Heritability of Lung Disease Severity in Cystic Fibrosis

Abstract

Rationale: Obstructive lung disease, the major cause of mortality in cystic fibrosis (CF), is poorly correlated with mutations in the diseasecausing gene, indicating that other factors determine severity of lung disease. Objectives: To quantify the contribution of modifier genes to variation in CF lung disease severity. Methods: Pulmonary function data from patients with CF living with their affected twin or sibling were converted into reference values based on both healthy and CF populations. The best measure of FEV 1 within the last year was used for cross-sectional analysis. FEV 1 measures collected over at least 4 years were used for longitudinal analysis. Genetic contribution to disease variation (i.e., heritability) was estimated in two ways: by comparing similarity of lung function in monozygous (MZ) twins ‫ف(‬ 100% gene sharing) with that of dizygous (DZ) twins/siblings ‫ف(‬ 50% gene sharing), and by comparing similarity of lung function measures for related siblings to similarity for all study subjects. Measurements and Main Results

Interactions Between Secondhand Smoke and Genes That Affect Cystic Fibrosis Lung Disease

“…Data for this study were collected by the US Cystic Fibrosis Twin and Sibling Study 2,22 with pulmonary function, growth parameter, zip code, and ethnicity/race data supplemented through the use of the Cystic Fibrosis Foundation Data Registry (Bethesda, Maryland). Approval and annual review of this study was obtained through the Johns Hopkins University institutional review board with review by local institutional review boards if required by participating institutions.…”

“…25 Use of CF-specific percentiles, which account for age, height, and sex, allows patients of different ages to be readily compared because the typical longitudinal decline in lung function measures with traditional predictive equations is not seen with CF-specific percentiles. 2 The maximum FEV 1 CF percentile, a cross-sectional measure of lung function, and the average FEV 1 CF percentile, a longitudinal measure, were derived as previously described. 2 The estimated FEV 1 percentile at 20 years, a longitudinal measure that predicts lung function at age 20 years, was derived as previously described.…”

“…2 The maximum FEV 1 CF percentile, a cross-sectional measure of lung function, and the average FEV 1 CF percentile, a longitudinal measure, were derived as previously described. 2 The estimated FEV 1 percentile at 20 years, a longitudinal measure that predicts lung function at age 20 years, was derived as previously described. 26 Body mass index (BMI) z scores were calculated using reference equations from the Centers for Disease Control and Prevention.…”

Identification of SNPs in the cystic fibrosis interactome influencing pulmonary progression in cystic fibrosis

“…16 We hypothesized that genes interacting with CFTR and epithelial sodium channel ENaC might be potential modifiers of CF disease severity. Therefore, we assessed the impact of variants of these interacters on CF disease outcome.…”

“…11,14,15 Owing to the great phenotypic variability in lung disease even observed among patients carrying the same CFTR genotype, several association studies have been conducted to find modifying genetic factors and to study their influence on CF disease outcome. 16 So far, five genes showed an association in at least two independent populations with more than 500 participants in total, namely MBL2, IFRD1, IL8 and TGFB1 that are involved in the immune response and EDNRA that might influence CF lung disease by altering smooth muscle tone in the airways and/or vasculature. [17][18][19][20][21] IFRD1 was initially found in a genome-wide association study (GWAS) comprising 160 severe and 160 mild CF patients from the GMS (extremes of phenotype) cohort and replicated in the TSS cohort (family-based CF Twin and Sibling study cohort).…”