Morbidity and mortality in carriers of the cystic fibrosis mutation CFTR Phe508del in the general population.

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Cystic fibrosis is caused by autosomal-recessive inheritance of a dysfunctional cystic fibrosis transmembrane conductance regulator (CFTR), up to 90% due to Phe508del mutation in the CFTR gene. We tested the hypothesis that CFTR Phe508del carriers versus non-carriers in the general population have increased morbidity and mortality.We genotyped 108 035 randomly selected white Danish individuals aged 20-100 from the Copenhagen General Population Study for CFTR Phe508del (rs113993960). We assessed risk of chronic bronchitis and airflow limitation cross-sectionally, and overall survival and risk of bronchiectasis, lung cancer, pneumonia, chronic rhinosinusitis, airway bleeding, spontaneous pneumothorax, respiratory failure, acute and chronic pancreatitis, liver cirrhosis, ileus, gastric and colorectal cancer, and male infertility prospectively during up to 15 years follow-up (median:9 years). A single individual was excluded due to homozygosity for CFTR Phe508del and known cystic fibrosis. No other individuals had diagnosed cystic fibrosis at baseline examination or during follow-up.Among 108 034 individuals, 105 176(97%) were non-carriers and 2858(3%) were carriers, i.e. heterozygous for CFTR Phe508del. Overall survival was similar between carriers and non-carriers. Compared to non-carriers and multivariable adjusted, carriers had odds ratio of 1.31(95% confidence interval:1.16-1.48) for chronic bronchitis, hazard ratio of 1.88(1.03-3.45) for bronchiectasis, and hazard ratio of 1.52(1.12-2.08) for lung cancer. Carriers did not differ from non-carriers concerning lung function or any other morbidity outcomes as mentioned above.In the general population, carriers of CFTR Phe508del have a normal lifespan but an increased risk of chronic bronchitis by 1.3-fold, bronchiectasis by 1.9-fold, and lung cancer by 1.5-fold.


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