Diversity of CFTR variants across ancestries characterized using 454,727 UK biobank whole exome sequences.

Background: Limited understanding of the diversity of variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene across ancestries hampers efforts to advance molecular diagnosis of cystic fibrosis (CF). The consequences pose a risk of delayed diagnoses and subsequently worsened health outcomes for patients. Therefore, characterizing the spectrum of CFTR variants across ancestries is critical for revolutionizing molecular diagnoses of CF.

CFTR-mediated monocyte/macrophage dysfunction revealed by cystic fibrosis proband-parent comparisons.

Cystic fibrosis (CF) is an inherited disorder caused by biallelic mutations of the CF transmembrane conductance regulator (CFTR) gene. Converging evidence suggests that CF carriers with only 1 defective CFTR copy are at increased risk for CF-related conditions and pulmonary infections, but the molecular mechanisms underpinning this effect remain unknown. We performed transcriptomic profiling of peripheral blood mononuclear cells (PBMCs) of CF child-parent trios (proband, father, and mother) and healthy control (HC) PBMCs or THP-1 cells incubated with the plasma of these participants.

variants are associated with chronic bronchitis in smokers.

Introduction: Loss-of-function variants in both copies of the cystic fibrosis transmembrane conductance regulator () gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesise that variants in individuals with a history of smoking are associated with chronic obstructive pulmonary disease (COPD) and related phenotypes.

Methods: Whole-genome sequencing was performed through the National Heart, Lung, and Blood Institute TOPMed (TransOmics in Precision Medicine) programme in 8597 subjects from the COPDGene (Genetic Epidemiology of COPD) study, an observational study of current and former smokers.

Genomic, transcriptomic, and protein landscape profile of CFTR and cystic fibrosis.

Cystic Fibrosis (CF) is caused most often by removal of amino acid 508 (Phe508del, deltaF508) within CFTR, yet dozens of additional CFTR variants are known to give rise to CF and many variants in the genome are known to contribute to CF pathology. To address CFTR coding variants, we developed a sequence-to-structure-to-dynamic matrix for all amino acids of CFTR using 233 vertebrate species, CFTR structure within a lipid membrane, and 20 ns of molecular dynamic simulation to assess known variants from the CFTR1, CFTR2, ClinVar, TOPmed, gnomAD, and COSMIC databases. Surprisingly, we identify 18 variants of uncertain significance within CFTR from diverse populations that are heritable and a likely cause of CF that have been understudied due to nonexistence in Caucasian populations.

Microarray profiling identifies extracellular circulating miRNAs dysregulated in cystic fibrosis.

Extracellular circulating miRNAs (ECmiRNAs) play a crucial role in cell-to-cell communication and serve as non-invasive biomarkers in a wide range of diseases, but their abundance and functional relevance in cystic fibrosis (CF) remain poorly understood. In this study, we employed microarray technology to identify aberrantly expressed plasma ECmiRNAs in CF and elucidate the functional relevance of their targets. Overall, we captured several ECmiRNAs abundantly expressed in CF.

Transcriptional consequences of impaired immune cell responses induced by cystic fibrosis plasma characterized via dual RNA sequencing.

Background: In cystic fibrosis (CF), impaired immune cell responses, driven by the dysfunctional CF transmembrane conductance regulator (CFTR) gene, may determine the disease severity but clinical heterogeneity remains a major therapeutic challenge. The characterization of molecular mechanisms underlying impaired immune responses in CF may reveal novel targets with therapeutic potential. Therefore, we utilized simultaneous RNA sequencing targeted at identifying differentially expressed genes, transcripts, and miRNAs that characterize impaired immune responses triggered by CF and its phenotypes.

Impact of Intermediate Cystic Fibrosis Classification on Parents' Perceptions of Child Vulnerability and Protectiveness.

This cross-sectional, mixed-method study examined factors associated with parent perceptions of child vulnerability and protectiveness in three groups: cystic fibrosis (CF-group, n = 40), intermediate CF classification (I-group, n = 20), and healthy (H-group, n = 50). A composite indicator structural equation (CISE) using Bayesian estimation tested two mediational models: psychological and biological. Significant results ( p < .

Cystic Fibrosis Plasma Blunts the Immune Response to Bacterial Infection.

Cystic fibrosis (CF) is caused by mutations of the gene encoding the CF transmembrane conductance regulator. It remains unclear whether the abnormal immune response in CF involves extrinsic signals released from the external or internal environment. We sought to characterize the peripheral immune signatures in CF and its association with clinical phenotypes.

Transcriptome Profiling and Molecular Therapeutic Advances in Cystic Fibrosis: Recent Insights.

In cystic fibrosis (CF), mutations in the cystic fibrosis transmembrane conductance regulator () gene disrupt the capacity of the encoded protein to function as a channel to transport chloride ions and water across cell membranes. The consequences are deleterious, system-wide, and immensely variable, even among patients with the same genotype. This underscores the need to characterize the mechanisms contributing to CF pathophysiology.

Identification of molecular signatures of cystic fibrosis disease status with plasma-based functional genomics.

Although cystic fibrosis (CF) is attributed to dysfunction of a single gene, the relationships between the abnormal gene product and the development of inflammation and progression of lung disease are not fully understood, which limits our ability to predict an individual patient's clinical course and treatment response. To better understand CF progression, we characterized the molecular signatures of CF disease status with plasma-based functional genomics. Peripheral blood mononuclear cells (PBMCs) from healthy donors were cultured with plasma samples from CF patients ( n = 103) and unrelated, healthy controls ( n = 31).

Estimating the age of p.(Phe508del) with family studies of geographically distinct European populations and the early spread of cystic fibrosis.

The high incidence of cystic fibrosis (CF) is due to the frequency of the c.1521_1523delCTT variant in the cystic fibrosis transmembrane conductance regulator (CFTR), but its age and origin are uncertain. This gap limits attempts to shed light on the presumed heterozygote selective advantage that accounts for the variant's high prevalence among Caucasian Europeans and Europe-derived populations.

Clinical course and significance of nontuberculous mycobacteria and its subtypes in cystic fibrosis.

Background: Nontuberculous mycobacteria (NTM) infections in patients with cystic fibrosis (CF) is increasing globally. However, the related epidemiology, comorbidities, and clinical impact of NTM infection remains unclear in the progress of CF lung disease and patient survival.

Methods: We performed a retrospective, case-control, cohort study (10 years), comparing NTM culture-positive CF patients (N = 28) to matched controls (N = 26).

Increased Expression of Plasma-Induced ABCC1 mRNA in Cystic Fibrosis.

The gene is structurally and functionally related to the cystic fibrosis transmembrane conductance regulator gene (). Upregulation of is thought to improve lung function in patients with cystic fibrosis (CF); the mechanism underlying this effect is unknown. We analyzed the promoter single nucleotide polymorphism (SNP rs504348), plasma-induced mRNA expression levels, and methylation status and their correlation with clinical variables among CF subjects with differing mutations.

Cystic Fibrosis Transmembrane Conductance Regulator-Related Metabolic Syndrome and Cystic Fibrosis Screen Positive, Inconclusive Diagnosis.

Objective: An unintended consequence of cystic fibrosis (CF) newborn screening (NBS) is the identification of infants with a positive NBS test but inconclusive diagnostic testing. These infants are classified as CF transmembrane conductance regulator-related metabolic syndrome (CRMS) in the US and CF screen positive, inconclusive diagnosis (CFSPID) in other countries. Diagnostic and management decisions of these infants are challenges for CF healthcare professionals and stressful situations for families.

Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis.

The identification of small molecules that target specific CFTR variants has ushered in a new era of treatment for cystic fibrosis (CF), yet optimal, individualized treatment of CF will require identification and targeting of disease modifiers. Here we use genome-wide association analysis to identify genetic modifiers of CF lung disease, the primary cause of mortality. Meta-analysis of 6,365 CF patients identifies five loci that display significant association with variation in lung disease.

Changing incidence of cystic fibrosis in Wisconsin, USA.

Rationale: Previous investigations of cystic fibrosis (CF) incidence in Massachusetts, Colorado, and Minnesota (USA) yielded contradictory results, particularly regarding allele p.Phe508del; the racial compositions of the cohorts were not reported.

Objectives: To clarify discrepancies in reported incidence with the ultimate goal of improving screening and quality of care, we assessed CF incidence, stratified by race and mutations in cystic fibrosis transmembrane conductance regulator (CFTR), in Wisconsin (USA) from 1994 to 2011.

Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis.

Objectives: To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including known CF modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels.

Study Design: NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9, SLC6A14, and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT.

Comparison of WHO and CDC growth charts in predicting pulmonary outcomes in cystic fibrosis.

Objectives: The relation of weight-for-length (WFL) and weight-for-age (WFA) measurements with pulmonary function in patients with cystic fibrosis (CF) using the World Health Organization (WHO) growth standards has not been evaluated. The objective of the present study was to show that the relation of WFL and WFA measurements at 2 years with forced expiratory volume in 1 second (FEV1) at 6 to 8 years differs when using the WHO versus the Centers for Disease Control and Prevention (CDC) growth charts.

Methods: We assessed 1155 patients in the CF Foundation Patient Registry born between 2001 and 2004.

Risk factors for the progression of cystic fibrosis lung disease throughout childhood.

Rationale: Previous studies of risk factors for progression of lung disease in cystic fibrosis (CF) have suffered from limitations that preclude a comprehensive understanding of the determinants of CF lung disease throughout childhood. The epidemiologic component of the 27-year Wisconsin Randomized Clinical Trial of CF Neonatal Screening Project (WI RCT) afforded us a unique opportunity to evaluate the significance of potential intrinsic and extrinsic risk factors for lung disease in children with CF.

Objectives: Describe the most important intrinsic and extrinsic risk factors for progression of lung disease in children with CF.

Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia*.

Objectives: The cystic fibrosis transmembrane conductance regulator regulates fluid balance in alveolar epithelial cells and appears to modulate the inflammatory response. To determine whether more severe lung injury in children who develop community-acquired pneumonia is associated with variations known to affect function in the gene coding for cystic fibrosis transmembrane conductance regulator.

Design: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia.

Factors accounting for a missed diagnosis of cystic fibrosis after newborn screening.

Newborn screening is a public health policy program involving the centralized testing laboratory, infant and their family, primary care provider, and subspecialist for confirmatory testing and follow-up of abnormal results. Cystic fibrosis (CF) newborn screening has now been enacted in all 50 states and the District of Columbia and throughout many countries in the world. Although CF neonatal screening will identify the vast majority of infants with CF, there are many factors in the newborn screening system that can lead to a missed diagnosis of CF.

Growth and pulmonary outcomes during the first 2 y of life of breastfed and formula-fed infants diagnosed with cystic fibrosis through the Wisconsin Routine Newborn Screening Program.

Background: The optimal feeding (breast milk, formula, or a combination) for infants with cystic fibrosis (CF) is unknown. Recommendations from the CF Foundation are based on limited data.

Objective: We compared growth and pulmonary outcomes between breastfed and formula-fed infants through the age of 2 y.

Optimal DNA tier for the IRT/DNA algorithm determined by CFTR mutation results over 14 years of newborn screening.

Background: There has been great variation and uncertainty about how many and what CFTR mutations to include in cystic fibrosis (CF) newborn screening algorithms, and very little research on this topic using large populations of newborns.

Methods: We reviewed Wisconsin screening results for 1994-2008 to identify an ideal panel.

Results: Upon analyzing approximately 1 million screening results, we found it optimal to use a 23 CFTR mutation panel as a second tier when an immunoreactive trypsinogen (IRT)/DNA algorithm was applied for CF screening.