Infection and Immunity, September 1999, p. 4744-4750, Vol. 67, No. 9
0019-9567/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.
Division of Pulmonary Medicine,
Received 3 May 1999/Returned for modification 21 June 1999/Accepted 29 June 1999
Whether allelic variants of the cystic fibrosis (CF) transmembrane
conductance regulator (CFTR) independently contribute to pulmonary
outcome in CF patients has not been resolved. We used both
cross-sectional and mixed-model longitudinal analyses of data from CF
patients that were at least 12 years old to determine the influence on
pulmonary function (percent predicted forced expiratory volume
[FEV1]) of the CFTR gene genotype, gender, mucoid Pseudomonas aeruginosa (MPA) infection status, presence of
total opsonic antibody to MPA, and, separately, the opsonic antibody activity specific to the mucoid exopolysaccharide (MEP) surface antigen. Two different factors were independently associated with the
lack of MPA infection: a high level of MEP-specific opsonic activity
(MSOA), implicating an immunologically based mechanism of resistance to
infection, and a lack of any type of opsonic antibody to MPA,
indicative of no 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 infection 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 infection 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
infection. 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 the CFTR gene genotype only
modestly modified the constant (y intercept) of the derived
equations, while gender and MPA infection status had the largest
effects on annual rates of decline in percent predicted
FEV1. These results indicate that the CFTR genotype is
usually not a primary determinant of pulmonary function in most CF
patients, but gender and MPA infection status are. Infection status is
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 infection that is
comparable to that of the wild-type CFTR gene.
*
Corresponding author. Mailing address: Channing
Laboratory, 181 Longwood Ave., Boston, MA 02115. Phone: (617) 525-2269. Fax: (617) 731-1541. E-mail: gpier{at}channing.harvard.edu.
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