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Variability in response to short-acting β2-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

Baseline lung function is a standard diagnostic criterion used by clinicians to detect lung diseases. It is a complex trait significantly influenced by both genetics and environmental factors..., Baseline lung function, quantified as forced expiratory volume in the first second of exhalation (FEV1), is a standard diagnostic criterion used by clinicians to identify and classify lung diseases. Using whole-genome sequencing data from the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine project, we identified a novel genetic association with FEV1 on chromosome 12 in 867 African American children with asthma (P = 1.26 × 10−8, β = 0.302). Conditional analysis within 1 Mb of the tag signal (rs73429450) yielded one major and two other weaker independent signals within this peak. We explored statistical and functional evidence for all variants in linkage disequilibrium with the three independent signals and yielded nine variants as the most likely candidates responsible for the association with FEV1. Hi-C data and expression QTL analysis demonstrated that these variants physically interacted with KITLG (KIT ligand, also known as SCF), and their minor alleles were associated with increased expression of the KITLG gene in nasal epithelial cells. Gene-by-air-pollution interaction analysis found that the candidate variant rs58475486 interacted with past-year ambient sulfur dioxide exposure (P = 0.003, β = 0.32). This study identified a novel protective genetic association with FEV1, possibly mediated through KITLG, in African American children with asthma. This is the first study that has identified a genetic association between lung function and KITLG, which has established a role in orchestrating allergic inflammation in asthma.

Sex-specific differences have been noted among people with chronic obstructive pulmonary disease (COPD), but whether these differences are attributable to genetic variation is poorly understood. The availability of large biobanks with deeply phenotyped subjects such as the UK Biobank enables the investigation of sex-specific genetic associations that may provide new insights into COPD risk factors. We performed sex-stratified genome-wide association studies (GWAS) of COPD (male: 12,958 cases and 95,631 controls; female: 11,311 cases and 123,714 controls) and found that while most associations were shared between sexes, several regions had sex-specific contributions, including respiratory viral infection-related loci in/near C5orf56 and PELI1. Using the newly developed R package 'snpsettest', we performed gene-based association tests and identified gene-level sex-specific associations, including C5orf56 on 5q31.1, CFDP1/TMEM170A/CHST6 on 16q23.1 and ASTN2/TRIM32 on 9q33.1. Our results identified promising genes to pursue in functional studies to better understand sexual dimorphism in COPD.

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 datasets are available to interrogate their biological effects. OBJECTIVE: We sought to identify functionally relevant ICS response genetic associations by integrating complementary multiomics datasets. METHODS: Variants with p-values

BACKGROUND/OBJECTIVES: Little is currently known about how exercise may influence dietary patterns and/or food preferences. The present study aimed to examine the effect of a 15-week exercise training program on overall dietary patterns among young adults. SUBJECTS/METHODS: This study consisted of 2680 young adults drawn from the Training Intervention and Genetics of Exercise Response (TIGER) study. Subjects underwent 15 weeks of aerobic exercise training, and exercise duration, intensity, and dose were recorded for each session using computerized heart rate monitors. In total, 4355 dietary observations with 102 food items were collected using a self-administered food frequency questionnaire before and after exercise training (n = 2476 at baseline; n = 1859 at 15 weeks). Dietary patterns were identified using a Bayesian sparse latent factor model. Changes in dietary pattern preferences were evaluated based on the pre/post-training differences in dietary pattern scores, accounting for the effects of gender, race/ethnicity, and BMI. RESULTS: Within each of the seven dietary patterns identified, most dietary pattern scores were decreased following exercise training, consistent with increased voluntary regulation of food intake. A longer duration of exercise was associated with decreased preferences for the Western (β: −0.0793; 95% credible interval: −0.1568, −0.0017) and Snacking (β: −0.1280; 95% credible interval: −0.1877, −0.0637) patterns, while a higher intensity of exercise was linked to an increased preference for the Prudent pattern (β: 0.0623; 95% credible interval: 0.0159, 0.1111). Consequently, a higher dose of exercise was related to a decreased preference for the Snacking pattern (β: −0.0023; 95% credible interval: −0.0042, −0.0004) and an increased preference for the Prudent pattern (β: 0.0029; 95% credible interval: 0.0009, 0.0048). CONCLUSION: The 15-week exercise training appeared to motivate young adults to pursue healthier dietary preferences and to regulate their food intake.

BACKGROUND: Principal components analysis (PCA) has been the most widely used method for deriving dietary patterns to date. However, PCA requires arbitrary ad hoc decisions for selecting food variables in interpreting dietary patterns and does not easily accommodate covariates. Sparse latent factor models can be utilized to address these issues. OBJECTIVE: The objective of this study was to compare Bayesian sparse latent factor models with PCA for identifying dietary patterns among young adults. METHODS: Habitual food intake was estimated in 2730 sedentary young adults from the Training Interventions and Genetics of Exercise Response (TIGER) Study [aged 18–35 y; body mass index (BMI; in kg/m(2)): 26.5 ± 6.1] who exercised

Aim: Identifying differences in plasma metabolic profiling between Lp-PLA2 279VV and 279FF in individuals without metabolic syndrome (MetS) can be used to elucidate the roles of novel Lp-PLA2 activities in normal physiological processes.Methods: Non-MetS individuals with 279FF (n=36) and age-, sex- and BMI-matched VV subjects (n=36) were included in this analysis.Results: The FF subjects exhibited no appreciable enzyme activity. No significant differences were observed between the VV and FF subjects in the serum lipid profiles or hs-CRP, plasma ox-LDL, MDA or urinary 8-epi-PGF2α levels. The FF subjects also showed lower activities of lyso-phosphatidylcholine (lysoPC) (16:0) (p=0.003) and oleamide (p＜0.001) and a higher activity of L-tryptophan (p=0.016) than the VV subjects. In addition, the Lp-PLA2 activity positively correlated with the lysoPC (16:0) and lysoPC (18:0) activities and negatively correlated with the PC (16:0/22:6) and L-tryptophan activities in the VV subjects. Furthermore, in the VV subjects, the lysoPC (16:0) and lysoPC (18:0) activities negatively correlated with the presence of PCs containing 14:0/20:2, 14:0/22:4 and 16:0/22:6, while the oleamide activity exhibited a strong positive correlation with lysoPCs and a negative correlation with PCs, whereas the relationship between oleamide and lysoPCs and PCs was weaker in the FF subjects.Conclusions: The present results indicate that the natural absence of the plasma Lp-PLA2 activity due to carriage of the Lp-PLA2 279FF genotype may reduce the generation of lysoPC (16:0) and oleamide and thereby enhance the activity of plasma tryptophan in normal physiological processes.