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2.  Copy Number Variation of the Beta-Defensin Genes in Europeans: No Supporting Evidence for Association with Lung Function, Chronic Obstructive Pulmonary Disease or Asthma 
PLoS ONE  2014;9(1):e84192.
Lung function measures are heritable, predict mortality and are relevant in diagnosis of chronic obstructive pulmonary disease (COPD). COPD and asthma are diseases of the airways with major public health impacts and each have a heritable component. Genome-wide association studies of SNPs have revealed novel genetic associations with both diseases but only account for a small proportion of the heritability. Complex copy number variation may account for some of the missing heritability. A well-characterised genomic region of complex copy number variation contains beta-defensin genes (DEFB103, DEFB104 and DEFB4), which have a role in the innate immune response. Previous studies have implicated these and related genes as being associated with asthma or COPD. We hypothesised that copy number variation of these genes may play a role in lung function in the general population and in COPD and asthma risk. We undertook copy number typing of this locus in 1149 adult and 689 children using a paralogue ratio test and investigated association with COPD, asthma and lung function. Replication of findings was assessed in a larger independent sample of COPD cases and smoking controls. We found evidence for an association of beta-defensin copy number with COPD in the adult cohort (OR = 1.4, 95%CI:1.02–1.92, P = 0.039) but this finding, and findings from a previous study, were not replicated in a larger follow-up sample(OR = 0.89, 95%CI:0.72–1.07, P = 0.217). No robust evidence of association with asthma in children was observed. We found no evidence for association between beta-defensin copy number and lung function in the general populations. Our findings suggest that previous reports of association of beta-defensin copy number with COPD should be viewed with caution. Suboptimal measurement of copy number can lead to spurious associations. Further beta-defensin copy number measurement in larger sample sizes of COPD cases and children with asthma are needed.
doi:10.1371/journal.pone.0084192
PMCID: PMC3880289  PMID: 24404154
3.  Catch-up Alveolarization in Ex-Preterm Children. Evidence from 3He Magnetic Resonance 
Rationale: Histologic data from fatal cases suggest that extreme prematurity results in persisting alveolar damage. However, there is new evidence that human alveolarization might continue throughout childhood and could contribute to alveolar repair.
Objectives: To examine whether alveolar damage in extreme-preterm survivors persists into late childhood, we compared alveolar dimensions between schoolchildren born term and preterm, using hyperpolarized helium-3 magnetic resonance.
Methods: We recruited schoolchildren aged 10–14 years stratified by gestational age at birth (weeks) to four groups: (1) term-born (37–42 wk; n = 61); (2) mild preterm (32–36 wk; n = 21); (3) extreme preterm (<32 wk, not oxygen dependent at 4 wk; n = 19); and (4) extreme preterm with chronic lung disease (<32 wk and oxygen dependent beyond 4 wk; n = 18). We measured lung function using spirometry and plethysmography. Apparent diffusion coefficient, a surrogate for average alveolar dimensions, was measured by helium-3 magnetic resonance.
Measurements and Main Results: The two extreme preterm groups had a lower FEV1 (P = 0.017) compared with term-born and mild preterm children. Apparent diffusion coefficient was 0.092 cm2/second (95% confidence interval, 0.089–0.095) in the term group. Corresponding values were 0.096 (0.091–0.101), 0.090 (0085–0.095), and 0.089 (0.083–0.094) in the mild preterm and two extreme preterm groups, respectively, implying comparable alveolar dimensions across all groups. Results did not change after controlling for anthropometric variables and potential confounders.
Conclusions: Alveolar size at school age was similar in survivors of extreme prematurity and term-born children. Because extreme preterm birth is associated with deranged alveolar structure in infancy, the most likely explanation for our finding is catch-up alveolarization.
doi:10.1164/rccm.201210-1850OC
PMCID: PMC3734619  PMID: 23491406
alveolar structure; lung acinus; bronchopulmonary dysplasia; neonatal chronic lung disease
4.  Alveolarization Continues during Childhood and Adolescence 
Rationale: The current hypothesis that human pulmonary alveolarization is complete by 3 years is contradicted by new evidence of alveolarization throughout adolescence in mammals.
Objectives: We reexamined the current hypothesis using helium-3 (3He) magnetic resonance (MR) to assess alveolar size noninvasively between 7 and 21 years, during which lung volume nearly quadruples. If new alveolarization does not occur, alveolar size should increase to the same extent.
Methods: Lung volumes were measured by spirometry and plethysmography in 109 healthy subjects aged 7–21 years. Using 3HeMR we determined two independent measures of peripheral airspace dimensions: apparent diffusion coefficient (ADC) of 3He at FRC (n = 109), and average diffusion distance of helium (Xrms¯) by q-space analysis (n = 46). We compared the change in these parameters with lung growth against a model of lung expansion with no new alveolarization.
Measurements and Main Results: ADC increased by 0.19% for every 1% increment in FRC (95% confidence interval [CI], 0.13–0.25), whereas the expected change in the absence of neoalveolarization is 0.41% (95% CI, 0.31–0.52). Similarly, increase of (Xrms¯) with FRC was significantly less than the predicted increase in the absence of neoalveolarization. The number of alveoli is estimated to increase 1.94-fold (95% CI, 1.64–2.30) across the age range studied.
Conclusions: Our observations are best explained by postulating that the lungs grow partly by neoalveolarization throughout childhood and adolescence. This has important implications: developing lungs have the potential to recover from early life insults and respond to emerging alveolar therapies. Conversely, drugs, diseases, or environmental exposures could adversely affect alveolarization throughout childhood.
doi:10.1164/rccm.201107-1348OC
PMCID: PMC3410735  PMID: 22071328
growth and development; lung development; alveolarization

Results 1-4 (4)