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While the microbiome has an established role in asthma development, less is known about its contribution to morbidity in children with asthma.In this ancillary study of the Vitamin D Antenatal Asthma Reduction Trial (VDAART), we analyzed the gut microbiome and metabolome of wheeze frequency in children with asthma.Bacterial 16S ribosomal RNA microbiome and untargeted metabolomic profiling were performed on fecal samples collected from 3-year-old children with parent-reported physician-diagnosed asthma. We analyzed wheeze frequency by calculating the proportion of quarterly questionnaires administered between ages 3 and 5 years in which parents reported the child had wheezed (wheeze proportion). Taxa and metabolites associated with wheeze were analyzed by identifying log fold changes with respect to wheeze frequency and correlation/linear regression analyses, respectively. Microbe-metabolite and microbe-microbe correlation networks were compared between subjects with high and low wheeze proportion.Specific taxa, including the genus Veillonella and histidine pathway metabolites, were enriched in subjects with high wheeze proportion. Among wheeze-associated taxa, Veillonella and Oscillospiraceae UCG-005, which was inversely associated with wheeze, were correlated with the greatest number of fecal metabolites. Microbial networks were similar between subjects with low versus high wheeze frequency.Gut microbiome features are associated with wheeze frequency in children with asthma, suggesting an impact of the gut microbiome on morbidity in childhood asthma.

Background: Plasma proteins are critical mediators of cardiovascular processes and are the targets of many drugs. Previous efforts to characterize the genetic architecture of the plasma proteome have been limited by a focus on individuals of European descent and leveraged genotyping arrays and imputation. Here we describe whole genome sequence analysis of the plasma proteome in individuals with greater African ancestry, increasing our power to identify novel genetic determinants. Methods: Proteomic profiling of 1301 proteins was performed in 1852 Black adults from the Jackson Heart Study using aptamer-based proteomics (SomaScan). Whole genome sequencing association analysis was ascertained for all variants with minor allele count ≥5. Results were validated using an alternative, antibody-based, proteomic platform (Olink) as well as replicated in the Multi-Ethnic Study of Atherosclerosis and the HERITAGE Family Study (Health, Risk Factors, Exercise Training and Genetics). Results: We identify 569 genetic associations between 479 proteins and 438 unique genetic regions at a Bonferroni-adjusted significance level of 3.8×10 -11 . These associations include 114 novel locus-protein relationships and an additional 217 novel sentinel variant-protein relationships. Novel cardiovascular findings include new protein associations at the APOE gene locus including ZAP70 (sentinel single nucleotide polymorphism [SNP] rs7412-T, β=0.61±0.05, P =3.27×10 -30 ) and MMP-3 (β=-0.60±0.05, P =1.67×10 -32 ), as well as a completely novel pleiotropic locus at the HPX gene, associated with 9 proteins. Further, the associations suggest new mechanisms of genetically mediated cardiovascular disease linked to African ancestry; we identify a novel association between variants linked to APOL1-associated chronic kidney and heart disease and the protein CKAP2 (rs73885319-G, β=0.34±0.04, P =1.34×10 -17 ) as well as an association between ATTR amyloidosis and RBP4 levels in community-dwelling individuals without heart failure. Conclusions: Taken together, these results provide evidence for the functional importance of variants in non-European populations, and suggest new biological mechanisms for ancestry-specific determinants of lipids, coagulation, and myocardial function.

RATIONALE: Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a more detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes (i.e., subtypes defined by functional and/or pathobiological mechanisms). OBJECTIVES: To validate metabolomic-driven endotypes of asthma and explore their underlying biology. METHODS: In the Genetics of Asthma in Costa Rica Study (GACRS), untargeted metabolomic profiling, similarity network fusion, and spectral clustering was used to identify metabo-endotypes of asthma, and differences in asthma-relevant phenotypes across these metabo-endotypes were explored. The metabo-endotypes were recapitulated in the Childhood Asthma Management Program (CAMP), and clinical differences were determined. Metabolomic drivers of metabo-endotype membership were investigated by meta-analyzing findings from GACRS and CAMP. MEASUREMENTS AND MAIN RESULTS: Five metabo-endotypes were identified in GACRS with significant differences in asthma-relevant phenotypes, including prebronchodilator (p-ANOVA = 8.3 × 10(−5)) and postbronchodilator (p-ANOVA = 1.8 × 10(−5)) FEV(1)/FVC. These differences were validated in the recapitulated metabo-endotypes in CAMP. Cholesterol esters, trigylcerides, and fatty acids were among the most important drivers of metabo-endotype membership. The findings suggest dysregulation of pulmonary surfactant homeostasis may play a role in asthma severity. CONCLUSIONS: Clinically meaningful endotypes may be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes has the potential to help understand their pathophysiology.

Genomic medicine holds great promise for improving health care, but integrating searchable and actionable genetic data into electronic health records (EHRs) remains a challenge. Here we describe Neptune, a system for managing the interaction between a clinical laboratory and an EHR system during the clinical reporting process. We developed Neptune and applied it to two clinical sequencing projects that required report customization, variant reanalysis, and EHR integration. Neptune has been applied for the generation and delivery of over 15,000 clinical genomic reports. This work spans two clinical tests based on targeted gene panels that contain 68 and 153 genes respectively. These projects demanded customizable clinical reports that contained a variety of genetic data types including single-nucleotide variants (SNVs), copy-number variants (CNVs), pharmacogenomics, and polygenic risk scores. Two variant reanalysis activities were also supported, highlighting this important workflow. Methods are needed for delivering structured genetic data to EHRs. This need extends beyond developing data formats to providing infrastructure that manages the reporting process itself. Neptune was successfully applied on two high-throughput clinical sequencing projects to build and deliver clinical reports to EHR systems. The software is open source and available at https://gitlab.com/bcm-hgsc/neptune .

Background: Many microRNAs (miRNAs) have been associated with asthma and chronic obstructive pulmonary disease (COPD). Longitudinal lung function growth trajectories of children with asthma—normal growth, reduced growth (RG), early decline (ED), and RG with an ED (RGED)—have been observed, with RG and RGED associated with adverse outcomes, including COPD. Objective: Our aim was to determine whether circulating miRNAs from an early age in children with asthma would be prognostic of reduced lung function growth patterns over the next 16 years. Methods: We performed small RNA sequencing on sera from 492 children aged 5 to 12 years with mild-to-moderate asthma from the CAMP clinical trial, who were subsequently followed for 12 to 16 years. miRNAs were assessed for differential expression between previously assigned lung function growth patterns. Results: We had 448 samples and 259 miRNAs for differential analysis. In a comparison of the normal and the most severe group (ie, normal growth compared with RGED), we found 1 strongly dysregulated miRNA, hsa-miR-145-5p (P < 8.01E–05). This miR was downregulated in both ED groups (ie, ED and RGED). We verified that miR-145-5p was strongly associated with airway smooth muscle cell growth in vitro. Conclusion: Our results showed that miR-145-5p is associated with the ED patterns of lung function growth leading to COPD in children with asthma and additionally increases airway smooth muscle cell proliferation. This represents a significant extension of our understanding of the role of miR-145-5p in COPD and suggests that reduced expression of miR-145-5p is a risk factor for ED of long-term lung function., GRAPHICAL ABSTRACT

Age is the dominant risk factor for infectious diseases, but the mechanisms linking the two are incompletely understood1,2. Age-related mosaic chromosomal alterations (mCAs) detected from blood-derived DNA genotyping, are structural somatic variants associated with aberrant leukocyte cell counts, hematological malignancy, and mortality3-11. Whether mCAs represent independent risk factors for infection is unknown. Here we use genome-wide genotyping of blood DNA to show that mCAs predispose to diverse infectious diseases. We analyzed mCAs from 767,891 individuals without hematological cancer at DNA acquisition across four countries. Expanded mCA (cell fraction10%) prevalence approached 4% by 60 years of age and was associated with diverse incident infections, including sepsis, pneumonia, and coronavirus disease 2019 (COVID-19) hospitalization. A genome-wide association study of expanded mCAs identified 63 significant loci. Germline genetic alleles associated with expanded mCAs were enriched at transcriptional regulatory sites for immune cells. Our results link mCAs with impaired immunity and predisposition to infections. Furthermore, these findings may also have important implications for the ongoing COVID-19 pandemic, particularly in prioritizing individual preventive strategies and evaluating immunization responses.

Most genome-wide association studies of obesity and body mass index (BMI) have so far assumed an additive mode of inheritance in their analysis, although association testing supports a recessive effect for some of the established loci, for example, rs1421085 in FTO. In two whole-genome sequencing (WGS) studies of children with asthma and their parents (892 Costa Rican trios and 286 North American trios), we discovered an association between a locus (rs9292139) in LOC102724122 and BMI that reaches genome-wide significance under a recessive model in the combined analysis. As the association does not achieve significance under an additive model, our finding illustrates the benefits of the recessive model in WGS analyses.

Rationale: A link among sphingolipids, 17q21 genetic variants, and childhood asthma has been suggested, but the underlying mechanisms and characteristics of such an asthma endotype remain to be elu...

Background Nasal transcriptomics can provide an accessible window into asthma pathobiology. Objective Our goal was to move beyond gene signatures of asthma to identify master regulator genes that causally regulate genes associated with asthma phenotypes. Methods We recruited 156 children with severe persistent asthma and controls for nasal transcriptome profiling and applied network-based and probabilistic causal methods to identify severe asthma genes and their master regulators. We then took the same approach in an independent cohort of 190 adults with mild/moderate asthma and controls to identify mild/moderate asthma genes and their master regulators. Comparative analysis of the master regulator genes followed by validation testing in independent children with severe asthma (n = 21) and mild/moderate asthma (n = 154) was then performed. Results Nasal gene signatures for severe persistent asthma and for mild/moderate persistent asthma were identified; both were found to be enriched in coexpression network modules for ciliary function and inflammatory response. By applying probabilistic causal methods to these gene signatures and validation testing in independent cohorts, we identified (1) a master regulator gene common to asthma across severity and ages (FOXJ1); (2) master regulator genes of severe persistent asthma in children (LRRC23, TMEM231, CAPS, PTPRC, and FYB); and (3) master regulator genes of mild/moderate persistent asthma in children and adults (C1orf38 and FMNL1). The identified master regulators were statistically inferred to causally regulate the expression of downstream genes that modulate ciliary function and inflammatory response to influence asthma. Conclusion The identified master regulator genes of asthma provide a novel path forward to further uncovering asthma mechanisms and therapy.

BackgroundHemodynamic stress, conditioned by the morphology of the surrounding vasculature, plays an important role in aneurysm formation. Our goal was to identify image-based location-specific parameters that are associated with posterior communicating artery (PCoA) aneurysms.MethodsThree-dimensional morphological parameters obtained from CT angiography or digital subtraction angiography from 187 patients with unilateral PCoA aneurysms, diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, were evaluated. In order to control for genetic and clinical risk factors, we chose the contralateral unaffected PCoA as a control group. We examined diameters and angles of the surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. Sensitivity analyses with small aneurysms (≤5 mm) only and an unmatched analysis of 432 PCoA aneurysms and 197 control patients without PCoA aneurysms were also performed.ResultsIn a multivariable conditional logistic regression model we showed that smaller diameter size ratio (OR 1.45×10−5, 95% CI 1.12×10−7 to 1.88×10−3) and larger daughter-daughter angle (OR 1.04, 95% CI 1.02 to 1.07) were significantly associated with PCoA aneurysm presence after correcting for other variables. In subgroup analyses of small aneurysms (≤5 mm) and in an unmatched analysis the significance and direction of these results were preserved.ConclusionsLarger daughter-daughter angles and smaller diameter size ratio are significantly associated with the presence of PCoA aneurysms. These simple parameters can be utilized to guide the risk assessment for the formation of PCoA aneurysms in high risk patients.

OBJECTIVE: To examine whether maternal race could affect the relationship between fetal sex and preeclampsia. MATERIAL AND METHODS: This study was a cohort analysis using prospectively collected data from pregnant women who participated in the Vitamin Antenatal Asthma Reduction Trial (VDAART). Preeclampsia was the secondary outcome of VDAART. We examined the association of fetal sex with preeclampsia and its potential interaction with maternal race in 813 pregnant women (8% with preeclampsia) in logistic regression models with adjustment for preterm birth (

Rationale: Inhaled corticosteroids (ICS) are key treatments for controlling asthma and preventing asthma attacks. However, the responsiveness to ICS varies among individuals. MicroRNAs (miRNAs) hav...

Polygenic risk scores (PRS) for coronary artery disease (CAD) identify high-risk individuals more likely to benefit from primary prevention statin therapy. Whether polygenic CAD risk is captured by conventional paradigms for assessing clinical cardiovascular risk remains unclear.This study sought to intersect polygenic risk with guideline-based recommendations and management patterns for CAD primary prevention.A genome-wide CAD PRS was applied to 47,108 individuals across 3 U.S. health care systems. The authors then assessed whether primary prevention patients at high polygenic risk might be distinguished on the basis of greater guideline-recommended statin eligibility and higher rates of statin therapy.Of 47,108 study participants, the mean age was 60 years, and 11,020 (23.4%) had CAD. The CAD PRS strongly associated with prevalent CAD (odds ratio: 1.4 per SD increase in PRS; p 0.0001). High polygenic risk (top 20% of PRS) conferred 1.9-fold odds of developing CAD (p 0.0001). However, among primary prevention patients (n = 33,251), high polygenic risk did not correspond with increased recommendations for statin therapy per the American College of Cardiology/American Heart Association (46.2% for those with high PRS vs. 46.8% for all others, p = 0.54) or U.S. Preventive Services Task Force (43.7% vs. 43.7%, p = 0.99) or higher rates of statin prescriptions (25.0% vs. 23.8%, p = 0.04). An additional 4.1% of primary prevention patients may be recommended for statin therapy if high CAD PRS were considered a guideline-based risk-enhancing factor.Current paradigms for primary cardiovascular prevention incompletely capture a polygenic susceptibility to CAD. An opportunity may exist to improve CAD prevention efforts by integrating both genetic and clinical risk.

BACKGROUND: We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze. METHODS: In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children’s sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D(3) per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D(3) per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups. RESULTS: There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance. CONCLUSIONS: Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.)

Summary Genome-wide association studies (GWAS) have revealed thousands of genetic loci for common diseases. One of the main challenges in the post-GWAS era is to understand the causality of the genetic variants. Expression quantitative trait locus (eQTL) analysis is an effective way to address this question by examining the relationship between gene expression and genetic variation in a sufficiently powered cohort. However, it is frequently a challenge to determine the sample size at which a variant with a specific allele frequency will be detected to associate with gene expression with sufficient power. This is a particularly difficult task for single-cell RNAseq studies. Therefore, a user-friendly tool to estimate statistical power for eQTL analyses in both bulk tissue and single-cell data is needed. Here, we presented an R package called powerEQTL with flexible functions to estimate power, minimal sample size or detectable minor allele frequency for both bulk tissue and single-cell eQTL analysis. A user-friendly, program-free web application is also provided, allowing users to calculate and visualize the parameters interactively. Availability and implementation The powerEQTL R package source code and online tutorial are freely available at CRAN: https://cran.r-project.org/web/packages/powerEQTL/. The R shiny application is publicly hosted at https://bwhbioinfo.shinyapps.io/powerEQTL/. Supplementary information Supplementary data are available at Bioinformatics online.

We present a cohort of patients with anterior communicating artery (ACoA) aneurysms to investigate morphological characteristics and clinical factors associated with rupture of the aneurysms. 505 patients with ACoA aneurysms were identified at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016, with available CT angiography (CTA). Three-dimensional (3D) reconstructions were performed to evaluate aneurysmal morphologic features, including location, projection, irregularity, the presence of daughter dome, height, height/width ratio, and relationships between surrounding vessels. Patient risk factors assessed included patient age, sex, tobacco use, alcohol use, and family history of aneurysms and aneurysmal subarachnoid hemorrhage. Logistic regression was used to build a predictive ACoA score for rupture. Morphologic features associated with ruptured ACoA aneurysms were the presence of a daughter dome (OR 21.4, 95% CI 10.6–43.1), smaller neck diameter (OR 0.55, 95% CI 0.42–0.71), larger aspect ratio (OR 3.57, 95% CI 2.05–6.24), larger flow angle (OR 1.03, 95% CI 1.02–1.05), and smaller ipsilateral A2-ACoA angle (OR 0.98, 95% CI 0.97–1.00). Tobacco use was predominantly associated with morphological factors intrinsic to the aneurysm that were associated with rupture while younger age was also associated with morphologic features extrinsic to the aneurysm that were associated with rupture. The ACoA score had good predictive capacity for rupture with AUC = 0.92 using the 0.632 bootstrap cross-validation for correction of overfitting bias. Ruptured ACoA aneurysms were associated with morphological features that are simple to assess using a simple scoring system. Tobacco use and younger age were predominantly associated with intrinsic and extrinsic morphological features characteristic of rupture, respectively.

Morphological factors of intracranial aneurysms and the surrounding vasculature could affect aneurysm rupture risk in a location specific manner. Our goal was to identify image-based morphological parameters that correlated with ruptured basilar tip aneurysms. Three-dimensional morphological parameters obtained from CT-angiography (CTA) or digital subtraction angiography (DSA) from 200 patients with basilar tip aneurysms diagnosed at the Brigham and Women’s Hospital and Massachusetts General Hospital between 1990 and 2016 were evaluated. We examined aneurysm wall irregularity, the presence of daughter domes, hypoplastic, aplastic or fetal PCoAs, vertebral dominance, maximum height, perpendicular height, width, neck diameter, aspect and size ratio, height/width ratio, and diameters and angles of surrounding parent and daughter vessels. Univariable and multivariable statistical analyses were performed to determine statistical significance. In multivariable analysis, presence of a daughter dome, aspect ratio, and larger flow angle were significantly associated with rupture status. We also introduced two new variables, diameter size ratio and parent-daughter angle ratio, which were both significantly inversely associated with ruptured basilar tip aneurysms. Notably, multivariable analyses also showed that larger diameter size ratio was associated with higher Hunt-Hess score while smaller flow angle was associated with higher Fisher grade. These easily measurable parameters, including a new parameter that is unlikely to be affected by the formation of the aneurysm, could aid in screening strategies in high-risk patients with basilar tip aneurysms. One should note, however, that the changes in parameters related to aneurysm morphology may be secondary to aneurysm rupture rather than causal.

Metabolomic indicators of asthma treatment responses have yet to be identified. In this study, we aimed to uncover plasma metabolomic profiles associated with asthma exacerbations while on inhaled corticosteroid (ICS) treatment. We determined whether these profiles change with age from adolescence to adulthood. We utilized data from 170 individuals with asthma on ICS from the Mass General Brigham Biobank to identify plasma metabolites associated with asthma exacerbations while on ICS and examined potential effect modification of metabolite-exacerbation associations by age. We used liquid chromatography–high-resolution mass spectrometry-based metabolomic profiling. Sex-stratified analyses were also performed for the significant associations. The age range of the participating individuals was 13–43 years with a mean age of 33.5 years. Of the 783 endogenous metabolites tested, eight demonstrated significant associations with exacerbation after correction for multiple comparisons and adjusting for potential confounders (Bonferroni p value &lt, 6.2 × 10−4). Potential effect modification by sex was detected for fatty acid metabolites, with males showing a greater reduction in their metabolite levels with ICS exacerbation. Thirty-eight metabolites showed suggestive interactions with age on exacerbation (nominal p-value &lt, 0.05). Our findings demonstrate that plasma metabolomic profiles differ for individuals who experience asthma exacerbations while on ICS. The differentiating metabolites may serve as biomarkers of ICS response and may highlight metabolic pathways underlying ICS response variability.

Rationale: The 17q12–21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants. Objectives: To identify functional variants at 17q12–21.1 associated with early-onset asthma among African American individuals. Methods: We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race–Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders–Asthma) (n = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant. Measurements and Main Results: The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of GSDMB (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms. Conclusions: A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12–21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.

RationaleThe biochemical mechanisms underlying lung function are incompletely understood.ObjectivesTo identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery—the European Prospective Investigation into Cancer–Norfolk (EPIC-Norfolk, n=10 460) and validation—the VA Normative Aging Study (NAS) metabolomic cohort (n=437).MethodsWe ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and pMeasurements and main resultsOf 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC.ConclusionsThe validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.

Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for an equitable deployment of PRS to clinical practice that benefits global populations. Here we integrate T2D GWAS in European, African American and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and evaluate the PRS in the multi-ethnic eMERGE study, four African American cohorts, and the Taiwan Biobank. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined, and the top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5 fold of increase in T2D risk, suggesting the potential of using the trans-ancestry PRS as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

Obesity is a significant co-morbidity that associates with increased prevalence and severity of asthma. The mechanism underlying the obesity-asthma association remains poorly understood, and for obese asthmatics there is no effective therapy for obese asthmatics. Here we show that cholecystokinin (CCK)—a metabolic hormone best known for its roles in satiety regulation and fat metabolism–is increased in the lungs of obese mice and that pharmacological blockade of CCK and its receptor (CCKAR) signaling in the lung abolishes obesity-associated airway hyperresponsiveness (AHR)—a hallmark of asthma. By mining existing RNA-seq transcriptomic data, we first discovered CCKAR as a highly expressed G-protein-coupled receptor in primary human airway smooth muscle (ASM) cells. Interestingly, CCK is also expressed in ASM cells and is induced by free fatty acids. Activation of CCKAR by CCK induces ASM stiffening and contraction, which is abolished by either CRISPR-mediated CCKAR inactivation or CCKAR antagonists. In vivo, CCK levels are elevated in the lung of both genetically obese (db/db) and diet-induced obese mice. Importantly, intranasal administration of highly potent CCKAR antagonists (proglumide and devazepide) abolishes AHR in both genetically obese and diet-induced obese mice. Together, our results reveal an unexpected role for the metabolic hormone CCK and its receptor CCKAR in airway smooth muscle cells and in obesity-associated asthma. Our study provides critical pre-clinical data that support the repurposing of CCKAR antagonists as a novel therapy for obese asthmatics.

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes. Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV1 and FEV1/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV1/FVC 1

Background Global gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context. Methods We used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age. Results The SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10− 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10− 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells. Conclusion Focusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.

BACKGROUND: Asthma is a common respiratory disorder with a highly heterogeneous nature that remains poorly understood. The objective was to use whole genome sequencing (WGS) data to identify regions of common genetic variation contributing to lung function in individuals with a diagnosis of asthma. METHODS: WGS data were generated for 1,053 individuals from trios and extended pedigrees participating in the family-based Genetic Epidemiology of Asthma in Costa Rica study. Asthma affection status was defined through a physician’s diagnosis of asthma, and most participants with asthma also had airway hyperresponsiveness (AHR) to methacholine. Family-based association tests for single variants were performed to assess the associations with lung function phenotypes. RESULTS: A genome-wide significant association was identified between baseline FEV(1)/FVC ratio and a single-nucleotide polymorphism in the top hit cysteine-rich secretory protein LCCL domain-containing 2 (CRISPLD2) (rs12051168; P = 3.6 × 10(−8) in the unadjusted model) that retained suggestive significance in the covariate-adjusted model (P = 5.6 × 10(−6)). Rs12051168 was also nominally associated with other related phenotypes: baseline FEV(1) (P = 3.3 × 10(−3)), postbronchodilator (PB) FEV(1) (7.3 × 10(−3)), and PB FEV(1)/FVC ratio (P = 2.7 × 10(−3)). The identified baseline FEV(1)/FVC ratio and rs12051168 association was meta-analyzed and replicated in three independent cohorts in which most participants with asthma also had confirmed AHR (combined weighted z-score P = .015) but not in cohorts without information about AHR. CONCLUSIONS: These findings suggest that using specific asthma characteristics, such as AHR, can help identify more genetically homogeneous asthma subgroups with genotype-phenotype associations that may not be observed in all children with asthma. CRISPLD2 also may be important for baseline lung function in individuals with asthma who also may have AHR.

The advancement of precision medicine requires new methods to coordinate and deliver genetic data from heterogeneous sources to physicians and patients. The eMERGE III Network enrolled >25,000 participants from biobank and prospective cohorts of predominantly healthy individuals for clinical genetic testing to determine clinically actionable findings. The network developed protocols linking together the 11 participant collection sites and 2 clinical genetic testing laboratories. DNA capture panels targeting 109 genes were used for testing of DNA and sample collection, data generation, interpretation, reporting, delivery, and storage were each harmonized. A compliant and secure network enabled ongoing review and reconciliation of clinical interpretations, while maintaining communication and data sharing between clinicians and investigators. A total of 202 individuals had positive diagnostic findings relevant to the indication for testing and 1,294 had additional/secondary findings of medical significance deemed to be returnable, establishing data return rates for other testing endeavors. This study accomplished integration of structured genomic results into multiple electronic health record (EHR) systems, setting the stage for clinical decision support to enable genomic medicine. Further, the established processes enable different sequencing sites to harmonize technical and interpretive aspects of sequencing tests, a critical achievement toward global standardization of genomic testing. The eMERGE protocols and tools are available for widespread dissemination.

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. CLINICAL TRIAL REGISTRATION: Childhood Asthma Management Program (CAMP) Phases I (Trial), II (CAMPCS), III (CAMPCS/2) and IV (CAMPCS/3) NCT00000575.

Asthma is the most common chronic disease in children. Inhaled corticosteroids (ICS) are the first-line treatment for asthma control, but up to one-third of children have a poor treatment response. The mechanism of ICS resistance is poorly understood, and the role of DNA methylation in ICS treatment response is not known. We examined the association between peripheral blood DNA methylation and ICS treatment response in 152 pediatric persistent asthmatics from the Childhood Asthma Management Program. Response to ICS was measured by the percentage change in forced expiratory volume in 1 s (FEV1) 8 weeks after treatment initiation. The top CpG sites with a nominal P value less than 0.001 were correlated with gene expression using Pearson's and partial correlations. In 152 participants, mean±SD age was 9.8±2.0 years and median change in FEV1 after ICS initiation was 4.6% (interquartile range: 10.4%). A total of 545 CpG sites were differentially methylated (nominal P

BackgroundAsthma is a common but complex disease with racial/ethnic differences in prevalence, morbidity, and response to therapies.ObjectiveWe sought to perform an analysis of genetic ancestry to identify new loci that contribute to asthma susceptibility.MethodsWe leveraged the mixed ancestry of 3902 Latinos and performed an admixture mapping meta-analysis for asthma susceptibility. We replicated associations in an independent study of 3774 Latinos, performed targeted sequencing for fine mapping, and tested for disease correlations with gene expression in the whole blood of more than 500 subjects from 3 racial/ethnic groups.ResultsWe identified a genome-wide significant admixture mapping peak at 18q21 in Latinos (P=6.8×10-6), where Native American ancestry was associated with increased risk of asthma (odds ratio [OR], 1.20; 95% CI, 1.07-1.34; P=.002) and European ancestry was associated with protection (OR, 0.86; 95% CI, 0.77-0.96; P=.008). Our findings were replicated in an independent childhood asthma study in Latinos (P=5.3×10-3, combined P=2.6×10-7). Fine mapping of 18q21 in 1978 Latinos identified a significant association with multiple variants 5' of SMAD family member 2 (SMAD2) in Mexicans, whereas a single rare variant in the same window was the top association in Puerto Ricans. Low versus high SMAD2 blood expression was correlated with case status (13.4% lower expression; OR, 3.93; 95% CI, 2.12-7.28; P&nbsp

IntroductionOlder adults have the greatest burden of asthma and poorest outcomes. The pharmacogenetics of inhaled corticosteroid (ICS) treatment response is not well studied in older adults.MethodsA genome-wide association study of ICS response was performed in asthmatics of European ancestry in Genetic Epidemiology Research on Adult Health and Aging (GERA) by fitting Cox proportional hazards regression models, followed by validation in the Mass General Brigham (MGB) Biobank and Rotterdam Study. ICS response was measured using two definitions in asthmatics on ICS treatment: (1) absence of oral corticosteroid (OCS) bursts using prescription records and (2) absence of asthma-related exacerbations using diagnosis codes. A fixed-effect meta-analysis was performed for each outcome. The validated single-nucleotide polymorphisms (SNPs) were functionally annotated to standard databases.ResultsIn 5710 subjects in GERA, 676 subjects in MGB Biobank, and 465 subjects in the Rotterdam Study, four novel SNPs on chromosome six nearPTCHD4validated across all cohorts and met genome-wide significance on meta-analysis for the OCS burst outcome. In 4541 subjects in GERA and 505 subjects in MGB Biobank, 152 SNPs with p−5were validated across these two cohorts for the asthma-related exacerbation outcome. The validated SNPs included methylation and expression quantitative trait loci forCPED1,CRADDandDSTfor the OCS burst outcome andGM2A,SNW1,CACNA1C,DPH1, andRPS10for the asthma-related exacerbation outcome.ConclusionsMultiple novel SNPs associated with ICS response were identified in older adult asthmatics. Several SNPs annotated to genes previously associated with asthma and other airway or allergic diseases, includingPTCHD4.

Electronic health records (EHR) provide an unprecedented opportunity to conduct large, cost-efficient, population-based studies. However, the studies of heterogeneous diseases, such as chronic obstructive pulmonary disease (COPD), often require labor-intensive clinical review and testing, limiting widespread use of these important resources. To develop a generalizable and efficient method for accurate identification of large COPD cohorts in EHRs, a COPD datamart was developed from 3420 participants meeting inclusion criteria in the Mass General Brigham Biobank. Training and test sets were selected and labeled with gold-standard COPD classifications obtained from chart review by pulmonologists. Multiple classes of algorithms were built utilizing both structured (e.g. ICD codes) and unstructured (e.g. medical notes) data via elastic net regression. Models explicitly including and excluding spirometry features were compared. External validation of the final algorithm was conducted in an independent biobank with a different EHR system. The final COPD classification model demonstrated excellent positive predictive value (PPV; 91.7%), sensitivity (71.7%), and specificity (94.4%). This algorithm performed well not only within the MGBB, but also demonstrated similar or improved classification performance in an independent biobank (PPV 93.5%, sensitivity 61.4%, specificity 90%). Ancillary comparisons showed that the classification model built including a binary feature for FEV1/FVC produced substantially higher sensitivity than those excluding. This study fills a gap in COPD research involving population-based EHRs, providing an important resource for the rapid, automated classification of COPD cases that is both cost-efficient and requires minimal information from unstructured medical records.

Genome-wide association studies (GWAS) of response to asthma medications have primarily focused on Caucasian populations, with findings that may not be generalizable to minority populations. We derived a polygenic risk score (PRS) for response to albuterol as measured by bronchodilator response (BDR), and examined the PRS in a cohort of Hispanic school-aged children with asthma. We leveraged a published GWAS of BDR to identify relevant genetic variants, and ranked the top variants according to their Combined Annotation Dependent Depletion (CADD) scores. Variants with CADD scores greater than 10 were used to compute the PRS. Once we derived the PRS, we determined the association of the PRS with BDR in a cohort of Hispanic children with asthma (the Genetics of Asthma in Costa Rica Study (GACRS)) in adjusted linear regression models. Mean BDR in GACRS participants was5.6% with a standard deviation of 10.2%. We observed a 0.63% decrease in BDR in response to albuterol for a standard deviation increase in the PRS (p = 0.05). We also observed decreased odds of a BDR response at or above the 12% threshold for a one standard deviation increase in the PRS (OR = 0.80 (95% CI 0.67 to 0.95)). Our findings show that combining variants from a pharmacogenetic GWAS into a PRS may be useful for predicting medication response in asthma.

Of children with recurrent wheezing in early childhood, approximately half go on to develop asthma. MicroRNAs have been described as excellent non-invasive biomarkers due to their prognostic utility. We hypothesized that circulating microRNAs can predict incident asthma and that that prediction might be modified by vitamin D. We selected 75 participants with recurrent wheezing at 3 years old from the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Plasma samples were collected at age 3 and sequenced for small RNA-Seq. The read counts were normalized and filtered by depth and coverage. Logistic regression was employed to associate miRNAs at age 3 with asthma status at age 5. While the overall effect of miRNA on asthma occurrence was weak, we identified 38 miRNAs with a significant interaction effect with vitamin D and 32 miRNAs with a significant main effect in the high vitamin D treatment group in VDAART. We validated the VDAART results in Project Viva for both the main effect and interaction effect. Meta-analysis was performed on both cohorts to obtain the combined effect and a logistic regression model was used to predict incident asthma at age 7 in Project Viva. Of the 23 overlapped miRNAs in the stratified and interaction analysis above, 9 miRNAs were replicated in Project Viva with strong effect size and remained in the meta-analysis of the two populations. The target genes of the 9 miRNAs were enriched for asthma-related Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways. Using logistic regression, microRNA hsa-miR-574-5p had a good prognostic ability for incident asthma prognosis with an area under the receiver operating characteristic (AUROC) of 0.83. In conclusion, miRNAs appear to be good biomarkers of incident asthma, but only when vitamin D level is considered.

Severe asthma exacerbations are a major cause of school absences and healthcare costs in children, particularly those in high-risk racial/ethnic groups.To identify susceptibility genes for severe asthma exacerbations in Latino children and adolescents, we conducted a meta-analysis of genome-wide association studies (GWAS) in 4010 Latino youth with asthma in four independent cohorts, including 1693 Puerto Ricans, 1019 Costa Ricans, 640 Mexicans, 256 Brazilians and 402 members of other Latino subgroups. We then conducted methylation quantitative trait locus, expression quantitative trait locus and expression quantitative trait methylation analyses to assess whether the top single nucleotide polymorphism (SNP) in the meta-analysis is linked to DNA methylation and gene expression in nasal (airway) epithelium in separate cohorts of Puerto Rican and Dutch children and adolescents.In the meta-analysis of GWAS, an SNP inFLJ22447(rs2253681) was significantly associated with 1.55 increased odds of severe asthma exacerbation (95% CI 1.34–1.79, p=6.3×10−9). This SNP was significantly associated with DNA methylation of a CpG site (cg25024579) at theFLJ22447locus, which was in turn associated with increased expression ofKCNJ2-AS1in nasal airway epithelium from Puerto Rican children and adolescents (β=0.10, p=2.18×10−7).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG inFLJ22447and severe asthma exacerbations in Latino youth. This may be partly explained by changes in airway epithelial expression of a gene recently implicated in atopic asthma in Puerto Rican children and adolescents (KCNJ2-AS1).

Current guidelines do not sufficiently capture the heterogeneous nature of asthma; a detailed molecular classification is needed. Metabolomics represents a novel and compelling approach to derive asthma endotypes, i.e., subtypes defined by functional/pathobiological mechanisms. In two cohorts of asthmatics, untargeted metabolomic profiling and Similarity Network Fusion was used to derive and validate five “metabo-endotypes” of asthma, which displayed significant differences in asthma-relevant phenotypes including pre-bronchodilator and post-bronchodilator forced expiratory volume/forced vital capacity (FEV1/FVC). The “most-severe” asthma metabo-endotype was defined by the lowest FEV1/FVC and characterized by altered levels of phospholipids and polyunsaturated fatty acids, suggesting dysregulation of pulmonary surfactant homeostasis. This was supported by genetic analyses as members of this endotype were more likely to carry variants in key pulmonary surfactant regulation genes including BMPR1B (meta-analyzed p=2.8x10-4) and BMP3 (meta-analyzed p=5.23x10-4). These findings suggest clinically meaningful endotypes can be derived and validated using metabolomic data. Interrogating the drivers of these metabo-endotypes can help understand their pathophysiology.

Background Vitamin D facilitates the absorption of calcium but may also increase absorption of other metals; the literature is conflicting. Objective To examine whether 25OHD in the first trimester of pregnancy was associated with subsequent metals levels in the late second trimester of pregnancy. Methods We used data from a sample of women in the LIFECODES pregnancy cohort (N = 381). 25-hydroxyvitamin D (25OHD) was measured with a chemiluminescence immunoassay in plasma samples drawn at 10 weeks of gestation. A panel of 17 metals and elements was measured in urine collected at 26 weeks of gestation. We used linear or logistic regression to estimate associations between 25OHD (dichotomous, linear, and in tertiles) and either urinary metal concentrations or the proportion of samples below the limit of detection, respectively. Multivariable models included urinary specific gravity, age, race/ethnicity, education, body mass index, insurance type, gestational age, and season. Results After multivariable adjustment, low 25OHD was associated with a 47% increase in lead level, a 60% increase in tin level, and 1.58 times the odds of detectable tungsten. A 10 ng/ml increase in 25OHD was associated with a 12% decrease in tin and an 8% increase in molybdenum. While we had a small sample size, we found some evidence of effect modification by race. Women who reported their race as Black or were classified in the other race category, who also had low 25OHD, had 40% higher thallium than women with higher 25OHD and were more likely to have detectable beryllium and tungsten. These metals were not associated with low 25OHD in women who reported their race as White. Tin and lead were higher in women with low 25OHD in all race groups. Discussion In total, further research is warranted to determine if vitamin D levels alter metal levels, and to elucidate the shape of the association for each metal across a range of corresponding 25OHD levels, and longitudinally, across pregnancy. This is especially true for pregnant people as exposure to metals during pregnancy has health consequences for the fetus.

There is an acute need for advances in pharmacologic therapies and a better understanding of novel drug targets for severe asthma. Imatinib, a tyrosine kinase inhibitor, has been shown to improve forced expiratory volume in 1 s (FEV1) in a clinical trial of patients with severe asthma. In a pilot study, we applied systems biology approaches to epithelium gene expression from these clinical trial patients treated with imatinib to better understand lung function response with imatinib treatment. Bronchial brushings from ten imatinib-treated patient samples and 14 placebo-treated patient samples were analyzed. We used personalized perturbation profiles (PEEPs) to characterize gene expression patterns at the individual patient level. We found that strong responders—patients with greater than 20% increase in FEV1—uniquely shared multiple downregulated mitochondrial-related pathways. In comparison, weak responders (5–10% FEV1 increase), and non-responders to imatinib shared none of these pathways. The use of PEEP highlights its potential for application as a systems biology tool to develop individual-level approaches to predicting disease phenotypes and response to treatment in populations needing innovative therapies. These results support a role for mitochondrial pathways in airflow limitation in severe asthma and as potential therapeutic targets in larger clinical trials.

The application of large-scale metabolomic profiling provides new opportunities to realize the potential of omics-based precision medicine with regard to asthma. We leveraged over 14,000 individuals from four distinct epidemiological studies. We identified and independently replicated seventeen steroid metabolites that were significantly reduced in individuals with prevalent asthma. Importantly steroid levels were reduced among all individuals with asthma regardless of medication use; however, the largest reduction was associated with inhaled corticosteroids use (ICS) that was further confirmed in a four-year ICS clinical trial. Cortisol levels extracted from electronic medical records confirmed that cortisol is reduced among asthmatics taking ICS over the entire 24-hour period, compared with all other groups. Clinical-grade adrenal suppression in asthmatics on ICS, resulting from substantial reductions in steroid metabolites, represents a larger public health problem than previously recognized. Regular cortisol testing may identify at-risk individuals, enabling personalized treatment modifications and improving overall patient care.

Corticosteroid resistance causes significant morbidity in asthma, and drug repurposing may identify timely and cost-effective adjunctive treatments for corticosteroid resistance. In 95 subjects from the Childhood Asthma Management Program (CAMP) and 19 subjects from the Severe Asthma Research Program (SARP), corticosteroid response was measured by the change in percent predicted forced expiratory volume in one second (FEV1). In each cohort, differential gene expression analysis was performed comparing poor (resistant) responders, defined as those with zero to negative change in FEV1, to good responders, followed by Connectivity Map (CMap) analysis to identify inversely associated (i.e., negatively connected) drugs that reversed the gene expression profile of poor responders to resemble that of good responders. Mean connectivity scores weighted by sample size were calculated. The top five drug compound candidates underwent in vitro validation in NF-κB-based luciferase reporter A549 cells stimulated by IL-1β ± dexamethasone. In CAMP and SARP, 134 and 178 respective genes were differentially expressed in poor responders. CMap analysis identified 46 compounds in common across both cohorts with connectivity scores &lt, −50. γ-linolenic acid, ampicillin, exemestane, brinzolamide, and INCA-6 were selected for functional validation. γ-linolenic acid, brinzolamide, and INCA-6 significantly reduced IL-1β induced luciferase activity and potentiated the anti-inflammatory effect of dexamethasone in A549/NF-κB-luc reporter cells. These results demonstrate how existing drugs, including γ-linolenic acid, brinzolamide, and INCA-6, may be repurposed to improve corticosteroid response in asthmatics.

Background Previous studies have related vitamin D supplementation to a lower risk of acute respiratory tract infection. Emerging evidence suggests that vitamin D insufficiency is related to a higher risk of coronavirus disease 2019 (COVID‐19) infection. Objectives We aimed to investigate the prospective association between habitual use of vitamin D supplements and risk of COVID-19 infection, and assess whether such an association differed according to the different levels of circulating and genetically predicted vitamin D. Methods This study included 8297 adults who have records of COVID-19 test results from UK Biobank (from 16 March 2020 to 29 June 2020). The use of vitamin D supplements, circulating vitamin D levels, and main covariates were measured at baseline (2006–2010). Genetically predicted vitamin D levels were evaluated by genetic risk score. Results After adjustment for covariates, the habitual use of vitamin D supplements was significantly associated with a 34% lower risk of COVID-19 infection (OR, 0.66; 95% CI, 0.45–0.97; P = 0.034). Circulating vitamin D levels at baseline or genetically predicted vitamin D levels were not associated with the risk of COVID-19 infection. The association between the use of vitamin D supplements and the risk of COVID-19 infection did not vary according to the different levels of circulating or genetically predicted vitamin D (P-interactions = 0.75 and 0.74, respectively). Conclusions Our findings suggest that habitual use of vitamin D supplements is related to a lower risk of COVID-19 infection, although we cannot rule out the possibility that the inverse association is due to residual confounding or selection bias. Further clinical trials are needed to verify these results.

The in utero environment during pregnancy has important implications for the developing health of the child. We aim to examine the potential impact of maternal metabolome at two different timepoints in pregnancy on offspring respiratory health in early life. In 685 mother-child pairs from the Vitamin D Antenatal Asthma Reduction Trial, we assessed the prospective associations between maternal metabolites at both baseline (10–18 weeks gestation) and third trimester (32–38 weeks gestation) and the risk of child asthma or recurrent wheeze by age three using logistic regression models accounting for confounding factors. Subgroup analyses were performed by child sex. Among 632 metabolites, 19 (3.0%) and 62 (9.8%) from baseline and third trimester, respectively, were associated with the outcome (p-value &lt, 0.05). Coffee-related metabolites in the maternal metabolome appeared to be of particular importance. Caffeine, theophylline, trigonelline, quinate, and 3-hydroxypyridine sulfate were inversely associated with asthma risk at a minimum of one timepoint. Additional observations also highlight the roles of steroid and sphingolipid metabolites. Overall, there was a stronger relationship between the metabolome in later pregnancy and offspring asthma risk. Our results suggest that alterations in prenatal metabolites may act as drivers of the development of offspring asthma.

Background Randomized controlled trials (RCTs) suggest a protective effect of high-dose vitamin D supplementation in pregnancy on offspring risk of persistent wheeze, but only in some individuals, which might be explained by variations in vitamin D pathway genes. This study aimed to investigate the effect of vitamin D supplementation by maternal and offspring vitamin D receptor (VDR) genotype and GC genotype, encoding vitamin D binding protein (VDBP), in two RCTs. Methods In the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2010 ) RCT, we analyzed the effect of high-dose vitamin D during pregnancy on the risk of persistent wheeze age 0-3 years by variants in single nucleotide polymorphisms (SNPs) in VDR (rs1544410, rs2228570, rs7975128, rs7975232) and GC (rs4588, rs7041). Replication was sought in the Vitamin D Antenatal Asthma Reduction Trial (VDAART). Results In COPSAC2010 , VDR SNP rs1544410 influenced the effect of high-dose vitamin D: maternal Pinteraction = .049 and child Pinteraction = .001, with the largest effect in offspring from mothers with TT genotype: hazard ratio (95% CI), 0.26 (0.10-0.68), P = .006, and no effect among CT or CC genotypes: 0.85 (0.48-1.51), P = .58 and 0.94 (0.47-1.89), P = .87, respectively. However, these findings were not replicated in VDAART. There was no significant effect modification from maternal or offspring GC genotype in either COPSAC2010 or VDAART: all Pinteraction ≥ .17. Conclusions We found that the effect of high-dose vitamin D supplementation during pregnancy on offspring risk of persistent wheeze was significantly influenced by VDR genotype in the COPSAC2010 RCT, but not VDAART, which may be due to population differences.

Pharmaceutical drugs targeting dyslipidemia and cardiovascular disease (CVD) may increase the risk of fatty liver disease and other metabolic disorders. To identify potential novel CVD drug targets without these adverse effects, we perform genome-wide analyses of participants in the HUNT Study in Norway (n = 69,479) to search for protein-altering variants with beneficial impact on quantitative blood traits related to cardiovascular disease, but without detrimental impact on liver function. We identify 76 (11 previously unreported) presumed causal protein-altering variants associated with one or more CVD- or liver-related blood traits. Nine of the variants are predicted to result in loss-of-function of the protein. This includes ZNF529:p.K405X, which is associated with decreased low-density-lipoprotein (LDL) cholesterol (P = 1.3 × 10−8) without being associated with liver enzymes or non-fasting blood glucose. Silencing of ZNF529 in human hepatoma cells results in upregulation of LDL receptor and increased LDL uptake in the cells. This suggests that inhibition of ZNF529 or its gene product should be prioritized as a novel candidate drug target for treating dyslipidemia and associated CVD., Drugs targeting cardiovascular disease (CVD) can have negative consequences for liver function. Here, the authors combine genome wide analyses on 69,479 individuals to identify loss-of-function variants with beneficial effects on CVD-related traits without negative impacts on liver function.

Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11–1.25), Pdiscovery = 2.6 × 10−9) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis., Genetic variants discovered through genome-wide association studies for asthma together account for a small portion of the heritability. Here, the authors identify a possible epistatic relationship between coding variants in FUT2 and ABO, especially pronounced in severe and early onset asthma.

Background: In utero smoke (IUS) exposure is associated with asthma susceptibility. Objective: We sought to test the hypothesis that changes in miRNA expression by IUS exposure during human lung development is associated with asthma susceptibility. Methods: Gene expression was profiled from 53 IUS unexposed and 51 IUS exposed human fetal lung tissues. We tested for the differential expression of miRNAs across post-conception age and by IUS using linear models with covariate adjustment. We tested the IUS-associated miRNAs for association with their gene expression targets using pair-wise inverse correlation. Using our mouse model, we investigated the persistence of the IUS-associated miRNA signature using RT-PCR from the lungs of mouse pups with and without IUS at postnatal day 14. MiRNAs were then tested for association with asthma and exacerbations using whole blood gene expression profiles from Asthma BRIDGE. Results: Five miRNAs were differentially expressed across post-conception age (adjusted p &lt, 0.0002) including two that were differentially expressed by IUS exposure in human fetal lung (p &lt, 0.05). MiR-15a was differentially expressed by post-conception age (p = 0.00002), IUS exposure in human fetal lung (p = 0.005), and in the post-natal mouse lung (p = 0.01). MiR-15a was also associated with the in utero expression of GSDMB (adjusted p = 0.0002), a known childhood asthma gene and with asthma exacerbations (p = 0.0009) in Asthma BRIDGE. Thus, miR-15a is expressed during human lung development, is impacted by IUS exposure, regulates the intrauterine expression of asthma genes, and is associated with asthma severity. Conclusions: These results provide evidence for the role of miR-15a in the fetal origin of asthma.