Allelic heterogeneity in disease-causing genes presents a substantial challenge to the translation of genomic variation into clinical practice. Few of the almost 2,000 variants in the cystic fibrosis ...transmembrane conductance regulator gene CFTR have empirical evidence that they cause cystic fibrosis. To address this gap, we collected both genotype and phenotype data for 39,696 individuals with cystic fibrosis in registries and clinics in North America and Europe. In these individuals, 159 CFTR variants had an allele frequency of ł0.01%. These variants were evaluated for both clinical severity and functional consequence, with 127 (80%) meeting both clinical and functional criteria consistent with disease. Assessment of disease penetrance in 2,188 fathers of individuals with cystic fibrosis enabled assignment of 12 of the remaining 32 variants as neutral, whereas the other 20 variants remained of indeterminate effect. This study illustrates that sourcing data directly from well-phenotyped subjects can address the gap in our ability to interpret clinically relevant genomic variation.
Genetic modifiers of lung disease in cystic fibrosis Drumm, Mitchell L; Konstan, Michael W; Schluchter, Mark D ...
New England journal of medicine/The New England journal of medicine,
10/2005, Letnik:
353, Številka:
14
Journal Article
Recenzirano
Odprti dostop
Polymorphisms in genes other than the cystic fibrosis transmembrane conductance regulator (CFTR) gene may modify the severity of pulmonary disease in patients with cystic fibrosis.
We performed two ...studies with different patient samples. We first tested 808 patients who were homozygous for the DeltaF508 mutation and were classified as having either severe or mild lung disease, as defined by the lowest or highest quartile of forced expiratory volume in one second (FEV1), respectively, for age. We genotyped 16 polymorphisms in 10 genes reported by others as modifiers of disease severity in cystic fibrosis and tested for an association in patients with severe disease (263 patients) or mild disease (545). In the replication (second) study, we tested 498 patients, with various CFTR genotypes and a range of FEV1 values, for an association of the TGFbeta1 codon 10 CC genotype with low FEV1.
In the initial study, significant allelic and genotypic associations with phenotype were seen only for TGFbeta1 (the gene encoding transforming growth factor beta1), particularly the -509 and codon 10 polymorphisms (with P values obtained with the use of Fisher's exact test and logistic regression ranging from 0.006 to 0.0002). The odds ratio was about 2.2 for the highest-risk TGFbeta1 genotype (codon 10 CC) in association with the phenotype for severe lung disease. The replication study confirmed the association of the TGFbeta1 codon 10 CC genotype with more severe lung disease in comparisons with the use of dichotomized FEV1 for severity status (P=0.0002) and FEV1 values directly (P=0.02).
Genetic variation in the 5' end of TGFbeta1 or a nearby upstream region modifies disease severity in cystic fibrosis.
Objective To assess the effectiveness and safety of high-dose ibuprofen when used as part of routine therapy in patients with cystic fibrosis (CF). Study design In this multicenter, double-blinded, ...placebo-controlled trial, a total of 142 patients age 6 to 18 years with mild lung disease (forced expiratory volume in 1 minute FEV1 > 60 predicted) were randomized to receive either high-dose ibuprofen (70 subjects, 20 to 30 mg/kg/twice daily, adjusted to a peak serum concentration of 50 to 100 μg/mL) or placebo (72 subjects) for a 2-year period. The primary outcome was the annualized rate of change in FEV1 % predicted. Results The patients in the high-dose ibuprofen group exhibited a significant reduction in the rate of decline of forced vital capacity percent predicted (0.07 ± 0.51 vs –1.62 ± 0.52; P = .03), but not FEV1 %. The ibuprofen group also spent fewer days in hospital after adjusting for age (1.8 vs 4.1 days per year; P = .07). A total of 11 patients (4 in the ibuprofen group and 7 in the placebo group) withdrew due to adverse events. Conclusions High-dose ibuprofen has a significant effect on slowing the progression of lung disease in CF and generally is well tolerated.
The objectives of this study were to determine the prevalence of morphometric vertebral fractures in a large cohort of adult cystic fibrosis (CF) patients, and to examine the association between ...fractures and bone mineral density (BMD).
Cross-sectional retrospective study.
A tertiary care academic hospital.
Adult CF patients who had undergone BMD testing and chest radiography within 1 month of each other.
BMD was measured by dual-energy x-ray absorptiometry (DXA) at the lumbar spine (LS) and femoral neck (FN). Vertebral fractures were diagnosed using lateral chest radiographs. Several clinical and biochemical variables were assessed as correlates. Sixty subjects (36%) had z scores between −1.0 and −2.5, and 15 subjects (9%) had z scores of < −2.5. Twelve patients (7.2%) had 19 morphometric fractures. The mean BMD at the LS was 1.266 g/cm2 in the fracture group and 1.112 g/cm2 in the nonfracture group (p = 0.0002). The mean BMD at the FN was 1.129 g/cm2 in the fracture group and 0.987 g/cm2 in the nonfracture group (p = 0.0006). Both FEV1 and body mass index were significantly associated with BMD at both the LS and the FN.
Seven percent of adult patients with CF had vertebral fractures as determined by morphometry. Subjects in the fracture group had both clinically and statistically higher BMD as measured by DXA. Our findings raise the intriguing possibility that BMD may not be useful in identifying CF patients with fractures.
To define the clinical characteristics and diagnostic parameters of patients with cystic fibrosis (CF) diagnosed in adulthood.
Retrospective cohort study.
Tertiary care center.
All patients with a ...diagnosis of CF made at the Toronto CF Clinics between 1960 and June 2001. Data were collected prospectively and analyzed retrospectively.
There were 73 of 1,051 patients (7%) with CF diagnosed in adulthood. Over time, an increasing number and proportion of patients received a diagnosis in adulthood: 27 patients (3%) before 1990, compared to 46 patients (18%) after 1990 (p < 0.001). The mean sweat chloride level was lower for those with CF diagnosed as adults, compared to those with a diagnosis as children (75 ± 26 mmol/L and 100 ± 19 mmol/L, respectively; p < 0.001) mean ± SD, and adults were more likely to have pancreatic sufficiency (PS) than children (73% vs 13%, respectively; p < 0.0001). In 46 adults who received a diagnosis since 1990, the reason for the initial sweat test was pancreatitis (2 patients, 4%), pulmonary symptoms (18 patients, 39%), pulmonary and GI symptoms (10 patients, 22%), infertility (12 patients, 26%), and genetic screening (4 patients, 9%). Other manifestations were biliary cirrhosis (one patient) and diabetes mellitus (four patients, 9%). The diagnosis could be confirmed by sweat test alone in 30 of 46 patients (65%), by mutation analysis alone in 15 patients (33%), and by a combination in 31 patients (67%). Nasal potential difference (PD) measurements alone confirmed the diagnosis in the remaining 15 patients (33%).
Patients with CF presenting in adulthood often have PS, inconclusive sweat test results, and a high prevalence of mutations that are not commonly seen in CF diagnosed in childhood. Although most patients have lung disease of variable degrees, single-organ manifestations such as congenital bilateral absence of the vas deferens and pancreatitis are seen. Repeated sweat tests and extensive mutation analysis are often required. Nasal PD may aid the diagnosis, but has not been standardized for clinical diagnosis.
Background Children with complex heart defects are sedentary, with activity level unrelated to exercise capacity. We sought to identify factors associated with physical activity level for children ...who have the Fontan procedure. Methods We used a cross-sectional study, 64 children (25 female, 5-11 years) after Fontan. Measurements were weekly minutes of moderate-to-vigorous physical activity, cardiac status, resting/exercise cardiopulmonary capacity, gross motor skill, health-related endurance/strength/body composition, and parent/child activity perceptions. Results Participants performed 361 ± 137 minutes per week of moderate-to-vigorous physical activity. Increased activity related to antithrombotic medication use (86 min/wk), lower resting heart rate (3 min/wk), higher weekday outdoor time (0.7 minutes per outside minute), lower family income (13 minutes per $10,000), and higher parent rating of child's activity relative to peers (36 min/wk). Factors related to decreased activity were winter season (−84 min/wk), history of arrhythmia (−96 min/wk), and greater child confidence in own ability to be active (−113 min/wk). Conclusions Physical activity after the Fontan procedure is primarily associated with factors unrelated to cardiac status. Interventions that impact these modifiable factors would be expected to enable these children to achieve the recommended activity levels associated with optimal health.
Objectives: With the use of clinical data from a large international cohort, we evaluated and compared affected siblings and isolated cases. Study design: Data from 116 families were collected, and ...patients conforming to our predetermined diagnostic criteria were analyzed. Phenotypic manifestations of affected siblings and singletons were compared with the use of t tests, Wilcoxon scores, and χ2 analysis. Results: Eighty-eight patients (33 female, 55 male; median age 5.20 years) fulfilled our predetermined diagnostic criteria for Shwachman syndrome; 63 patients were isolated cases, and 25 affected siblings were from 12 multiplex families. Steatorrhea was present in 86% (57 of 66), and 91% (78 of 86) displayed a low serum trypsinogen concentration. Patients older than 4 years more often had pancreatic sufficiency. Neutropenia occurred in 98%, anemia in 42%, and thrombocytopenia in 34%. Myelodysplasia or cytogenetic abnormalities were reported in 7 patients. Short stature with normal nutritional status was a prominent feature. Conclusions: Clinical features among patients with Shwachman syndrome varied between patients and with age. Similarities in phenotype between isolated cases and affected sibling sets support the hypothesis that Shwachman syndrome is a single disease entity. (J Pediatr 1999;135:81-8.)
The Third National Health and Nutrition Examination Survey (NHANES III) reference is currently recommended for interpreting spirometry results, but it is limited by the lack of subjects younger than ...8 years and does not continuously model spirometry across all ages.
By collating pediatric data from other large-population surveys, we have investigated ways of developing reference ranges that more accurately describe the relationship between spirometric lung function and height and age within the pediatric age range, and allow a seamless transition to adulthood.
Data were obtained from four surveys and included 3,598 subjects aged 4-80 years. The original analyses were sex specific and limited to non-Hispanic white subjects. An extension of the LMS (lambda, mu, sigma) method, widely used to construct growth reference charts, was applied.
The extended models have four important advantages over the original NHANES III analysis as follows: (1) they extend the reference data down to 4 years of age, (2) they incorporate the relationship between height and age in a way that is biologically plausible, (3) they provide smoothly changing curves to describe the transition between childhood and adulthood, and (4) they highlight the fact that the range of normal values is highly dependent on age.
The modeling technique provides an elegant solution to a complex and longstanding problem. Furthermore, it provides a biologically plausible and statistically robust means of developing continuous reference ranges from early childhood to old age. These dynamic models provide a platform from which future studies can be developed to continue to improve the accuracy of reference data for pulmonary function tests.
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