Nasal Epithelium Transcriptomics Predict Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor.

Elexacaftor/tezacaftor/ivacaftor (ETI) has made a substantial positive impact for people living with CF (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF prior to ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in FEV1 (∆FEV1), year's best FEV1 (∆ybFEV1), and body mass index (∆BMI). Using the top differentially expressed genes (DEGs), we generated transcriptomic risk scores (TRS) and evaluated their predictive performance. The study included 40 pwCF aged ≥6 years (mean 27.7 [SD=15.1] years; 40% female). After ETI initiation, FEV1 improved ≥5% in 22 (61.1%) participants and ybFEV1 improved ≥5% in 19 (50%). TRS were constructed using top over-expressed and under-expressed genes for each. Adding the ∆FEV1 TRS for to a model with age, sex, and baseline FEV1 increased the AUC from 0.41 to 0.88; the ∆ybFEV1 TRS increased the AUC from 0.51 to 0.88; and the ∆BMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ~85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRS could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.

Persistent cat ownership and asthma in a longitudinal study of Puerto Rican youth.

BACKGROUND: Epidemiologic studies have reported conflicting findings for cat or dog exposure and childhood asthma. No study has evaluated whether persistent pet exposure from early life to school age is associated with asthma or allergic sensitization in youth. OBJECTIVE: To evaluate whether persistent ownership of a cat or a dog throughout childhood is associated with asthma in Puerto Rican youth, a group disproportionately affected with asthma. METHODS: Prospective study of 384 youth who completed a baseline visit at ages 6 to 14 years and a second visit at ages 9 to 20 years. Persistent cat or dog ownership was defined as ownership of a cat or a dog in early life (during pregnancy or the first year of life) at either study visit (at school age). An allergen-specific IgE result was considered positive if more than or equal to 0.35 IU/mL. Logistic regression was used for the multivariable analysis of asthma and allergic sensitization. RESULTS: In an analysis adjusting for household income, family history of atopy, persistent overweight or obesity, a persistent unhealthy diet, the time interval between study visits, and other covariates, persistent cat ownership was significantly associated with 68% reduced odds of asthma (95% CI for odds ratio = 0.11-0.92) but not with any allergic sensitization or sensitization to cat allergen. In contrast, persistent dog ownership was not significantly associated with asthma or allergic sensitization. CONCLUSION: Among school-aged Puerto Rican youth followed for an average of 5 years, persistent cat ownership from early life to school age was inversely associated with asthma.

Socioeconomic status, diet, and recurrent severe asthma exacerbations in Puerto Rican youth.

Background: Why Puerto Rican youths have higher rates of severe asthma exacerbations (SAEs) than their non-Hispanic White peers is unclear. Objective: We aimed to identify risk factors associated with recurrent SAEs in Puerto Rican youths with asthma. Methods: We performed cross-sectional and longitudinal analyses of recurrent SAEs in 209 Puerto Rican youths with asthma who participated in 2 cross-sectional studies approximately 5.2 years apart: the Puerto Rico Genetics of Asthma and Lifestyle study (visit 1, participants aged 6-14 years) and the Epigenetic Variation and Childhood Asthma in Puerto Ricans study (visit 2, participants aged 9-20 years). Recurrent SAEs were defined as at least 2 SAEs in the previous year. Results: Of the youths in our study, there were 80 (38.3%) and 47 (22.4%) with recurrent SAEs at visit 1 and visit 2, respectively, and 31 participants (14.8%) had persistent recurrent SAEs (ie, recurrent SAEs at both visits). In multivariable analyses, low household income was significantly associated with 2.4 to 12.3 times increased odds of recurrent SAEs in all analyses, with stronger longitudinal associations. Low parental education level, nonprivate or employer-based health insurance, overweight or obesity, residential proximity to a major road, and low or moderate level of outdoor activity were each significantly associated with recurrent SAEs in at least 1 analysis. Further, persistence of low parental numeracy level, low household income, and an unhealthy diet were each associated with persistent recurrent SAEs. Conclusion: In this study of Puerto Rican youths with asthma, persistence of low parental numeracy level, a low household income, and an unhealthy diet were associated with persistent recurrent SAEs. Our findings support policies promoting equity and healthy lifestyles for Puerto Rican children and their families.

Long-Term PM2.5 Exposure and Upregulation of CLCA1 Expression in Nasal Epithelium from Youth with Asthma.

BACKGROUND: Little is known about long-term PM2.5 exposure and airway epithelial gene expression. OBJECTIVE: To test for association between long-term PM2.5 exposure and nasal epithelial gene expression in youth with asthma. METHODS: Transcriptome-wide association study (TWAS) of long-term PM2.5 in nasal epithelium from youth aged 6-20 years in the: 1) Epigenetic Variation and Childhood Asthma in Puerto Ricans study (EVA-PR, n=182); 2) Vitamin D Kids Asthma Study (VDKA, n=58); and 3) Stress and Treatment Response in Puerto Rican and African American Children with Asthma study (STAR, n=81). Satellite hybrid models were used to estimate PM2.5 exposure in the prior year at each participant's residence. Multivariable negative binomial regression was used for each TWAS, adjusting for age, sex, and other covariates. A meta-analysis of all TWAS results was then conducted using an inverse variance-weighted average approach. RESULTS: Most participants (~95%) in the meta-analysis of TWAS for PM2.5 exposure identified as Puerto Rican or Black. Long-term PM2.5 was associated with: 1) upregulated expression of CLCA1 (calcium-activated chloride channel regulator 1, false discovery rate-adjusted P [FDR-P]=0.008), SYCP2 (synaptonemal complex protein 2, FDR-P=0.01), and CYP2A6 (cytochrome p450 family 2 subfamily A member 6, FDR-P=0.02), and 2) downregulated expression of EDAR (ectodysplasin A receptor, FDR-P=0.01). In a meta-analysis, CLCA1 upregulation was associated with ≥1 positive allergen-specific IgE (FDR-P <0.001) and increased blood eosinophils (FDR-P <0.001) and total IgE (FDR-P <0.001). CONCLUSIONS: In a meta-analysis of TWASs in predominantly Puerto Rican and Black youth with asthma, long-term PM2.5 exposure was associated with upregulated airway epithelial CLCA1 expression, in turn linked to biomarkers of T2-high immunity.