Aelko H. Zwinderman

Three phenotypes of adult-onset asthma.

Adult‐onset asthma differs from childhood‐onset asthma in many respects. It is more heterogeneous, often severe and frequently associated with loss of lung function. To identify underlying mechanisms of adult‐onset asthma and to capture predictors of disease progression, detailed characterization and phenotyping is necessary.

Preoperative Prediction of the Occurrence and Severity of Complications After Esophagectomy for Cancer With Use of a Nomogram

BACKGROUND Predicting the severity of complications after esophagectomy may supply important information for both patient and surgeon. The aim of the present study was to develop a nomogram based on preoperative risk factors to predict the severity of complications in patients who undergo esophagectomy for cancer. METHODS A consecutive series of 663 patients who underwent esophagectomy between January 1993 and August 2005 was used to develop a prognostic model. The model was validated in a second group of patients who were operated between August 2005 and November 2006. Ordinal logistic regression analysis was performed to predict the severity of complications. Diverse simple and conventional preoperative risk factors were evaluated. A nomogram was developed to enhance clinical applicability. RESULTS Patients were divided into three complication categories: those who suffered from no complications (n = 197); minor complications (n = 354); and major complications (n = 112). The following predictors remained in the model after multivariate analysis: higher age (p = 0.014); cerebrovascular accident/transient ischemic attack (CVA/TIA) (p = 0.009) or myocardial infarction in the medical history (p = 0.066); lower forced expiratory volume in the first second of expiration (FEV(1)) (p = 0.030); presence of electrocardiogram-changes (p = 0.008); and more extensive surgery (p < 0.001). A nomogram based on these variables was constructed. Overall agreement between the predicted probabilities and the observed frequencies was good in the development and the validation set. CONCLUSIONS The nomogram predicts the severity of complications for individual patients and may help in informing the patient before undergoing esophagectomy for cancer and in choosing the optimal extent of surgery. When externally validated, the nomogram may play a role in risk-adjusted audit of morbidity after esophagectomy.

Genome-wide association study of multiple congenital heart disease phenotypes identifies a susceptibility locus for atrial septal defect at chromosome 4p16.

We carried out a genome-wide association study (GWAS) of congenital heart disease (CHD). Our discovery cohort comprised 1,995 CHD cases and 5,159 controls and included affected individuals from each of the 3 major clinical CHD categories (with septal, obstructive and cyanotic defects). When all CHD phenotypes were considered together, no region achieved genome-wide significant association. However, a region on chromosome 4p16, adjacent to the MSX1 and STX18 genes, was associated (P = 9.5 × 10−7) with the risk of ostium secundum atrial septal defect (ASD) in the discovery cohort (N = 340 cases), and this association was replicated in a further 417 ASD cases and 2,520 controls (replication P = 5.0 × 10−5; odds ratio (OR) in replication cohort = 1.40, 95% confidence interval (CI) = 1.19–1.65; combined P = 2.6 × 10−10). Genotype accounted for ∼9% of the population-attributable risk of ASD.

Genome-wide association study identifies loci on 12q24 and 13q32 associated with Tetralogy of Fallot

We conducted a genome-wide association study to search for risk alleles associated with Tetralogy of Fallot (TOF), using a northern European discovery set of 835 cases and 5159 controls. A region on chromosome 12q24 was associated (P = 1.4 × 10−7) and replicated convincingly (P = 3.9 × 10−5) in 798 cases and 2931 controls [per allele odds ratio (OR) = 1.27 in replication cohort, P = 7.7 × 10−11 in combined populations]. Single nucleotide polymorphisms in the glypican 5 gene on chromosome 13q32 were also associated (P = 1.7 × 10−7) and replicated convincingly (P = 1.2 × 10−5) in 789 cases and 2927 controls (per allele OR = 1.31 in replication cohort, P = 3.03 × 10−11 in combined populations). Four additional regions on chromosomes 10, 15 and 16 showed suggestive association accompanied by nominal replication. This study, the first genome-wide association study of a congenital heart malformation phenotype, provides evidence that common genetic variation influences the risk of TOF.

Predicting individual survival after potentially curative esophagectomy for adenocarcinoma of the esophagus or gastroesophageal junction.

Introduction:Even after potentially curative esophagectomy, the majority of patients with adenocarcinoma of the esophagus or gastroesophageal junction die due to cancer recurrence. To predict individual disease-specific survival, a nomogram has been developed in a high-volume center in the Netherlands. The validity of this nomogram was externally tested in patients treated in another country at a different high-volume institution. Methods:Clinicopathological data from patients who underwent a macroscopically radical resection in a high-volume center in Leuven, Belgium, were used to validate the original nomogram based on a Cox regression model. Moreover, it was examined whether adjusting the value of the original coefficients of the predictors or adding new predictors would improve the fit of the nomogram in the validation cohort. Calibration was evaluated by comparing the observed survival with the expected survival as predicted by the original nomogram across patients with different risk profiles. The discriminatory ability of the nomogram was determined in the validation cohort, using the concordance index and compared with the original estimate. Results:A total of 382 patients were used in the validation study. The median esophageal cancer-specific survival was 38 months. None of the coefficients re-estimated in the validation cohort differed significantly from the values of the original nomogram. Observed and expected survival curves showed good calibration. Discrimination of the original nomogram was preserved in the validation cohort: the concordance index hardly decreased from 0.77 in the original cohort to 0.76 in the validation cohort. Conclusions:The nomogram model that was originally developed in a Dutch institute had good individual discriminatory properties and good overall calibration when applied to an independent series of patients. The nomogram was updated using the data from both cohorts to provide even more robust estimates of survival for individual patients. This tool is clinically helpful to supply more reliable prognostic information, to offer tailored follow-up schedules and/or novel therapeutic strategies in subgroups of patients with higher risk of recurrence.

Gene expression profiling of laser microdissected airway smooth muscle tissue in asthma and atopy

Asthma and atopy share common characteristics including type 2 helper‐T‐cell‐mediated inflammation. However, only asthma is associated with variable airways obstruction. The complex cellular and molecular pathways distinguishing asthma and atopy can now be captured by transcriptomic analysis (RNA‐Seq). We hypothesized that the transcriptomic profile of airway smooth muscle (ASM) distinguishes atopic asthma from atopic healthy controls. First, we compared the ASM transcriptomic profiles of endobronchial biopsies between glucocorticoid‐free, atopic asthma patients, and atopic and nonatopic healthy controls. Second, we investigated the association between ASM transcriptomic profiles and airway function.

Association between C677T polymorphism of methylene tetrahydrofolate reductase and congenital heart disease: meta-analysis of 7697 cases and 13,125 controls.

Background—Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. Methods and Results—We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87–1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03–1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I2=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91–1.03]) without significant heterogeneity (I2=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87–1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. Conclusions—The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.

The effect of age on the systemic inflammatory response in patients with community-acquired pneumonia.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Increasing age has been associated with elevated circulating levels of pro-inflammatory mediators. We aimed to determine the impact of ageing on the systemic inflammatory response to CAP. In total 201 CAP patients were enrolled. Blood samples were obtained upon presentation, and on days 2, 3 and 5. For the current analysis patients≤50 and ≥80 years were included. The Pneumonia Severity Index (PSI) score was calculated at presentation. The study encompassed 46 CAP patients aged ≤50 years (median 37 years) and 41 CAP patients aged ≥80 years (median 84 years). In both groups Streptococcus pneumoniae was the common causative microorganism. Whereas most young patients had a PSI score of I (54%), 98% of elderly patients had a PSI score≥III (p<0.001). Four elderly patients died vs. none of the young patients (p 0.045). Older patients demonstrated lower serum C-reactive protein levels on admission and during the course of their hospitalization (p 0.001) in spite of more severe disease. Serum concentrations of pro-inflammatory (interleukin (IL)-6 and IL-8) and anti-inflammatory cytokines (IL-10 and IL-1 receptor antagonist) did not differ between age groups, although admission IL-8 levels tended to be higher in elderly patients (p 0.05). Cytokine levels were positively correlated with PSI in young but not in elderly patients. These results suggest that elderly patients show an absolute (C-reactive protein) or relative (cytokines) reduction in their systemic inflammatory response on admission for CAP.

Association Between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart DiseaseClinical Perspective

Background—Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. Methods and Results—We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87–1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03–1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I2=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91–1.03]) without significant heterogeneity (I2=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87–1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. Conclusions—The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.

Association Between C677T Polymorphism of Methylene Tetrahydrofolate Reductase and Congenital Heart DiseaseClinical Perspective: Meta-Analysis of 7697 Cases and 13 125 Controls

Background—Association between the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and congenital heart disease (CHD) is contentious. Methods and Results—We compared genotypes between CHD cases and controls and between mothers of CHD cases and controls. We placed our results in context by conducting meta-analyses of previously published studies. Among 5814 cases with primary genotype data and 10 056 controls, there was no evidence of association between MTHFR C677T genotype and CHD risk (odds ratio [OR], 0.96 [95% confidence interval, 0.87–1.07]). A random-effects meta-analysis of all studies (involving 7697 cases and 13 125 controls) suggested the presence of association (OR, 1.25 [95% confidence interval, 1.03–1.51]; P=0.022) but with substantial heterogeneity among contributing studies (I2=64.4%) and evidence of publication bias. Meta-analysis of large studies only (defined by a variance of the log OR <0.05), which together contributed 83% of all cases, yielded no evidence of association (OR, 0.97 [95% confidence interval, 0.91–1.03]) without significant heterogeneity (I2=0). Moreover, meta-analysis of 1781 mothers of CHD cases (829 of whom were genotyped in this study) and 19 861 controls revealed no evidence of association between maternal C677T genotype and risk of CHD in offspring (OR, 1.13 [95% confidence interval, 0.87–1.47]). There was no significant association between MTHFR genotype and CHD risk in large studies from regions with different levels of dietary folate. Conclusions—The MTHFR C677T polymorphism, which directly influences plasma folate levels, is not associated with CHD risk. Publication biases appear to substantially contaminate the literature with regard to this genetic association.