Novel genes for airway wall thickness identified with combined genome-wide association and expression analyses.

RATIONALE: Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. OBJECTIVES: To investigate the genetic component of AWT. METHODS: AWT was measured on low-dose computed tomography scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome-wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by metaanalysis. An independent cohort was used for validation of the most strongly associated single-nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. MEASUREMENTS AND MAIN RESULTS: Three significant loci on chromosomes 2q (rs734556; P = 6.2 × 10(-7)) and 10q (rs10794108, P = 8.6 × 10(-8); rs7078439, P = 2.3 × 10(-7)) were associated with AWT and confirmed in the metaanalysis in cohorts with comparable lung function: P values = 4.6 × 10(-8), 7.4 × 10(-8), and 7.5 × 10(-8), respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (P = 5.8 × 10(-7)) and rs4796712 in NT5C3B (P = 3.1 × 10(-6)). Higher MAGI2 expression in bronchial biopsies of patients with chronic obstructive pulmonary disease was significantly associated with fewer inflammatory cells. The presence of the NT5C3B risk allele was associated with higher lung tissue expression (P = 1.09 × 10(-41)). CONCLUSIONS: Genetic variants contribute to AWT. Among others, the identified genes are also involved in emphysema, airway obstruction, and bronchial inflammation.

Quantitative Emphysema Distribution in Anatomic and Non-anatomic Lung Regions.

PURPOSE: The change of emphysema distribution with increasing COPD severity is not yet assessed. Especially, involvement of the upper aspect of the lower lobe is unknown. The primary aim was to quantitatively determine regional distribution of emphysema in anatomically (lung lobes) and non-anatomically defined lung regions (upper/lower lung halves as well as core and rind regions) in a cohort covering equally all COPD severity stages using CT. MATERIAL AND METHODS: Basically 100 CT data sets were quantitatively evaluated for regional distribution of emphysema. Emphysema characteristics (emphysema index, mean lung density and 15th percentile of the attenuation values of lung voxels) were compared (t-test) in: upper lobes vs. upper halves, lower lobes vs. lower halves, core vs. rind region. RESULTS: In patients with ≤ GOLD II, a significantly higher emphysema burden was found in the upper lobes as compared to upper halves. In subjects with GOLD III/IV the differences were not significant for all emphysema characteristics. A high difference between lobes and halves in subjects with ≤ GOLD II was found, in contrast to low difference in higher GOLD stages. CONCLUSIONS: Lobar segmentation provides improved characterization of cranio-caudal emphysema distribution compared to a non-anatomic approach in subjects up to GOLD stage II.

GOLD stage predicts thoracic aortic calcifications in patients with COPD.

Although some of the associations between chronic obstructive pulmonary disease (COPD) and atherosclerosis are based on shared risk factors such as smoking, recent epidemiological evidence suggests that COPD is a risk factor for vascular disease due to systemic inflammation. The present study assessed the hypothesis that disease severity (as expressed by the GOLD stage) independently predicts the extent of vascular calcifications. A total of 160 smokers diagnosed with COPD (GOLD I-IV, 40 subjects of each GOLD stage) and 40 smokers at risk (GOLD 0; median age of 60 years old; Q1:56;Q3:65; 135 males and 65 females) underwent non-contrast, non-electrocardiography synchronized chest computerised tomography. The volume of thoracic aortic calcifications was quantified semi-automatically within a region from T1 through T12. Multiparametric associations with GOLD stage, smoking history, sex, age, body mass index and emphysema index were evaluated using generalized linear regression analysis. Thoracic aortic calcifications were highly prevalent in this cohort (187/200 subjects, 709 (Q1:109;Q3:2163) mm3). Analysis of variance on ranks demonstrated a significant difference in calcium between different GOLD-stages as well as patients at risk of COPD (F=36.8, P<0.001). In the multivariable analysis, GOLD-stages were indicated to be predictive of thoracic aortic calcifications (P≤0.0033) besides age (P<0.0001), while age appeared to be the strongest predictor. Other variables were not statistically linked to thoracic aortic calcifications in the multivariable model. COPD severity, as expressed by the GOLD-stage, is a significant predictor of thoracic aortic calcifications, independent of covariates such as age or tobacco consumption.

[18F]FDG and [18F]FLT PET-CT and MR imaging of human neuroblastomas in a SCID mouse xenograft model.

BACKGROUND: Finding new therapeutic agents is of great clinical interest in neuroblastoma research because prognosis of children with disseminated stages of disease is still poor. As xenograft mouse models are frequently used for studying anticancer drugs in vivo, small animal imaging is an important method of monitoring in anticancer research. MATERIALS AND METHODS: SCID mice inoculated with human neuroblastoma SK-N-SH cells were examined with positron-emission tomography-computed tomography (PET-CT) using [18F]fluorodeoxyglucose (FDG) or [18F]fluoro-L-thymidine (FLT) and with magnetic resonance imaging (MRI). RESULTS: All neuroblastomas were detected by MRI. In PET-CT imaging, no tumour was visualized with [18F]FDG, but 13 out of 14 (93%) were found with [18F]FLT. Uptake of [18F]FLT was significantly associated with tumour weight. Necrotic areas could not be identified either by MR imaging or on PET-CT scans. CONCLUSION: Both MR and PET-CT imaging with [18F]FLT are highly qualified for the detection of neuroblastomas grown in SCID mice. However, [18F]FDG, which is the standard tracer in clinical PET-CT imaging, is not suited for PET-CT imaging in the neuroblastoma model.

Susceptibility to chronic mucus hypersecretion, a genome wide association study.

BACKGROUND: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. METHODS: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). RESULTS: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25×10(-6), OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3×10(-9)) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. CONCLUSIONS: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.

Incomplete pulmonary fissures evaluated by volumetric thin-section CT: semi-quantitative evaluation for small fissure gaps identification, description of prevalence and severity of fissural defects.

OBJECTIVE: To assess the interobserver agreement for a semi-quantitative evaluation of the interlobar fissures integrity in volumetric thin-section CT images, looking for more detailed information regarding fissural defects; and describe prevalence and severity of fissural defects between the different functional groups of subjects. MATERIALS AND METHODS: Volumetric scans of 247 individuals exposed to tobacco with different functional status (normal to severe COPD), were retrospectively and independently evaluated by 2 chest radiologists, with a consensual reading additionally with a third reader in disagreement cases. Right oblique (RO), right horizontal (RH) and left oblique fissures (LO) integrity was estimated using a 5% scale. GOLD classification was available for all subjects. RESULTS: Interobserver agreement (weighted Kappa-index) for fissural categorization was 0.76, 0.70 and 0.75, for RO, RH and LO, respectively. Final evaluation found 81%, 89% and 50% of RO, RH and LO to be incomplete, with respective mean integrity of 80%, 58% and 80%. Small fissure gaps (<10%) were present in 30% of patients. Prevalence and severity of fissural defects were not different between the GOLD categories. CONCLUSIONS: A substantial agreement between readers was found in the analysis of interlobar fissures integrity. The semi-quantitative method allowed a detailed description of the fissural defects, information that can be important, for example, in endoscopic lung volume reduction therapies for emphysema. Small fissure gaps, overlooked in previous studies, were found in almost a third of the patients. A higher than previously described prevalence of fissural defects was described, but without significant differences among the distinct functional groups.

Computed tomographic imaging of the airways in COPD and asthma.

Computed tomography (CT) is the modality of choice for imaging the airways. Volumetric data sets with isotropic spatial resolution based on multidetector thin-section CT with overlapping reconstruction should be used. Chronic obstructive pulmonary disease and asthma are the 2 most common disease entities that are defined by airflow obstruction. The morphologic correlates of airway changes are dilation of the lumen, thickening of the wall, visibility of small airways due to mucus or edema, air trapping, hypoxic vasoconstriction, and collapsibility. To assess air trapping, additional expiratory low-dose scans are recommended. In clinical routine, these findings are visually assessed and should be routinely reported. However, the interobserver variability is high, and there is a clear need for objective software-based measurements. The development of such tools is challenging, and they are just becoming available on a broader scale. Novel techniques based on dual-energy CT aim to measure iodine distribution maps to assess pulmonary perfusion as well as the distribution of inhaled xenon gas to assess the distribution and time course of pulmonary ventilation. However, these techniques are still being investigated in clinical studies. This review will provide an overview of CT for the diagnosis of chronic obstructive pulmonary disease and asthma, its role in phenotyping these diseases, and the measurement of disease severity and functional compromise.