Environmental management of asthma in clinical practice: Results from the 2012 National Ambulatory Medical Care Survey.

Background: The National Asthma Education and Prevention Program guidelines emphasize environmental control as an integral part of asthma management; however, limited national-level data exist on how clinicians implement environmental control recommendations. Objective: We analyzed data on clinicians' self-reported use of recommended environmental control practices in a nationally representative sample (n = 1645) of primary care physicians, asthma specialists, and advanced practice providers from the National Asthma Survey of Physicians, a supplemental questionnaire to the 2012 National Ambulatory Medical Care Survey. Methods: We examined clinician and practice characteristics as well as clinicians' decisions and strategies regarding environmental trigger assessment and environmental control across provider groups. Regression modeling was used to identify clinician and practice characteristics associated with implementation of guideline recommendations. Results: A higher percentage of specialists assessed asthma triggers at home, school, and/or work than primary care or advanced practice providers (almost always: 53.6% vs 29.4% and 23.7%, respectively, P < .001). Almost all clinicians (>93%) recommended avoidance of secondhand tobacco smoke, whereas recommendations regarding cooking appliances (eg, proper ventilation) were infrequent. Although assessment and recommendation practices differed between clinician groups, modeling results showed that clinicians who reported almost always assessing asthma control were 5- to 6-fold more likely to assess environmental asthma triggers. Use of asthma action plans was also strongly associated with implementation of environmental control recommendations. Conclusions: Environmental assessment and recommendations to patients varied among asthma care providers. High adherence to other key guideline components, such as assessing asthma control, was associated with environmental assessment and recommendation practices on environmental control.

Genome-wide association study in minority children with asthma implicates DNAH5 in bronchodilator responsiveness.

Variability in response to short-acting ß2-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10-8) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge.

Multi-ancestry genome-wide association study of asthma exacerbations.

BACKGROUND: Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. METHODS: A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. RESULTS: One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (ORT allele ) = 0.82, p = 9.05 × 10-6 and replication: ORT allele  = 0.89, p = 5.35 × 10-3 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: ORC allele  = 0.85, p = 3.10 × 10-5 and replication: ORC allele  = 0.89, p = 1.30 × 10-2 ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood. CONCLUSIONS: This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

A Practical Guide to Implementing SMART in Asthma Management.

The use of a single inhaler containing the combination of an inhaled corticosteroid (ICS) and formoterol, a specific long-acting bronchodilator, for both maintenance and quick relief therapy (single maintenance and reliever therapy [SMART or MART]) is recommended by both the Global Initiative for Asthma and the National Asthma Education and Prevention Program Coordinating Committee in steps 3 and 4 of asthma management. This article provides practical advice about implementing SMART in clinical practice based on evidence and clinical experience. Fundamental to SMART is that ICS-formoterol provides quick relief of asthma symptoms similar to that of short-acting ß2-agonists such as albuterol, while reducing the risk for severe asthma exacerbations and at an overall lower ICS exposure. Most SMART clinical trials were in adults and adolescents (aged ≥12 years), using budesonide-formoterol 160/4.5 µg (delivered dose), one inhalation once or twice daily (step 3) and two inhalations twice daily (step 4). For both steps 3 and 4, patients take additional inhalations of budesonide-formoterol 160/4.5 µg, one inhalation whenever needed for symptom relief, up to a maximum for adults and adolescents of 12 total inhalations in any single day (delivering 54 µg formoterol). The efficacy and safety of SMART with budesonide-formoterol and beclometasone-formoterol have been confirmed, but other ICS-long-acting bronchodilator combinations have not been studied. The SMART regimen should be introduced with a careful explanation of its role in self-management, preferably with a customized written asthma action plan. The cost to patients and the availability of SMART treatment will depend on the prescribed dose and national or local payer agreements.

Smoking cessation and counseling: A mixed methods study of pediatricians and parents.

OBJECTIVE: Pediatric providers play an important role in parental and youth smoking cessation. The goal of this study was to understand smoking cessation attitudes of parents and the behaviors, confidence and self-efficacy of pediatricians related to providing smoking cessation counseling to parents and youth. METHODS: A mixed methods study was conducted in a convenience sample of families (n = 1,549) and pediatric primary care clinicians (n = 95) in Connecticut using surveys and focus groups from April, 2016 to January, 2017. RESULTS: The smoking rate (cigarettes or electronic cigarettes) among all households surveyed was 21%. Interest in quitting smoking was high (71%) and did not differ based on smoking amount, duration, type of community of residence (urban, rural, etc), or race/ethnicity. For example, compared to participants who smoked for <10 years, those who smoked ≥20 years had a similar interest in quitting (OR = 1.12; 95% CI: 0.85-1.48). Ninety percent of clinicians surveyed asked parents about their smoking behavior at least annually but 36% offered no smoking cessation counseling services or referral. Clinicians almost always reported counseling youth about the dangers of nicotine and tobacco use (99%), were more confident about counseling youth than parents (p<0.01) and reported low self-efficacy about smoking cessation and prevention counseling of parents and youth. Ninety-three percent of clinicians opined that electronic cigarettes were equally or more dangerous than cigarettes but 34% never counseled youth about the dangers of electronic cigarettes. CONCLUSIONS: Clinicians frequently screen parents about their smoking behaviors, but rarely provide smoking cessation counseling and express low confidence in this activity. Clinicians are more confident counseling youth than parents. Clinicians also recognize the dangers of electronic cigarettes, yet they infrequently counsel youth about these dangers.

A genome-wide association study of asthma hospitalizations in adults.

BACKGROUND: Little is known about the genetic determinants of severe asthma exacerbations. OBJECTIVES: We aimed to identify genetic variants associated with asthma hospitalizations. METHODS: We conducted a genome-wide association study of asthma hospitalizations in 34,167 white British adults with asthma, 1,658 of whom had at least 1 asthma-related hospitalization. This analysis was conducted by using logistic regression under an additive genetic model with adjustment for age, sex, body mass index, smoking status, and the first 5 principal components derived from genotypic data. We then analyzed data from 2 cohorts of Latino children and adolescents for replication and conducted quantitative trait locus and functional annotation analyses. RESULTS: At the chromosome 6p21.3 locus, the single-nucleotide polymorphism (SNP) rs56151658 (8 kb from the promoter of HLA-DQB1) was most significantly associated with asthma hospitalizations (for test allele A, odds ratio = 1.36 [95% CI = 1.22-1.52]; P = 3.11 × 10-8); 21 additional SNPs in this locus were associated with asthma hospitalizations at a P value less than 1 × 10-6. In the replication cohorts, multiple SNPs in strong linkage disequilibrium with rs56151658 were associated with severe asthma exacerbations at a P value of .01 or less in the same direction of association as in the discovery cohort. Three HLA genes (HLA-DQA2, HLA-DRB6, and HLA-DOB) were also shown to mediate the estimated effects of the SNPs associated with asthma hospitalizations through effects on gene expression in lung tissue. CONCLUSIONS: We identified strong candidate genes for asthma hospitalizations in adults in the region for class II HLA genes through genomic, quantitative trait locus, and summary data-based mendelian randomization analyses.

A genome-wide association study of severe asthma exacerbations in Latino children and adolescents.

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 in FLJ22447 (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 the FLJ22447 locus, which was in turn associated with increased expression of KCNJ2-AS1 in nasal airway epithelium from Puerto Rican children and adolescents (ß=0.10, p=2.18×10-7).SNP rs2253681 was significantly associated with both DNA methylation of a cis-CpG in FLJ22447 and 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).

Managing Asthma in Adolescents and Adults: 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program.

Importance: Asthma is a major public health problem worldwide and is associated with excess morbidity, mortality, and economic costs associated with lost productivity. The National Asthma Education and Prevention Program has released the 2020 Asthma Guideline Update with updated evidence-based recommendations for treatment of patients with asthma. Objective: To report updated recommendations for 6 topics for clinical management of adolescents and adults with asthma: (1) intermittent inhaled corticosteroids (ICSs); (2) add-on long-acting muscarinic antagonists; (3) fractional exhaled nitric oxide; (4) indoor allergen mitigation; (5) immunotherapy; and (6) bronchial thermoplasty. Evidence Review: The National Heart, Lung, and Blood Advisory Council chose 6 topics to update the 2007 asthma guidelines based on results from a 2014 needs assessment. The Agency for Healthcare Research and Quality conducted systematic reviews of these 6 topics based on literature searches up to March-April 2017. Reviews were updated through October 2018 and used by an expert panel (n = 19) that included asthma content experts, primary care clinicians, dissemination and implementation experts, and health policy experts to develop 19 new recommendations using the GRADE method. The 17 recommendations for individuals aged 12 years or older are reported in this Special Communication. Findings: From 20 572 identified references, 475 were included in the 6 systematic reviews to form the evidence basis for these recommendations. Compared with the 2007 guideline, there was no recommended change in step 1 (intermittent asthma) therapy (as-needed short-acting ß2-agonists [SABAs] for rescue therapy). In step 2 (mild persistent asthma), either daily low-dose ICS plus as-needed SABA therapy or as-needed concomitant ICS and SABA therapy are recommended. Formoterol in combination with an ICS in a single inhaler (single maintenance and reliever therapy) is recommended as the preferred therapy for moderate persistent asthma in step 3 (low-dose ICS-formoterol therapy) and step 4 (medium-dose ICS-formoterol therapy) for both daily and as-needed therapy. A short-term increase in the ICS dose alone for worsening of asthma symptoms is not recommended. Add-on long-acting muscarinic antagonists are recommended in individuals whose asthma is not controlled by ICS-formoterol therapy for step 5 (moderate-severe persistent asthma). Fractional exhaled nitric oxide testing is recommended to assist in diagnosis and monitoring of symptoms, but not alone to diagnose or monitor asthma. Allergen mitigation is recommended only in individuals with exposure and relevant sensitivity or symptoms. When used, allergen mitigation should be allergen specific and include multiple allergen-specific mitigation strategies. Subcutaneous immunotherapy is recommended as an adjunct to standard pharmacotherapy for individuals with symptoms and sensitization to specific allergens. Sublingual immunotherapy is not recommended specifically for asthma. Bronchial thermoplasty is not recommended as part of standard care; if used, it should be part of an ongoing research effort. Conclusions and Relevance: Asthma is a common disease with substantial human and economic costs globally. Although there is no cure or established means of prevention, effective treatment is available. Use of the recommendations in the 2020 Asthma Guideline Update should improve the health of individuals with asthma.

2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group.

The 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group was coordinated and supported by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health. It is designed to improve patient care and support informed decision making about asthma management in the clinical setting. This update addresses six priority topic areas as determined by the state of the science at the time of a needs assessment, and input from multiple stakeholders:A rigorous process was undertaken to develop these evidence-based guidelines. The Agency for Healthcare Research and Quality's (AHRQ) Evidence-Based Practice Centers conducted systematic reviews on these topics, which were used by the Expert Panel Working Group as a basis for developing recommendations and guidance. The Expert Panel used GRADE (Grading of Recommendations, Assessment, Development and Evaluation), an internationally accepted framework, in consultation with an experienced methodology team for determining the certainty of evidence and the direction and strength of recommendations based on the evidence. Practical implementation guidance for each recommendation incorporates findings from NHLBI-led patient, caregiver, and clinician focus groups. To assist clincians in implementing these recommendations into patient care, the new recommendations have been integrated into the existing Expert Panel Report-3 (EPR-3) asthma management step diagram format.

Correction: Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritization.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Use of National Asthma Guidelines by Allergists and Pulmonologists: A National Survey.

BACKGROUND: Little is known about specialist-specific variations in guideline agreement and adoption. OBJECTIVE: To assess similarities and differences between allergists and pulmonologists in adherence to cornerstone components of the National Asthma Education and Prevention Program's Third Expert Panel Report. METHODS: Self-reported guideline agreement, self-efficacy, and adherence were assessed in allergists (n = 134) and pulmonologists (n = 99) in the 2012 National Asthma Survey of Physicians. Multivariate models were used to assess if physician and practice characteristics explained bivariate associations between specialty and "almost always" adhering to recommendations (ie, ≥75% of the time). RESULTS: Allergists and pulmonologists reported high guideline self-efficacy and moderate guideline agreement. Both groups "almost always" assessed asthma control (66.2%, standard error [SE] 4.3), assessed school/work asthma triggers (71.3%, SE, 3.9), and endorsed inhaled corticosteroids use (95.5%, SE 2.0). Repeated assessment of the inhaler technique, use of asthma action/treatment plans, and spirometry were lower (39.7%, SE 4.0; 30.6%, SE 3.6; 44.7%, SE 4.1, respectively). Compared with pulmonologists, more allergists almost always performed spirometry (56.6% vs 38.6%, P = .06), asked about nighttime awakening (91.9% vs 76.5%, P = .03) and emergency department visits (92.2% vs 76.5%, P = .03), assessed home triggers (70.5% vs 52.6%, P = .06), and performed allergy testing (61.8% vs 21.3%, P < .001). In multivariate analyses, practice-specific characteristics explained differences except for allergy testing. CONCLUSIONS: Overall, allergists and pulmonologists adhere to the asthma guidelines with notable exceptions, including asthma action plan use and inhaler technique assessment. Recommendations with low implementation offer opportunities for further exploration and could serve as targets for increasing guideline uptake.

Pharmacogenomic associations of adverse drug reactions in asthma: systematic review and research prioritisation.

A systematic review of pharmacogenomic studies capturing adverse drug reactions (ADRs) related to asthma medications was undertaken, and a survey of Pharmacogenomics in Childhood Asthma (PiCA) consortia members was conducted. Studies were eligible if genetic polymorphisms were compared with suspected ADR(s) in a patient with asthma, as either a primary or secondary outcome. Five studies met the inclusion criteria. The ADRs and polymorphisms identified were change in lung function tests (rs1042713), adrenal suppression (rs591118), and decreased bone mineral density (rs6461639) and accretion (rs9896933, rs2074439). Two of these polymorphisms were replicated within the paper, but none had external replication. Priorities from PiCA consortia members (representing 15 institution in eight countries) for future studies were tachycardia (SABA/LABA), adrenal suppression/crisis and growth suppression (corticosteroids), sleep/behaviour disturbances (leukotriene receptor antagonists), and nausea and vomiting (theophylline). Future pharmacogenomic studies in asthma should collect relevant ADR data as well as markers of efficacy.

Building Bridges for Asthma Care Program: A School-Centered Program Connecting Schools, Families, and Community Health-Care Providers.

Asthma imposes tremendous burden on children, families, and society. Successful management requires coordinated care among children, families, health providers, and schools. Building Bridges for Asthma Care Program, a school-centered program to coordinate care for successful asthma management, was developed, implemented, and evaluated. The program consists of five steps: (1) identify students with asthma; (2) assess asthma risk/control; (3) engage the family and student at risk; (4) provide case management and care coordination, including engagement of health-care providers; and (5) prepare for next school year. Implementation occurred in 28 schools from two large urban school districts in Colorado and Connecticut. Significant improvements were noted in the proportions of students with completed School Asthma Care Plans, a quick-relief inhaler at school, Home Asthma Action/Treatment Plans and inhaler technique (p < .01 for all variables). Building Bridges for Asthma Care was successfully implemented extending asthma care to at-risk children with asthma through engagement of schools, health providers, and families.

Primary care clinician adherence with asthma guidelines: the National Asthma Survey of Physicians.

Background and objectives: Although primary care clinicians provide >60% of U.S. asthma care, no nationally representative study has examined variation in adherence among primary care groups to four cornerstone domains of the Expert Panel Report-3 asthma guidelines: assessment/monitoring, patient education, environmental assessment, and medications. We used the 2012 National Asthma Survey of Physicians: National Ambulatory Medical Care Survey to compare adherence by family/general medicine practitioners (FM/GM), internists, pediatricians and Community Health Center mid-level clinicians (CHC). Methods: Adherence was self-reported (n = 1355 clinicians). Adjusted odds of almost always adhering to each recommendation (≥75% of the time) were estimated controlling for clinician/practice characteristics, and agreement and self-efficacy with guideline recommendations. Results: A higher percentage of pediatricians adhered to most assessment/monitoring recommendations compared to FM/GM and other groups (e.g. 71.6% [SE 4.0] almost always assessed daytime symptoms versus 50.6% [SE 5.1]-51.1% [SE 5.8], t-test p < 0.05) but low percentages from all groups almost always performed spirometry (6.8% [SE 2.0]-16.8% [SE 4.7]). Pediatricians were more likely to provide asthma action/treatment plans than FM/GM and internists. Internists were more likely to assess school/work triggers than pediatricians and CHC (environmental assessment). All groups prescribed inhaled corticosteroids for daily control (84.0% [SE 3.7]-90.7% [SE 2.5]) (medications). In adjusted analyses, pediatric specialty, high self-efficacy and frequent specialist referral were associated with high adherence. Conclusions: Pediatricians were more likely to report high adherence than other clinicians. Self- efficacy and frequent referral were also associated with adherence. Adherence was higher for history-taking recommendations and lower for recommendations involving patient education, equipment and expertise.

Asthma management in school: parents' and school personnel perspectives.

Objective: Effective asthma management at school can help students with asthma stay healthy, learn better and participate fully during their school day. This study sought to understand school-based asthma care from the perspective of parents and school personnel to improve asthma care at school. Methods: A cross-sectional study was conducted in Hartford, CT. School personnel from 59 schools and 322 parents/guardians were invited to participate. Four cross-sectional surveys using Likert-type scales assessed parental and school personnel satisfaction, confidence in managing asthma, policy awareness, management of asthma during physical activity, and perceived gaps surrounding school-based asthma care. Results: 263/322 (82%) eligible parents of children with asthma (mean age 8.5 ± 4.3, 56% Hispanic, 30% African American) completed surveys. Thirty six school nurses (62%), 131 teachers (8%), 14 coaches (14%), and 17 school principals (29%) participated. 90% of parents were satisfied with asthma management in school. School nurses were more aware of asthma policies than teachers (74% vs. 24%, p < 0.001). 34% of school nurses, 30% of teachers and 36% of coaches were unaware of asthma-related absences. 14% of physical education teachers/coaches reported no asthma training. Conclusion: In this convenience sample of parents and school personnel, parents reported overall satisfaction regarding the asthma care their children receive at school, yet a number of gaps pertaining to school-based asthma care were identified. Increased asthma training and enhanced communication among school personnel is needed to address these gaps. National guidelines and resources are readily available to improve asthma care at school.

A School Nurse-Led Asthma Program Reduces Absences: Evaluation of Easy Breathing for Schools.

OBJECTIVE: To evaluate whether school nurses can assist pediatricians in providing asthma care and reduce school absenteeism through a program called Easy Breathing for Schools (EzBfS), a 5-element school nurse-led asthma management program and the effectiveness in reducing school absenteeism. METHODS: Fifteen public school nurses in an urban community implemented EzBfS during the 2015-16 and 2016-17 school years. Program elements included assessment of asthma risk and asthma control, asthma education, medication review, and a pediatrician communication tool. School absence for any reason was the primary outcome; absentee rates for students with asthma enrolled in the program were compared to students with asthma in the entire school population using negative binomial regression. RESULTS: School nurses enrolled 251/2,126 students with physician-confirmed asthma (2015-16: n = 114 and 2016-17: n = 137). Sixty eight percent of participants were Latino and 25% were Black with a mean age of 8.7 ± 2.2 years. Absentee rates were higher in children with asthma compared to children without asthma (8.3% vs 7.0% absent, respectively P < .001). Students enrolled in the program experienced a 25% decrease in absentee rate after adjusting for age, sex, race/ethnicity, and school year (rate ratio = 0.75, 95% confidence interval, 0.67, 0.85) as compared to students with asthma not enrolled in the program. Participants also demonstrated improvement in inhaler technique score (P < .001). Ninety two percent of the nurses were satisfied with the program. CONCLUSION: EzBfS, a pragmatic, nurse-led asthma management program, was successfully implemented by school nurses and significantly decreased school absences among a sample of students with asthma.

Whole Genome Sequencing Identifies CRISPLD2 as a Lung Function Gene in Children With Asthma.

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 FEV1/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 FEV1 (P = 3.3 × 10-3), postbronchodilator (PB) FEV1 (7.3 × 10-3), and PB FEV1/FVC ratio (P = 2.7 × 10-3). The identified baseline FEV1/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.