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 <i>CFTR</i> (<i>Cystic Fibrosis Transmembrane Conductance Regulator</i>) gene, with wide clinical variability influence not only by the <i>CFTR</i> genotype but also by environmental and modifier genes such as <i>ADAM33</i> (<i>A Disintegrin and Metalloproteinase Domain 33</i>). The rs2280091 variant in <i>ADAM33</i> 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 <i>CFTR</i> 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 <i>ADAM33</i> 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. <i>CFTR</i> genotyping revealed F508del/F508del as the most common genotype (52.7%). Analysis of the <i>ADAM33</i> 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 <i>ADAM33</i> in peripheral airway function in CF. The G allele of the <i>ADAM33</i> 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.