Role of the ADAM33 rs2280091 Variant in Modulating Lung Function in Cystic Fibrosis

Cystic fibrosis (CF) is a rare genetic disease caused by pathogenic variants in the CFTR (Cystic Fibrosis Transmembrane Conductance Regulator) gene, with wide clinical variability influence not only by the CFTR genotype but also by environmental and modifier genes such as ADAM33 (A Disintegrin and Metalloproteinase Domain 33). The rs2280091 variant in ADAM33 may affect lung function and contribute to differences in disease severity. This study investigated the association between this genetic variant and lung function in CF patients. This cross-sectional study included 55 CF patients from a Brazilian center, with diagnosis confirmed by sweat testing and CFTR genotyping. Pulmonary function was evaluated by spirometry before and after bronchodilator (BD) administration according to the American Thoracic Society/European Respiratory Society guidelines, analyzing Forced Vital Capacity (FVC), Forced Expiratory Volume in one second (FEV1), FEV1/FVC ratio, Forced Expiratory Flow at 25%, 50%, and 75% of FVC (FEF25%, FEF50%, and FEF75%), mean Forced Expiratory Flow between 25% and 75% of FVC (FEF25-75%), and Maximal Expiratory Forced Flow (MEF). The ADAM33 rs2280091 variant was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and statistical analyses included Kruskal-Wallis and Mann-Whitney tests, chi-square (χ²) tests, and calculation of odds ratios (ORs) with 95% confidence intervals (95% CI). The study included 55 CF patients, predominantly female (96.4%) and Caucasian (52.7%), with a median age of 17 years. CFTR genotyping revealed F508del/F508del as the most common genotype (52.7%). Analysis of the ADAM33 rs2280091 variant demonstrated that the AA genotype was most frequent in both CF patients (69.1%) and healthy controls (78.6%). Notably, the GG genotype was significantly enriched in CF patients (18.2%) compared with the controls (0.02%), yielding an odds ratio of 12.06 (95% CI: 4.86-29.91), while the G allele was also associated with increased disease risk (24.5% vs. 11.6%). Pulmonary function assessment indicated that carriers of the GG genotype or G allele had higher Forced Expiratory Flow parameters (FEF25%, FEF50%, FEF25-75%, and MEF) and improved BD responsiveness, suggesting a potential modulatory role of ADAM33 in peripheral airway function in CF. The G allele of the ADAM33 rs2280091 variant was more frequent among recruited CF patients and associated with improved peripheral airway function and BD response. These findings may reflect a survivor effect, in which carriers of this allele are more likely to reach clinical follow-up and recruitment rather than indicating a direct association with increased disease risk.