-MS), ­ using plasma samples from 20 individuals with asthma. The outcome of interest was a binary indicator of asthma control defined by the use of albuterol inhalers in the preceding week. We integrated metabolomic data with genome-wide genotype, gene expression, and methylation data of this cohort to identify genomic and molecular indicators of asthma control. A Conditional Gaussian Bayesian Network (CGBN) was generated using the strongest predictors from each of these analyses. Integrative and metabolic pathway over-representation analyses (ORA) identified enrichment of known biological pathways within the strongest molecular determinants. Of the 64 metabolites measured, 32 had known identities. The CGBN model based on four SNPs (rs9522789, rs7147228, rs2701423, rs759582) and two metabolites-monoHETE_0863 and sphingosine-1-phosphate (S1P) could predict asthma control with an AUC of 95%. Integrative ORA identified 17 significantly enriched pathways related to cellular immune response, interferon signaling, and cytokine-related signaling, for which arachidonic acid, PGE2 and S1P, in addition to six genes (CHN1, PRKCE, GNA12, OASL, OAS1, and IFIT3) appeared to drive the pathway results. Of these predictors, S1P, GNA12, and PRKCE were enriched in the results from integrative and metabolic ORAs. Through an integrative analysis of metabolomic, genomic, and methylation data from a small cohort of asthmatics, we implicate altered metabolic pathways, related to sphingolipid metabolism, in asthma control. These results provide insight into the pathophysiology of asthma control. [ABSTRACT FROM AUTHOR]

Background— Distinct receptors likely exist for leukotriene(LT)E4, a potent mediator of airway inflammation. Purinergic receptor P2Y12 is needed for LTE4-induced airways inflammation, and P2Y12 antagonism attenuates house dust mite-induced pulmonary eosinophilia in mice. Although experimental data support a role for P2Y12 in airway inflammation, its role in human asthma has never been studied. Objective— To test for association between variants in the P2Y12 gene (P2RY12) and lung function in human subjects with asthma, and to examine for gene-by-environment interaction with house dust mite exposure. Methods— 19 single nucleotide polymorphisms (SNPs) in P2RY12 were genotyped in 422 children with asthma and their parents (n=1266). Using family-based methods, we tested for associations between these SNPs and five lung function measures. We performed haplotype association analyses and tested for gene-by-environment interactions using house dust mite exposure. We used the false discovery rate to account for multiple comparisons. Results— Five SNPs in P2RY12 were associated with multiple lung function measures (P values 0.006–0.025). Haplotypes in P2RY12 were also associated with lung function (P values 0.0055– 0.046). House dust mite exposure modulated associations between P2RY12 and lung function, with minor allele homozygotes exposed to house dust mite demonstrating worse lung function than those unexposed (significant interaction P values 0.0028–0.040). Conclusions and clinical relevance— P2RY12 variants were associated with lung function in a large family-based asthma cohort. House dust mite exposure caused significant gene-by- environment effects. Our findings add the first human evidence to experimental data supporting a role for P2Y12 in lung function. P2Y12 could represent a novel target for asthma treatment.

The cover image, by Monica H. Wojcik et al., is based on the Clinical Report A new diagnosis of Williams‐Beuren syndrome in a 49‐year‐old man with severe bullous emphysema, DOI: 10.1002/ajmg.a.38289. [ABSTRACT FROM AUTHOR]

Williams-Beuren syndrome (WBS) is caused by a submicroscopic deletion on chromosome 7q11.23 that encompasses the entire elastin (ELN) gene. Elastin, a key component of elastic fibers within the lung, is progressively destroyed in emphysema. Defects in the elastin gene have been associated with increased susceptibility towards developing chronic obstructive pulmonary disease (COPD) and emphysema in both humans and mice. We postulate that hemizygosity at the elastin gene locus may increase susceptibility towards the development of COPD and emphysema in subjects with WBS. We describe an adult subject with WBS who was a lifelong non-smoker and was found to have moderate emphysema. We also examined the pulmonary function of a separate cohort of adolescents and young adults with WBS. Although no significant spirometric abnormalities were identified, a significant proportion of subjects reported respiratory symptoms. Thus, while significant obstructive disease does not appear to be common in relatively young adults with WBS, subclinical emphysema and lung disease may exist which possibly could worsen with advancing age. Further investigation may elucidate the pathogenesis of non-smoking-related emphysema., ((c) 2010 Wiley-Liss, Inc.)