Science

Science. significant exposure or infection. This latter phenotype was found in a subset of CF patients who carried at least one uncommon CFTR gene allele suggestive of a genetic basis for resistance to contamination in this group of older CF patients. For CF patients in whom both CFTR gene alleles were identified by screening for the 12 most common variants (75% of alleles), cross-sectional analysis showed that MPA contamination was best correlated with lower percent predicted FEV1, while genotype (two versus one F508 CFTR gene allele) and a low level of MSOA were associated with increased risk of contamination. A mixed-model analysis of longitudinal spirometric measurements that considered multiple risk factors to derive regression equations was used to determine which clinical parameters had the greatest effect on the annual rate of decline in percent predicted FEV1. This analysis showed that this CFTR gene genotype only modestly altered the constant (intercept) of the derived equations, while gender and MPA contamination status had the 24, 25-Dihydroxy VD2 largest effects on annual rates of decline in percent predicted FEV1. These results indicate that this CFTR genotype is usually not a main determinant of pulmonary function in most 24, 25-Dihydroxy VD2 CF patients, but gender and MPA contamination status are. Infection status is usually potentially influenced by both immunologic (a high level of MSOA) and genetic factors, such as carriage of a CFTR gene allele that leads to a diagnosis of CF but still confers resistance to contamination that is comparable to that of the wild-type CFTR gene. Cystic fibrosis (CF) occurs with mutation in the CF transmembrane conductance regulator (CFTR) gene. Sixty-six percent of the CFTR gene alleles contain a 3-bp deletion in the CFTR gene which results in the loss of a phenylalanine residue at position 508 (F508 CFTR gene allele) (15). Therefore, about 44% of CF patients are homozygous for the F508 CFTR gene allele. Survival in CF is limited by progressive obstructive pulmonary disease secondary to abnormal secretions and injury from chronic contamination and inflammation. The predominant pathogen for CF patients is usually mucoid (MPA), and contamination with this pathogen is usually associated with more severe pulmonary disease (9, 16). While F508 and other CFTR gene alleles (e.g., W1282X, and G551D) can be categorized as severe with respect to the level of exocrine pancreatic dysfunction (20), correlations of genotype with the severity of pulmonary disease have been less obvious. Many analyses of cross-sectional data covarying steps of pulmonary function with the number of F508 CFTR gene alleles failed to demonstrate a dose effect of this allele on pulmonary disease severity (1, 3, 8, 17, 22, 34). Other evidence, however, suggests that the CFTR gene genotype may influence pulmonary phenotype (4, 5, 14, 18, 23, 25, 35). The observation that moderate pulmonary disease can exist in some patients homozygous for the F508 CFTR gene allele suggests that other genetic and environmental factors must change the pulmonary phenotype in CF (2, 33). Given the impact of chronic MPA contamination, factors that change the time of onset or the persistence of contamination may impact long-term end result. One such factor may be a CF patients immunologic status. An immune response composed of opsonic antibodies specific to the mucoid exopolysaccharide (MEP) coat of MPA was associated with the absence of MPA contamination in older CF 24, 25-Dihydroxy VD2 patients, and these antibodies were protective against contamination in animal models (30, 31). Tosi et al. (37) also found naturally 24, 25-Dihydroxy VD2 occurring opsonic antibodies of undefined antigenic specificity present in CF patients prior to contamination with a decline in opsonic activity following MPA contamination. The effect of genotype on MPA contamination or pulmonary status was not considered in these studies of CF patients. The identification of factors that explain the observed variability in pulmonary end result could be useful both in furthering our understanding of CF pathophysiology and in accelerating evaluation of the efficacy Slit1 of new therapies. Recently, Corey et al. (5) offered rates of decline in 24, 25-Dihydroxy VD2 pulmonary function based on a mixed-model statistical approach for 363 CF patients analyzed according to age, sex, CFTR gene genotype, and pancreatic status. However, neither contamination nor immunologic status to MPA was incorporated into their model. We therefore performed a multivariate assessment of known risk factors (5, 9), modeling age,.