Attitudes, Knowledge, and Risk Perceptions of Patients who Received Elective Genomic Testing as a Clinical Service.

BACKGROUND: Elective genomic testing (EGT) is increasingly available clinically. Limited real world evidence exists about attitudes and knowledge of EGT recipients. METHODS: After web-based education, patients who enrolled in an EGT program at a rural nonprofit healthcare system completed a survey that assessed attitudes, knowledge, and risk perceptions. RESULTS: From August 2020 to April 2022, 5,920 patients completed the survey and received testing. Patients most frequently cited interest in learning their personal disease risks as their primary motivation. Patients most often expected results to guide medication management (74.0%), prevent future disease (70.4%), and provide information about risks to offspring (65.4%). Patients were "very concerned" most frequently about the privacy of genetic information (19.8%) and how well testing predicted disease risks (18.0%). On average, patients answered 6.7 of 11 knowledge items correctly (61.3%). They more often rated their risks for colon and breast cancers as lower rather than higher than the average person, but more often rated their risk for a heart attack as higher rather than lower than the average person (all p<0.001). CONCLUSION: Patients pursued EGT because of the utility expectations, but often misunderstood the test's capabilities.

Polygenic risk scores identify heterogeneity in asthma and chronic obstructive pulmonary disease.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) have distinct and overlapping genetic and clinical features. OBJECTIVE: We sought to test the hypothesis that polygenic risk scores (PRSs) for asthma (PRSAsthma) and spirometry (FEV1 and FEV1/forced vital capacity; PRSspiro) would demonstrate differential associations with asthma, COPD, and asthma-COPD overlap (ACO). METHODS: We developed and tested 2 asthma PRSs and applied the higher performing PRSAsthma and a previously published PRSspiro to research (Genetic Epidemiology of COPD study and Childhood Asthma Management Program, with spirometry) and electronic health record-based (Mass General Brigham Biobank and Genetic Epidemiology Research on Adult Health and Aging [GERA]) studies. We assessed the association of PRSs with COPD and asthma using modified random-effects and binary-effects meta-analyses, and ACO and asthma exacerbations in specific cohorts. Models were adjusted for confounders and genetic ancestry. RESULTS: In meta-analyses of 102,477 participants, the PRSAsthma (odds ratio [OR] per SD, 1.16 [95% CI, 1.14-1.19]) and PRSspiro (OR per SD, 1.19 [95% CI, 1.17-1.22]) both predicted asthma, whereas the PRSspiro predicted COPD (OR per SD, 1.25 [95% CI, 1.21-1.30]). However, results differed by cohort. The PRSspiro was not associated with COPD in GERA and Mass General Brigham Biobank. In the Genetic Epidemiology of COPD study, the PRSAsthma (OR per SD: Whites, 1.3; African Americans, 1.2) and PRSspiro (OR per SD: Whites, 2.2; African Americans, 1.6) were both associated with ACO. In GERA, the PRSAsthma was associated with asthma exacerbations (OR, 1.18) in Whites; the PRSspiro was associated with asthma exacerbations in White, LatinX, and East Asian participants. CONCLUSIONS: PRSs for asthma and spirometry are both associated with ACO and asthma exacerbations. Genetic prediction performance differs in research versus electronic health record-based cohorts.

Association between antenatal corticosteroid treatment and severe adverse events in pregnant women.

BACKGROUND: Antenatal corticosteroids are considered the standard of care for pregnant women at risk for preterm birth, but studies examining their potential risks are scarce. We aimed to estimate the associations of antenatal corticosteroids with three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding, in pregnant women. METHODS: Of 2,157,321 pregnant women, 52,119 at 24 weeks 0/7 days to 36 weeks 6/7 days of gestation were included in this self-controlled case series study during the study period of 2009-2018. We estimated incidence rates of three severe adverse events: sepsis, heart failure, and gastrointestinal bleeding. Conditional Poisson regression was used to calculate incidence rate ratios (IRRs) for comparing incidence rates of the adverse events in each post-treatment period compared to those during the baseline period among pregnant women exposed to a single course of antenatal corticosteroid treatment. RESULTS: Among 52,119 eligible participants who received antenatal corticosteroid treatment, the estimated incidence rates per 1000 person-years were 0.76 (95% confidence interval (CI): 0.69-0.83) for sepsis, 0.31 (95% CI: 0.27-0.36) for heart failure, and 11.57 (95% CI: 11.27-11.87) for gastrointestinal bleeding. The IRRs at 5 ~ 60 days after administration of antenatal corticosteroids were 5.91 (95% CI: 3.10-11.30) for sepsis and 4.45 (95% CI: 2.63-7.55) for heart failure, and 1.26 (95% CI: 1.02-1.55) for gastrointestinal bleeding; and the IRRs for days 61 ~ 180 were 2.00 (95% CI: 1.01-3.96) for sepsis, 3.65 (95% CI: 2.14-6.22) for heart failure, and 1.81 (95% CI: 1.56-2.10) for gastrointestinal bleeding. CONCLUSIONS: This nationwide population-based study suggests that a single course of antenatal corticosteroids is significantly associated with a 1.3- to 5.9-fold increased risk of sepsis, heart failure, and gastrointestinal bleeding in pregnant women. Maternal health considerations, including recommendations for adverse event monitoring, should be included in future guidelines for antenatal corticosteroid treatment.

Benefits, harms, and costs of newborn genetic screening for hypertrophic cardiomyopathy: Estimates from the PreEMPT model.

PURPOSE: Population newborn genetic screening for hypertrophic cardiomyopathy (HCM) is feasible, however its benefits, harms, and cost-effectiveness are uncertain. METHODS: We developed a microsimulation model to simulate a US birth cohort of 3.7 million newborns. Those identified with pathogenic/likely pathogenic variants associated with increased risk of HCM underwent surveillance and recommended treatment, whereas in usual care, individuals with family histories of HCM underwent surveillance. RESULTS: In a cohort of 3.7 million newborns, newborn genetic screening would reduce HCM-related deaths through age 20 years by 44 (95% uncertainty interval [UI] = 10-103) however increase the numbers of children undergoing surveillance by 8127 (95% UI = 6308-9664). Compared with usual care, newborn genetic screening costs $267,000 per life year saved (95% UI, $106,000 to $919,000 per life year saved). CONCLUSION: Newborn genetic screening for HCM could prevent deaths but at a high cost and would require many healthy children to undergo surveillance. This study shows how modeling can provide insights into the tradeoffs between benefits and costs that will need to be considered as newborn genetic screening is more widely adopted.

The association of varying treatment thresholds of mepolizumab on asthma exacerbations in adults.

Background: Asthma has a high healthcare burden globally, with up to 10% of the asthma population suffering from severe disease. Biologic agents are a newer class of asthma treatments for severe asthma, with good evidence for efficacy in clinical trials. Nevertheless, real-world studies of its impact on clinical outcomes are limited.Methods: This is an observational cohort study using administrative claims data. The study population consisted of patients aged ≥18 years who had a diagnosis of asthma and initiated mepolizumab after November 4, 2015 and had continuous medical and drug coverage in both the 365 days prior to and following mepolizumab initiation. In patients treated with mepolizumab, we described clinically significant asthma exacerbations by minimum continuous treatment thresholds following initiation of mepolizumab, medication switching patterns and chronic oral corticosteroid (≥28 days) use.Results: We identified 2,536 adults with asthma who initiated mepolizumab. There was an association toward reduction in severe asthma-related events over the first one year of exposure. We observed associations with reduced dispensings of oral corticosteroids over the first year after mepolizumab initiation. Very few patients switched to other biologics during the study period.Conclusions: Treatment with mepolizumab may be associated with fewer asthma-related events in the first year. Over the first one year after initiating mepolizumab, we found associations with decreased concomitant dispensings of oral corticosteroids and medium to high dose ICS/LABA. Additionally, most patients who initiated mepolizumab did not switch to other biologics.

Multiomics analysis identifies BIRC3 as a novel glucocorticoid response-associated gene.

BACKGROUND: Inhaled corticosteroid (ICS) response among patients with asthma is influenced by genetics, but biologically actionable insights based on associations have not been found. Various glucocorticoid response omics data sets are available to interrogate their biological effects. OBJECTIVE: We sought to identify functionally relevant ICS-response genetic associations by integrating complementary multiomics data sets. METHODS: Variants with P values less than 10-4 from a previous ICS-response genome-wide association study were reranked on the basis of integrative scores determined from (1) glucocorticoid receptor- and (2) RNA polymerase II-binding regions inferred from ChIP-Seq data for 3 airway cell types, (3) glucocorticoid response element motifs, (4) differentially expressed genes in response to glucocorticoid exposure according to 20 transcriptomic data sets, and (5) expression quantitative trait loci from GTEx. Candidate variants were tested for association with ICS response and asthma in 6 independent studies. RESULTS: Four variants had significant (q value < 0.05) multiomics integrative scores. These variants were in a locus consisting of 52 variants in high linkage disequilibrium (r2 ≥ 0.8) near glucocorticoid receptor-binding sites by the gene BIRC3. Variants were also BIRC3 expression quantitative trait loci in lung, and 2 were within/near putative glucocorticoid response element motifs. BIRC3 had increased RNA polymerase II occupancy and gene expression, with glucocorticoid exposure in 2 ChIP-Seq and 13 transcriptomic data sets. Some BIRC3 variants in the 52-variant locus were associated (P < .05) with ICS response in 3 independent studies and others with asthma in 1 study. CONCLUSIONS: BIRC3 should be prioritized for further functional studies of ICS response.

Caution against examining the role of reverse causality in Mendelian Randomization.

Recently, Mendelian Randomization (MR) has gained in popularity as a concept to assess the causal relationship between phenotypes in genetic association studies. An extension of standard MR methodology, the MR Steiger approach, has recently been developed to infer the causal direction between two phenotypes in prospective studies. Through simulation studies, we examined and quantified the ability of the MR Steiger approach to determine the causal direction between two phenotypes (i.e., effect direction). Through simulation studies, our results show that the MR Steiger approach may fail to correctly identify the direction of causality. This is true, especially in the presence of pleiotropy. We also applied the MR Steiger method to the COPDGene study, a case-control study of chronic obstructive pulmonary disease (COPD) in current and former smokers, to examine the role of smoking on lung function. We have created an R package on Github called reverseDirection which runs simulations for user-specified scenarios to examine when the MR Steiger approach can correctly determine the causal direction between two phenotypes in any user specified scenario. In summary, our results emphasize the importance of caution when the MR Steiger approach is used in to infer the direction of causality.

Pharmacogenetics of inhaled corticosteroids and exacerbation risk in adults with asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are a cornerstone of asthma treatment. However, their efficacy is characterized by wide variability in individual responses. OBJECTIVE: We investigated the association between genetic variants and risk of exacerbations in adults with asthma and how this association is affected by ICS treatment. METHODS: We investigated the pharmacogenetic effect of 10 single nucleotide polymorphisms (SNPs) selected from the literature, including SNPs previously associated with response to ICS (assessed by change in lung function or exacerbations) and novel asthma risk alleles involved in inflammatory pathways, within all adults with asthma from the Dutch population-based Rotterdam study with replication in the American GERA cohort. The interaction effects of the SNPs with ICS on the incidence of asthma exacerbations were assessed using hurdle models adjusting for age, sex, BMI, smoking and treatment step according to the GINA guidelines. Haplotype analyses were also conducted for the SNPs located on the same chromosome. RESULTS: rs242941 (CRHR1) homozygotes for the minor allele (A) showed a significant, replicated increased risk for frequent exacerbations (RR = 6.11, P < 0.005). In contrast, rs1134481 T allele within TBXT (chromosome 6, member of a family associated with embryonic lung development) showed better response with ICS. rs37973 G allele (GLCCI1) showed a significantly poorer response on ICS within the discovery cohort, which was also significant but in the opposite direction in the replication cohort. CONCLUSION: rs242941 in CRHR1 was associated with poor ICS response. Conversely, TBXT variants were associated with improved ICS response. These associations may reveal specific endotypes, potentially allowing prediction of exacerbation risk and ICS response.

Universal newborn genetic screening for pediatric cancer predisposition syndromes: model-based insights.

PURPOSE: Genetic testing for pediatric cancer predisposition syndromes (CPS) could augment newborn screening programs, but with uncertain benefits and costs. METHODS: We developed a simulation model to evaluate universal screening for a CPS panel. Cohorts of US newborns were simulated under universal screening versus usual care. Using data from clinical studies, ClinVar, and gnomAD, the presence of pathogenic/likely pathogenic (P/LP) variants in RET, RB1, TP53, DICER1, SUFU, PTCH1, SMARCB1, WT1, APC, ALK, and PHOX2B were assigned at birth. Newborns with identified variants underwent guideline surveillance. Survival benefit was modeled via reductions in advanced disease, cancer deaths, and treatment-related late mortality, assuming 100% adherence. RESULTS: Among 3.7 million newborns, under usual care, 1,803 developed a CPS malignancy before age 20. With universal screening, 13.3% were identified at birth as at-risk due to P/LP variant detection and underwent surveillance, resulting in a 53.5% decrease in cancer deaths in P/LP heterozygotes and a 7.8% decrease among the entire cohort before age 20. Given a test cost of $55, universal screening cost $244,860 per life-year gained; with a $20 test, the cost fell to $99,430 per life-year gained. CONCLUSION: Population-based genetic testing of newborns may reduce mortality associated with pediatric cancers and could be cost-effective as sequencing costs decline.

A polygenic risk score for asthma in a large racially diverse population.

BACKGROUND: Polygenic risk scores (PRSs) will have important utility for asthma and other chronic diseases as a tool for predicting disease incidence and subphenotypes. OBJECTIVE: We utilized findings from a large multiancestry GWAS of asthma to compute a PRS for asthma with relevance for racially diverse populations. METHODS: We derived two PRSs for asthma using a standard approach (based on genome-wide significant variants) and a lasso sum regression approach (allowing all genetic variants to potentially contribute). We used data from the racially diverse Kaiser Permanente GERA cohort (68 638 non-Hispanic Whites, 5874 Hispanics, 6870 Asians and 2760 Blacks). Race was self-reported by questionnaire. RESULTS: For the standard PRS, non-Hispanic Whites showed the highest odds ratio for a standard deviation increase in PRS for asthma (OR = 1.16 (95% CI 1.14-1.18)). The standard PRS was also associated with asthma in Hispanic (OR = 1.12 (95% CI 1.05-1.19)) and Asian (OR = 1.10 (95% CI 1.04-1.17)) subjects, with a trend towards increased risk in Blacks (OR = 1.05 (95% CI 0.97-1.15)). We detected an interaction by sex, with men showing a higher risk of asthma with an increase in PRS as compared to women. The lasso sum regression-derived PRS showed stronger associations with asthma in non-Hispanic White subjects (OR = 1.20 (95% CI 1.18-1.23)), Hispanics (OR = 1.17 (95% 1.10-1.26)), Asians (OR = 1.18 (95% CI 1.10-1.27)) and Blacks (OR = 1.10 (95% CI 0.99-1.22)). CONCLUSION: Polygenic risk scores across multiple racial/ethnic groups were associated with increased asthma risk, suggesting that PRSs have potential as a tool for predicting disease development.

Pharmacogenetics of Bronchodilator Response: Future Directions.

PURPOSE OF REVIEW: Several genome-wide association studies (GWASs) of bronchodilator response (BDR) to albuterol have been published over the past decade. This review describes current knowledge gaps, including pharmacogenetic studies of albuterol response in minority populations, effect modification of pharmacogenetic associations by age, and relevance of BDR phenotype characterization to pharmacogenetic findings. New approaches, such as leveraging additional "omics" data to focus pharmacogenetic interrogation, as well as developing polygenic risk scores in asthma treatment responses, are also discussed. RECENT FINDINGS: Recent pharmacogenetic studies of albuterol response in minority populations have identified genetic polymorphisms in loci (DNAH5, NFKB1, PLCB1, ADAMTS3, COX18, and PRKG1), that are associated with BDR. Additional studies are needed to replicate these findings. Modification of the pharmacogenetic associations for SPATS2L and ASB3 polymorphisms by age has also been published. Evidence from metabolomic and epigenomic studies of BDR may point to new pharmacogenetic targets. Lastly, a polygenic risk score for response to albuterol has been developed but requires validation in additional cohorts. In order to expand our knowledge of pharmacogenetics of BDR, additional studies in minority populations are needed. Consideration of effect modification by age and leverage of other "omics" data beyond genomics may also help uncover novel pharmacogenetic loci for use in precision medicine for asthma treatment.

Association Between Oral Corticosteroid Bursts and Severe Adverse Events : A Nationwide Population-Based Cohort Study.

BACKGROUND: Long-term use of oral corticosteroids has known adverse effects, but the risk from brief oral steroid bursts (≤14 days) is largely unknown. OBJECTIVE: To examine the associations between steroid bursts and severe adverse events, specifically gastrointestinal (GI) bleeding, sepsis, and heart failure. DESIGN: Self-controlled case series. SETTING: Entire National Health Insurance Research Database of medical claims records in Taiwan. PARTICIPANTS: Adults aged 20 to 64 years with continuous enrollment in the National Health Insurance program from 1 January 2013 to 31 December 2015. MEASUREMENTS: Incidence rates of severe adverse events in steroid burst users and non-steroid users, as well as incidence rate ratios (IRRs) for severe adverse events within 5 to 30 and 31 to 90 days after initiation of steroid therapy. RESULTS: Of 15 859 129 adult participants, 2 623 327 who received a single steroid burst were included. The most common indications were skin disorders and respiratory tract infections. The incidence rates per 1000 person-years in steroid bursts were 27.1 (95% CI, 26.7 to 27.5) for GI bleeding, 1.5 (CI, 1.4 to 1.6) for sepsis, and 1.3 (CI, 1.2 to 1.4) for heart failure. Rates of GI bleeding (IRR, 1.80 [CI, 1.75 to 1.84]), sepsis (IRR, 1.99 [CI, 1.70 to 2.32]), and heart failure (IRR, 2.37 [CI, 2.13 to 2.63]) significantly increased within 5 to 30 days after steroid therapy initiation and attenuated during the subsequent 31 to 90 days. LIMITATION: Persons younger than 20 years or older than 64 years were not included. CONCLUSION: Oral corticosteroid bursts are frequently prescribed in the general adult population in Taiwan. The highest rates of GI bleeding, sepsis, and heart failure occurred within the first month after initiation of steroid therapy. PRIMARY FUNDING SOURCE: National Health Research Institutes, Ministry of Science and Technology of Taiwan, Chang Gung Medical Foundation, and Eunice Kennedy Shriver National Institute of Child Health and Human Development.

CEACAM3 decreases asthma exacerbations and modulates respiratory syncytial virus latent infection in children.

BACKGROUND: Respiratory syncytial virus (RSV) is associated with childhood asthma. Nevertheless, not all children exposed to RSV develop asthma symptoms, possibly because genes modulate the effects of RSV on asthma exacerbations. OBJECTIVE: The purpose of this study was to identify genes that modulate the effect of RSV latent infection on asthma exacerbations. METHODS: We performed a meta-analysis to investigate differentially expressed genes (DEGs) of RSV infection from Gene Expression Omnibus datasets. Expression quantitative trait loci (eQTL) methods were applied to select single nucleotide polymorphisms (SNPs) that were associated with DEGs. Gene-based analysis was used to identify SNPs that were significantly associated with asthma exacerbations in the Taiwanese Consortium of Childhood Asthma Study (TCCAS), and validation was attempted in an independent cohort, the Childhood Asthma Management Program (CAMP). Gene-RSV interaction analyses were performed to investigate the association between the interaction of SNPs and RSV latent infection on asthma exacerbations. RESULTS: A total of 352 significant DEGs were found by meta-analysis of RSV-related genes. We used 38 123 SNPs related to DEGs to investigate the genetic main effects on asthma exacerbations. We found that eight RSV-related genes (GADD45A, GYPB, MS4A3, NFE2, RNASE3, EPB41L3, CEACAM6 and CEACAM3) were significantly associated with asthma exacerbations in TCCAS and also validated in CAMP. In TCCAS, rs7251960 (CEACAM3) significantly modulated the effect of RSV latent infection on asthma exacerbations (false-discovery rate <0.05). The rs7251960 variant was associated with CEACAM3 mRNA expression in lung tissue (p for trend=1.2×10-7). CEACAM3 mRNA was reduced in nasal mucosa from subjects with asthma exacerbations in two independent datasets. CONCLUSIONS: rs7251960 is an eQTL for CEACAM3, and CEACAM3 mRNA expression is reduced in subjects experiencing asthma exacerbations. CEACAM3 may be a modulator of RSV latent infection on asthma exacerbations.

Expression of SMARCD1 interacts with age in association with asthma control on inhaled corticosteroid therapy.

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.

Current Status and Future Opportunities in Lung Precision Medicine Research with a Focus on Biomarkers. An American Thoracic Society/National Heart, Lung, and Blood Institute Research Statement.

BACKGROUND: Thousands of biomarker tests are either available or under development for lung diseases. In many cases, adoption of these tests into clinical practice is outpacing the generation and evaluation of sufficient data to determine clinical utility and ability to improve health outcomes. There is a need for a systematically organized report that provides guidance on how to understand and evaluate use of biomarker tests for lung diseases. METHODS: We assembled a diverse group of clinicians and researchers from the American Thoracic Society and leaders from the National Heart, Lung, and Blood Institute with expertise in various aspects of precision medicine to review the current status of biomarker tests in lung diseases. Experts summarized existing biomarker tests that are available for lung cancer, pulmonary arterial hypertension, idiopathic pulmonary fibrosis, asthma, chronic obstructive pulmonary disease, sepsis, acute respiratory distress syndrome, cystic fibrosis, and other rare lung diseases. The group identified knowledge gaps that future research studies can address to efficiently translate biomarker tests into clinical practice, assess their cost-effectiveness, and ensure they apply to diverse, real-life populations. RESULTS: We found that the status of biomarker tests in lung diseases is highly variable depending on the disease. Nevertheless, biomarker tests in lung diseases show great promise in improving clinical care. To efficiently translate biomarkers into tests used widely in clinical practice, researchers need to address specific clinical unmet needs, secure support for biomarker discovery efforts, conduct analytical and clinical validation studies, ensure tests have clinical utility, and facilitate appropriate adoption into routine clinical practice. CONCLUSIONS: Although progress has been made toward implementation of precision medicine for lung diseases in clinical practice in certain settings, additional studies focused on addressing specific unmet clinical needs are required to evaluate the clinical utility of biomarkers; ensure their generalizability to diverse, real-life populations; and determine their cost-effectiveness.

Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.

RATIONALE: Albuterol, a bronchodilator medication, is the first-line therapy for asthma worldwide. There are significant racial/ethnic differences in albuterol drug response. OBJECTIVES: To identify genetic variants important for bronchodilator drug response (BDR) in racially diverse children. METHODS: We performed the first whole-genome sequencing pharmacogenetics study from 1,441 children with asthma from the tails of the BDR distribution to identify genetic association with BDR. MEASUREMENTS AND MAIN RESULTS: We identified population-specific and shared genetic variants associated with BDR, including genome-wide significant (P < 3.53 × 10-7) and suggestive (P < 7.06 × 10-6) loci near genes previously associated with lung capacity (DNAH5), immunity (NFKB1 and PLCB1), and ß-adrenergic signaling (ADAMTS3 and COX18). Functional analyses of the BDR-associated SNP in NFKB1 revealed potential regulatory function in bronchial smooth muscle cells. The SNP is also an expression quantitative trait locus for a neighboring gene, SLC39A8. The lack of other asthma study populations with BDR and whole-genome sequencing data on minority children makes it impossible to perform replication of our rare variant associations. Minority underrepresentation also poses significant challenges to identify age-matched and population-matched cohorts of sufficient sample size for replication of our common variant findings. CONCLUSIONS: The lack of minority data, despite a collaboration of eight universities and 13 individual laboratories, highlights the urgent need for a dedicated national effort to prioritize diversity in research. Our study expands the understanding of pharmacogenetic analyses in racially/ethnically diverse populations and advances the foundation for precision medicine in at-risk and understudied minority populations.

Systems biology and in vitro validation identifies family with sequence similarity 129 member A (FAM129A) as an asthma steroid response modulator.

BACKGROUND: Variation in response to the most commonly used class of asthma controller medication, inhaled corticosteroids, presents a serious challenge in asthma management, particularly for steroid-resistant patients with little or no response to treatment. OBJECTIVE: We applied a systems biology approach to primary clinical and genomic data to identify and validate genes that modulate steroid response in asthmatic children. METHODS: We selected 104 inhaled corticosteroid-treated asthmatic non-Hispanic white children and determined a steroid responsiveness endophenotype (SRE) using observations of 6 clinical measures over 4 years. We modeled each subject's cellular steroid response using data from a previously published study of immortalized lymphoblastoid cell lines under dexamethasone (DEX) and sham treatment. We integrated SRE with immortalized lymphoblastoid cell line DEX responses and genotypes to build a genome-scale network using the Reverse Engineering, Forward Simulation modeling framework, identifying 7 genes modulating SRE. RESULTS: Three of these genes were functionally validated by using a stable nuclear factor κ-light-chain-enhancer of activated B cells luciferase reporter in A549 human lung epithelial cells, IL-1ß cytokine stimulation, and DEX treatment. By using small interfering RNA transfection, knockdown of family with sequence similarity 129 member A (FAM129A) produced a reduction in steroid treatment response (P < .001). CONCLUSION: With this systems-based approach, we have shown that FAM129A is associated with variation in clinical asthma steroid responsiveness and that FAM129A modulates steroid responsiveness in lung epithelial cells.

A functional splice variant associated with decreased asthma risk abolishes the ability of gasdermin B to induce epithelial cell pyroptosis.

BACKGROUND: Genetic variants in the chromosomal region 17q21 are consistently associated with asthma. However, mechanistic studies have not yet linked any of the associated variants to a function that could influence asthma, and as a result, the identity of the asthma gene(s) remains elusive. OBJECTIVES: We sought to identify and characterize functional variants in the 17q21 locus. METHODS: We used the Exome Aggregation Consortium browser to identify coding (amino acid-changing) variants in the 17q21 locus. We obtained asthma association measures for these variants in both the Genetic Epidemiology Research in Adult Health and Aging (GERA) cohort (16,274 cases and 38,269 matched controls) and the EVE Consortium study (5,303 asthma cases and 12,560 individuals). Gene expression and protein localization were determined by quantitative RT-PCR and fluorescence immunostaining, respectively. Molecular and cellular studies were performed to determine the functional effects of coding variants. RESULTS: Two coding variants (rs2305480 and rs11078928) of the gasdermin B (GSDMB) gene in the 17q21 locus were associated with lower asthma risk in both GERA (odds ratio, 0.92; P = 1.01 × 10-6) and EVE (odds ratio, 0.85; joint PEVE = 1.31 × 10-13). In GERA, rs11078928 had a minor allele frequency (MAF) of 0.45 in unaffected (nonasthmatic) controls and 0.43 in asthma cases. For European Americans in EVE, the MAF of rs2305480 was 0.45 for controls and 0.39 for cases; for all EVE subjects, the MAF was 0.32 for controls and 0.27 for cases. GSDMB is highly expressed in differentiated airway epithelial cells, including the ciliated cells. We found that, when the GSDMB protein is cleaved by inflammatory caspase-1 to release its N-terminal fragment, potent pyroptotic cell death is induced. The splice variant rs11078928 deletes the entire exon 6, which encodes 13 amino acids in the critical N-terminus, and abolishes the pyroptotic activity of the GSDMB protein. CONCLUSIONS: Our study identified a functional asthma variant in the GSDMB gene of the 17q21 locus and implicates GSDMB-mediated epithelial cell pyroptosis in pathogenesis.

The impact of FDA regulatory activities on incident dispensing of LABA-containing medication: 2005-2011.

OBJECTIVE: Evidence of safety issues associated with long-acting beta2-agonist (LABA) treatment has led to multiple regulatory activities by the U.S. Food and Drug Administration (FDA) on this class of medications. This study describes the impact of the regulatory activities on incident LABA-containing medication dispensing. METHODS: A monthly rolling cohort of asthma patients who were eligible to initiate a LABA-containing product was created in the Mini-Sentinel Distributed Database between January 2005 and June 2011. Cohorts of individuals who initiated LABA were examined for the changes in the proportions of single-ingredient to fixed-dose inhaled corticosteroid (ICS)-LABA initiators, appropriate initiation of LABA-containing products, and use of controller medications. The impact of the 2005 and 2010 FDA regulatory activities associated with LABA-containing products was measured using interrupted time series with segmented regression. RESULTS: LABA-containing product initiation was declining prior to the 2005 regulatory activities and continued to decline over the study period, accompanied by increased initiation of fixed dose ICS-LABA among LABA initiators. While the 2010 regulatory activities had no immediate impact on the proportion of LABA initiation in patients with prior controller medication dispensing and/or poor asthma control, there was an increasing positive trend toward LABA initiation in the appropriate patient population after the regulatory activities. CONCLUSION: The 2005 and 2010 FDA regulatory activities likely had an impact on communicating the safety concerns of LABA products. However, the impact cannot be viewed independent of scientific publications, guidelines for asthma treatment and other regulatory activities.