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1.  IL1B Polymorphisms Modulate Cystic Fibrosis Lung Disease 
Pediatric pulmonology  2009;44(6):580-593.
Rationale: Variability in pulmonary disease severity is found in patients with cystic fibrosis (CF) who have identical mutations in the CF transmembrane conductance regulator (CFTR) gene. We hypothesized that one factor accounting for heterogeneity in pulmonary disease severity is variation in the family of genes affecting the biology of interleukin-1 (IL-1), which impacts acquisition and maintenance of Pseudomonas aeruginosa infection in animal models of chronic infection. Methods: We genotyped 58 single nucleotide polymorphisms (SNPs) in the IL-1 gene cluster in 808 CF subjects from the University of North Carolina and Case Western Reserve University (UNC/CWRU) joint cohort. All were homozygous for ΔF508, and categories of “severe” (cases) or “mild” (control subjects) lung disease were defined by the lowest or highest quartile of forced expired volume (FEV1) for age in the CF population. After adjustment for age and gender, genotypic data were tested for association with lung disease severity. Odds ratios (ORs) comparing severe versus mild CF were also calculated for each genotype (with the homozygote major allele as the reference group) for all 58 SNPs. From these analyses, nine SNPs with a moderate effect size, OR ≤ 0.5or > 1.5, were selected for further testing. To replicate the case-control study results, we genotyped the same nine SNPs in a second population of CF parent-offspring trios (recruited from Children’s Hospital Boston), in which the offspring had similar pulmonary phenotypes. For the trio analysis, both family-based and population-based associations were performed. Results: SNPs rs1143634 and rs1143639 in the IL1B gene demonstrated a consistent association with lung disease severity categories (P < 0.10) and longitudinal analysis of lung disease severity (P < 0.10) in CF in both the case-control and family-based studies. In females, there was a consistent association (false discovery rate adjusted joint P-value < 0.06 for both SNPs) in both the analysis of lung disease severity in the UNC/CWRU cohort and the family-based analysis of affection status. Conclusion: Our findings suggest that IL1β is a clinically relevant modulator of CF lung disease.
PMCID: PMC3716579  PMID: 19431193
gene modifiers; cystic fibrosis; CFTR; IL-1 gene family
2.  Predictors of Mucoid Pseudomonas Colonization in Cystic Fibrosis Patients 
Pediatric pulmonology  2008;43(5):463-471.
Rationale: Chronic mucoid Pseudomonas aeruginosa within the airway in cystic fibrosis (CF) patients can determine prognosis. Understanding the risk factors of mucoid P. aeruginosa acquisition may change how we deliver care. This study aims to evaluate whether presence of risk factors reported to predict disease severity including gender, CFTR genotype, bacterial organisms in airway cultures, and serum levels of vitamins A and E, albumin, C-reactive protein, alpha 1-antitrypsin, and immunoglobulins increased the risk of mucoid P. aeruginosa acquisition. Methods: Primary endpoint was age at first transition from negative to positive culture for mucoid P. aeruginosa. Cox proportional hazards regression with time-dependent covariates examined development of mucoid P. aeruginosa infection and its association with longitudinally measured serum biomarkers, pulmonary function, and culture results for other organisms. Results: Median ages at CF diagnosis and at first culture were 0.55 and 5.7 years, respectively. Median number of cultures/patient was 17. Of the 323 subjects, 150 developed mucoid P. aeruginosa during a median 8.1 years’ follow-up. In multivariate analysis, gender (relative hazard [RH] 0.55 for male vs. female, P=0.001), number of DF508 alleles (RH 1.66 for1 or 2 vs. 0, P=0.04), FEV1 % (RH 1.16 for 10% decrease, P=0.008), and most recent Staphylococcus aureus status (RH 0.24 for positive vs. negative, P< 0.0001) remained statistically significant. Conclusion: Female gender, number of DF508 alleles, decreased lung function, and lack of S. aureus on recent sputum culture are important risk factors for early detection of mucoid P. aeruginosa.
PMCID: PMC3693457  PMID: 18361452
cystic fibrosis; Pseudomonas colonization
3.  Association of Birth Weight With Asthma-Related Outcomes at Age 2 Years 
Pediatric pulmonology  2006;41(7):643-648.
Summary. Background: Although lower birth weight associated with prematurity raises the risk of asthma in childhood, few prospective studies have examined higher birth weight, and few have separated the two components of birth weight, fetal growth and length of gestation.
Objective. To examine the associations of fetal growth and length of gestation with asthma-related outcomes by age 2 years.
Methods. We studied 1,372 infants and toddlers born after 34 weeks’ gestation in Project Viva, a prospective cohort study of pregnant mothers and their children. The main outcome measures were parent report of (1) any wheezing (or whistling in the chest) from birth to age 2 years, (2) recurrent wheezing during the first 2 years of life, and (3) doctor’s diagnosis of asthma, wheeze or reactive airwaydisease (“asthma”) by age 2. We calculated gestational age from the last menstrual period or ultrasound examination, and determined birth weight for gestational age z-value (“fetal growth”) using US national reference data.
Results. Infants’ mean birth weight was 3,527 (SD, 517; range, 1,559–5,528) grams. By age 2 years, 34% of children had any wheezing, 14% had recurrent wheezing, and 16% had doctor-diagnosed asthma. After adjusting for several parent, child, and household characteristics in logistic regression models, we found that infants with birth weight ≥4,000 g were not more likely to have any wheezing (odds ratio (OR), 0.91; 95% confidence interval (CI): 0.62, 1.34) or doctor-diagnosed asthma (OR, 0.80; 95% CI: 0.49, 1.31) than infants with birth weight 3,500–3,999 g. In models examining length of gestation and fetal growth separately, neither the highest nor the lowest groups of either predictor were associated with the three outcomes. Boys had a higher incidence of asthma-related outcomes than girls, and exposure to passive smoking, parental history of asthma, and exposure to older siblings were all associated with greater risk of recurrent wheeze or asthma-related outcomes at age 2 years.
Conclusion. Although male sex, exposure to smoking, parental history of asthma, and exposure to older siblingswere associated with increased riskof wheezing and asthma-related outcomes in this prospective study of children born after 34 weeks gestation, fetal growth and length of gestation were not.
PMCID: PMC1488724  PMID: 16703577
asthma; birth weight; fetal growth; length of gestation; wheezing

Results 1-3 (3)