Lifestyle exposures and bronchiectasis risk in CFTR p.Phe508del carriers

Genetic variations in CFTR gene may interact with lifestyle exposures to influence risk of non-cystic fibrosis pulmonary and gastrointestinal diseases. We investigated the impact of CFTR heterozygosity, smoking, and alcohol consumption on disease risk and circulating protein levels. Protein Quantitative Trait Loci (pQTL) analyses were conducted using proteomic data from UK Biobank. Associations between CFTR p.Phe508del heterozygosity and pulmonary and gastrointestinal outcomes were examined in 225 281 participants using Firth logistic regression, and effect modification by smoking and alcohol consumption was explored in stratified analyses. Among 35 989 participants with proteomic data, we identified five intronic trans pQTLs within CFTR associated with altered protein levels. CFTRp.Phe508del carriers showed reduced plasma levels of pancreatic enzymes (CPA1, CPB1, and REG3A), with greater reduction in very heavy drinkers. CLPS was increased in ever and previous smokers, and PNLIPRP1 reduced in current smokers. Heterozygotes had increased odds of bronchiectasis and duodenal ulcer, particularly in never smokers and very heavy drinkers, with higher bronchiectasis odds in current smokers. These findings indicate that genetic variation at the CFTR locus influences pancreatic enzyme levels in carriers, with lifestyle exposures. CFTRp.Phe508del heterozygosity combined with smoking/alcohol consumption increased susceptibility to bronchiectasis and duodenal ulcer, supporting phenotypic heterogeneity involving genetic and acquired CFTR impairment.