Modifies Chronic Airway Infection Risk in Cystic Fibrosis.

Chronic () airway infection is common and a key contributor to diminished lung function and early mortality in persons with cystic fibrosis (PwCF). Risk factors for chronic among PwCF include (cystic fibrosis transmembrane conductance regulator) genotype, genetic modifiers, and environmental factors. Intensive antibiotic therapy and highly effective modulators do not eradicate in most adolescents and adults with cystic fibrosis.

Genetic modifiers of body mass index in individuals with cystic fibrosis.

To identify modifier loci underlying variation in body mass index (BMI) in persons with cystic fibrosis (pwCF), we performed a genome-wide association study (GWAS). Utilizing longitudinal height and weight data, along with demographic information and covariates from 4,393 pwCF, we calculated AvgBMIz representing the average of per-quarter BMI Z scores. The GWAS incorporated 9.

The clinical utility of sequencing the entirety of CFTR.

Background: Cystic fibrosis (CF) is caused by deleterious variants in each CFTR gene. We investigated the utility of whole-gene CFTR sequencing when fewer than two pathogenic or likely pathogenic (P/LP) variants were detected by conventional testing (sequencing of exons and flanking introns) of CFTR.

Methods: Individuals with features of CF and a CF-diagnostic sweat chloride concentration with zero or one P/LP variants identified by conventional testing enrolled in the CF Mutation Analysis Program (MAP) underwent whole-gene CFTR sequencing.

MagicalRsq-X: A cross-cohort transferable genotype imputation quality metric.

Since genotype imputation was introduced, researchers have been relying on the estimated imputation quality from imputation software to perform post-imputation quality control (QC). However, this quality estimate (denoted as Rsq) performs less well for lower-frequency variants. We recently published MagicalRsq, a machine-learning-based imputation quality calibration, which leverages additional typed markers from the same cohort and outperforms Rsq as a QC metric.

Genetic Modifiers of Cystic Fibrosis Lung Disease Severity: Whole-Genome Analysis of 7,840 Patients.

Lung disease is the major cause of morbidity and mortality in persons with cystic fibrosis (pwCF). Variability in CF lung disease has substantial non-CFTR (CF transmembrane conductance regulator) genetic influence. Identification of genetic modifiers has prognostic and therapeutic importance.

MagicalRsq: Machine-learning-based genotype imputation quality calibration.

Whole-genome sequencing (WGS) is the gold standard for fully characterizing genetic variation but is still prohibitively expensive for large samples. To reduce costs, many studies sequence only a subset of individuals or genomic regions, and genotype imputation is used to infer genotypes for the remaining individuals or regions without sequencing data. However, not all variants can be well imputed, and the current state-of-the-art imputation quality metric, denoted as standard Rsq, is poorly calibrated for lower-frequency variants.

Leveraging TOPMed imputation server and constructing a cohort-specific imputation reference panel to enhance genotype imputation among cystic fibrosis patients.

Cystic fibrosis (CF) is a severe genetic disorder that can cause multiple comorbidities affecting the lungs, the pancreas, the luminal digestive system and beyond. In our previous genome-wide association studies (GWAS), we genotyped approximately 8,000 CF samples using a mixture of different genotyping platforms. More recently, the Cystic Fibrosis Genome Project (CFGP) performed deep (approximately 30×) whole genome sequencing (WGS) of 5,095 samples to better understand the genetic mechanisms underlying clinical heterogeneity among patients with CF.

Complete CFTR gene sequencing in 5,058 individuals with cystic fibrosis informs variant-specific treatment.

Background: Cystic fibrosis (CF) is a recessive condition caused by variants in each CF transmembrane conductance regulator (CFTR) allele. Clinically affected individuals without two identified causal variants typically have no further interrogation of CFTR beyond examination of coding regions, but the development of variant-specific CFTR-targeted treatments necessitates complete understanding of CFTR genotype.

Methods: Whole genome sequences were analyzed on 5,058 individuals with CF.

Comparing encounter-based and annualized chronic pseudomonas infection definitions in cystic fibrosis.

Chronic Pseudomonas aeruginosa (Pa) infection is associated with increased morbidity and mortality in people with cystic fibrosis (CF). There is no gold standard definition of chronic Pa infection in CF. We compared chronic Pa definitions using encounter-based versus annualized data in the Early Pseudomonas Infection Control (EPIC) Observational study cohort, and subsequently compared annualized chronic Pa definitions across a range of U.

Immunoglobulin GM and KM allotypes are associated with antibody responses to Pseudomonas aeruginosa antigens in chronically infected cystic fibrosis patients.

Background: Chronic infection with Pseudomonas aeruginosa (P. aeruginosa) is a leading cause of death in patients with cystic fibrosis (CF). Immunobiology of P.

SLC26A9 SNP rs7512462 is not associated with lung disease severity or lung function response to ivacaftor in cystic fibrosis patients with G551D-CFTR.

Background: The CFTR modulator ivacaftor has been variably effective in treating individuals with cystic fibrosis (CF) who harbor CFTR gating variants such as G551D, as well as other classes of CFTR variants when used with other modulators. Because CFTR genotype does not fully explain this variability, defining genetic modifiers of response to modulator therapy is of particular interest to the field of individualized CF drug therapy. Previous studies have proposed that a variant in SLC26A9 (rs7512462) is associated with lung disease severity and with response to treatment with ivacaftor in individuals with CF who carry G551D or gating variants.

Genetic Modifiers of Cystic Fibrosis-Related Diabetes Have Extensive Overlap With Type 2 Diabetes and Related Traits.

Context: Individuals with cystic fibrosis (CF) develop a distinct form of diabetes characterized by β-cell dysfunction and islet amyloid accumulation similar to type 2 diabetes (T2D), but generally have normal insulin sensitivity. CF-related diabetes (CFRD) risk is determined by both CFTR, the gene responsible for CF, and other genetic variants.

Objective: To identify genetic modifiers of CFRD and determine the genetic overlap with other types of diabetes.

Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population.

Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume in 1 second (FEV1), compared to CF patients without liver disease. Varying definitions of CF liver disease likely contribute to these inconsistent relationships reported between CF lung function and liver disease. We retrospectively evaluated spirometric data in 179 subjects (62% male; 58% Phe508del homozygous) with severe CF liver disease (CFLD; defined by presence of portal hypertension due to cirrhosis).

Airway Mucosal Host Defense Is Key to Genomic Regulation of Cystic Fibrosis Lung Disease Severity.

Rationale: The severity of cystic fibrosis (CF) lung disease varies widely, even for Phe508del homozygotes. Heritability studies show that more than 50% of the variability reflects non-cystic fibrosis transmembrane conductance regulator (CFTR) genetic variation; however, the full extent of the pertinent genetic variation is not known.

Objectives: We sought to identify novel CF disease-modifying mechanisms using an integrated approach based on analyzing "in vivo" CF airway epithelial gene expression complemented with genome-wide association study (GWAS) data.

Corrigendum: Novel variation at chr11p13 associated with cystic fibrosis lung disease severity.

[This corrects the article DOI: 10.1038/hgv.2016.

Deep resequencing of in 762 F508del homozygotes reveals clusters of non-coding variants associated with cystic fibrosis disease traits.

Extensive phenotypic variability is commonly observed in individuals with Mendelian disorders, even among those with identical genotypes in the disease-causing gene. To determine whether variants within and surrounding contribute to phenotypic variability in cystic fibrosis (CF), we performed deep sequencing of in 762 patients homozygous for the common CF-causing variant, F508del. In phase 1, ~200 kb encompassing and extending 10 kb 5' and 5 kb 3' of the gene was sequenced in 486 F508del homozygotes selected from the extremes of sweat chloride concentration.

Novel variation at chr11p13 associated with cystic fibrosis lung disease severity.

Published genome-wide association studies (GWASs) identified an intergenic region with regulatory features on chr11p13 associated with cystic fibrosis (CF) lung disease severity. Targeted resequencing in n=377, followed by imputation to n=6,365 CF subjects, was used to identify unrecognized genetic variants (including indels and microsatellite repeats) associated with phenotype. Highly significant associations were in strong linkage disequilibrium and were seen only in Phe508del homozygous CF subjects, indicating a CFTR genotype-specific mechanism.

Sources of Variation in Sweat Chloride Measurements in Cystic Fibrosis.

Rationale: Expanding the use of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators and correctors for the treatment of cystic fibrosis (CF) requires precise and accurate biomarkers. Sweat chloride concentration provides an in vivo assessment of CFTR function, but it is unknown the degree to which CFTR mutations account for sweat chloride variation.

Objectives: To estimate potential sources of variation for sweat chloride measurements, including demographic factors, testing variability, recording biases, and CFTR genotype itself.

Features of Severe Liver Disease With Portal Hypertension in Patients With Cystic Fibrosis.

Background & Aims: Liver disease is the third leading cause of death in patients with cystic fibrosis (CF), but features of patients with CF, severe liver disease, and portal hypertension have not been characterized fully.

Methods: We performed a retrospective analysis of data from 561 patients with CF (63% male, 99% with pancreatic insufficiency), liver disease (hepatic parenchymal abnormalities consistent with cirrhosis, confirmed by imaging), and portal hypertension (esophageal varices, portosystemic collaterals, or splenomegaly), with no alternate causes of liver disease. All patients were enrolled in the Genetic Modifier Study of Severe CF Liver Disease at 76 international centers, from January 1999 through July 2013.

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.

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.

Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes.

Variation in cystic fibrosis (CF) phenotypes, including lung disease severity, age of onset of persistent Pseudomonas aeruginosa (P. aeruginosa) lung infection, and presence of meconium ileus (MI), has been partially explained by genome-wide association studies (GWASs). It is not expected that GWASs alone are sufficiently powered to uncover all heritable traits associated with CF phenotypic diversity.