The Importance of Esophagography in Patients With Recessive Dystrophic Epidermolysis Bullosa.

OBJECTIVE: The purpose of this study was to assess esophageal damage in patients with recessive dystrophic epidermolysis bullosa (RDEB) with or without dysphagia. SUBJECTS AND METHODS: Fourteen patients with either severe generalized or another generalized form of RDEB recruited through a research and support foundation were evaluated for obstructive esophageal lesions by means of barium esophagography. RESULTS: All patients, even those without dysphagia, had at least one stenosis; five patients had two stenoses. Stenotic lesions occurred most often (74%) in the upper third of the esophagus. CONCLUSION: Esophageal stenosis is a common complication in patients with RDEB, even when they do not have dysphagia. We recommend regular esophagographic examinations of all patients with RDEB.

The current status of emergent laparoscopic colectomy: a population-based study of clinical and financial outcomes.

BACKGROUND: Population-based studies evaluating laparoscopic colectomy and outcomes compared with open surgery have concentrated on elective resections. As such, data assessing non-elective laparoscopic colectomies are limited. Our goal was to evaluate the current usage and outcomes of laparoscopic in the urgent and emergent setting in the USA. METHODS: A national inpatient database was reviewed from 2008 to 2011 for right, left, and sigmoid colectomies in the non-elective setting. Cases were stratified by approach into open or laparoscopic groups. Demographics, perioperative clinical variables, and financial outcomes were compared across each group. RESULTS: A total of 22,719 non-elective colectomies were analyzed. The vast majority (95.8 %) was open. Most cases were performed in an urban setting at non-teaching hospitals by general surgeons. Colorectal surgeons were significantly more likely to perform a case laparoscopic than general surgeons (p < 0.001). Demographics were similar between open and laparoscopic groups; however, the disease distribution by approach varied, with significantly more severe cases in the open colectomy arm (p < 0.001). Cases performed laparoscopically had significantly better mortality and complication rates. Laparoscopic cases also had significantly improved outcomes, including shorter length of stay and hospital costs (all p < 0.001). CONCLUSIONS: Our analysis revealed less than 5 % of urgent and emergent colectomies in the USA are performed laparoscopically. Colorectal surgeons were more likely to approach a case laparoscopically than general surgeons. Outcomes following laparoscopic colectomy in this setting resulted in reduced length of stay, lower complication rates, and lower costs. Increased adoption of laparoscopy in the non-elective setting should be considered.

Outcomes for single-incision laparoscopic colectomy surgery in obese patients: a case-matched study.

BACKGROUND: Single-incision laparoscopic surgery (SILS) is safe and feasible for benign and malignant colorectal diseases. SILS offers several patient-related benefits over multiport laparoscopy. However, its use in obese patients has been limited from concerns of technical difficulty, oncologic compromise, and higher complication and conversion rates. Our objective was to evaluate the feasibility and efficacy of SILS for colectomy in obese patients. METHODS: Review of a prospective database identified patients undergoing elective colectomy using SILS from 2009 to 2014. They were stratified into obese (BMI ≥ 30 kg/m(2)) and non-obese cohorts (BMI < 30 kg/m(2)) and then matched on patient characteristics, diagnosis, and operative procedure. Demographic and perioperative outcome data were evaluated. The primary outcome measures were operative time, length of stay (LOS), and conversion, complication, and readmission rates for each cohort. RESULTS: A total of 160 patients were evaluated-80 in each cohort. Patients were well matched in demographics, diagnosis, and procedure variables. The obese cohort had significantly higher BMI (p < 0.001) and ASA scores (p = 0.035). Operative time (176.9 ± 64.0 vs. 144.4 ± 47.2 min, p < 0.001) and estimated blood loss (89.0 ± 139.5 vs. 51.6 ± 38.0 ml, p < 0.001) were significantly higher in the obese. There were no significant differences in conversion rates (p = 0.682), final incision length (p = 0.088), LOS (p = 0.332), postoperative complications (p = 0.430), or readmissions (p = 1.000) in the obese versus non-obese. Further, in malignant cases, lymph nodes harvested (p = 0.757) and negative distal margins (p = 1.000) were comparable across cohorts. CONCLUSIONS: Single-incision laparoscopic colectomy in obese patients had significantly longer operative times, but comparable conversion rates, oncologic outcomes, lengths of stay, complication, and readmission rates as the non-obese cohorts. In the obese, where higher morbidity rates are typically associated with surgical outcomes, SILS may be the ideal platform to optimize outcomes in colorectal surgery. With additional operative time, the obese can realize the same clinical and quality benefits of minimally invasive surgery as the non-obese.

Prenatal methylmercury exposure and genetic predisposition to cognitive deficit at age 8 years.

BACKGROUND: Cognitive consequences at school age associated with prenatal methylmercury (MeHg) exposure may need to take into account nutritional and sociodemographic cofactors as well as relevant genetic polymorphisms. METHODS: A subsample (n = 1,311) of the Avon Longitudinal Study of Parents and Children (Bristol, UK) was selected, and mercury (Hg) concentrations were measured in freeze-dried umbilical cord tissue as a measure of MeHg exposure. A total of 1135 children had available data on 247 single-nucleotide polymorphisms (SNPs) within relevant genes, as well as the Wechsler Intelligence Scale for Children Intelligence Quotient (IQ) scores at age 8 years. Multivariate regression models were used to assess the associations between MeHg exposure and IQ and to determine possible gene-environment interactions. RESULTS: Hg concentrations indicated low background exposures (mean = 26 ng/g, standard deviation = 13). Log10-transformed Hg was positively associated with IQ, which attenuated after adjustment for nutritional and sociodemographic cofactors. In stratified analyses, a reverse association was found in higher social class families (for performance IQ, P value for interaction = 0.0013) among whom there was a wider range of MeHg exposure. Among 40 SNPs showing nominally significant main effects, MeHg interactions were detected for rs662 (paraoxonase 1) and rs1042838 (progesterone receptor) (P < 0.05) and for rs3811647 (transferrin) and rs2049046 (brain-derived neurotrophic factor) (P < 0.10). CONCLUSIONS: In this population with a low level of MeHg exposure, there were only equivocal associations between MeHg exposure and adverse neuropsychological outcomes. Heterogeneities in several relevant genes suggest possible genetic predisposition to MeHg neurotoxicity in a substantial proportion of the population. Future studies need to address this possibility.

Nutritional Modulation of Associations between Prenatal Exposure to Persistent Organic Pollutants and Childhood Obesity: A Prospective Cohort Study.

BACKGROUND: Prenatal exposure to persistent organic pollutants (POPs) may contribute to the development of childhood obesity and metabolic disorders. However, little is known about whether the maternal nutritional status during pregnancy can modulate these associations. OBJECTIVES: The main objective was to characterize the joint associations and interactions between prenatal levels of POPs and nutrients on childhood obesity. METHODS: We used data from to the Spanish INfancia y Medio Ambiente-Environment and Childhood (INMA) birth cohort, on POPs and nutritional biomarkers measured in maternal blood collected at the first trimester of pregnancy and child anthropometric measurements at 7 years of age. Six organochlorine compounds (OCs) [dichlorodiphenyldichloroethylene, hexachlorobenzene (HCB), ß-hexachlorocyclohexane (ß-HCH) and polychlorinated biphenyls 138, 153, 180] and four per- and polyfluoroalkyl substances (PFAS) were measured. Nutrients included vitamins (D, B12, and folate), polyunsaturated fatty acids (PUFAs), and dietary carotenoids. Two POPs-nutrients mixtures data sets were established: a) OCs, PFAS, vitamins, and carotenoids (n=660), and b) OCs, PUFAs, and vitamins (n=558). Joint associations of mixtures on obesity were characterized using Bayesian kernel machine regression (BKMR). Relative importance of biomarkers and two-way interactions were identified using gradient boosting machine, hierarchical group lasso regularization, and BKMR. Interactions were further characterized using multivariate regression models in the multiplicative and additive scale. RESULTS: Forty percent of children had overweight or obesity. We observed a positive overall joint association of both POPs-nutrients mixtures on overweight/obesity risk, with HCB and vitamin B12 the biomarkers contributing the most. Recurrent interactions were found between HCB and vitamin B12 across screening models. Relative risk for a natural log increase of HCB was 1.31 (95% CI: 1.11, 1.54, pInteraction=0.02) in the tertile 2 of vitamin B12 and in the additive scale a relative excess risk due to interaction of 0.11 (95% CI: 0.02, 0.20) was found. Interaction between perfluorooctane sulfonate and ß-cryptoxanthin suggested a protective effect of the antioxidant on overweight/obesity risk. CONCLUSION: These results support that maternal nutritional status may modulate the effect of prenatal exposure to POPs on childhood overweight/obesity. These findings may help to develop a biological hypothesis for future toxicological studies and to better interpret inconsistent findings in epidemiological studies. https://doi.org/10.1289/EHP11258.

Transient receptor potential genes, smoking, occupational exposures and cough in adults.

BACKGROUND: Transient receptor potential (TRP) vanilloid and ankyrin cation channels are activated by various noxious chemicals and may play an important role in the pathogenesis of cough. The aim was to study the influence of single nucleotide polymorphisms (SNPs) in TRP genes and irritant exposures on cough. METHODS: Nocturnal, usual, and chronic cough, smoking, and job history were obtained by questionnaire in 844 asthmatic and 2046 non-asthmatic adults from the Epidemiological study on the Genetics and Environment of Asthma (EGEA) and the European Community Respiratory Health Survey (ECRHS). Occupational exposures to vapors, gases, dusts, and/or fumes were assessed by a job-exposure matrix. Fifty-eight tagging SNPs in TRPV1, TRPV4, and TRPA1 were tested under an additive model. RESULTS: Statistically significant associations of 6 TRPV1 SNPs with cough symptoms were found in non-asthmatics after correction for multiple comparisons. Results were consistent across the eight countries examined. Haplotype-based association analysis confirmed the single SNP analyses for nocturnal cough (7-SNP haplotype: p-global = 4.8 × 10-6) and usual cough (9-SNP haplotype: p-global = 4.5 × 10-6). Cough symptoms were associated with exposure to irritants such as cigarette smoke and occupational exposures (p < 0.05). Four polymorphisms in TRPV1 further increased the risk of cough symptoms from irritant exposures in asthmatics and non-asthmatics (interaction p < 0.05). CONCLUSIONS: TRPV1 SNPs were associated with cough among subjects without asthma from two independent studies in eight European countries. TRPV1 SNPs may enhance susceptibility to cough in current smokers and in subjects with a history of workplace exposures.

Susceptibility genetic variants associated with colorectal cancer risk correlate with cancer phenotype.

BACKGROUND & AIMS: Ten common low-penetrant genetic variants have been consistently associated with colorectal cancer (CRC) risk; little is known about the correlation between these variants and CRC phenotype. Characterization of such a correlation would improve CRC management and prevention programs. We assessed the association between these genetic variants and CRC phenotype in patients and modeled pairwise combinations to detect epistasis. METHODS: The validation population corresponded to a prospective, multicenter, population-based cohort (EPICOLON I) of 1096 patients with newly diagnosed CRC. The replication set was an independent, prospective, multicenter Spanish cohort (EPICOLON II) of 895 patients with newly diagnosed CRC. For individual single nucleotide polymorphism (SNP) association analyses, a multivariate method using logistic regression was applied in EPICOLON I and subsequently prospectively validated in EPICOLON II. Interactions between SNPs were assessed using the likelihood ratio test. RESULTS: Validated results confirmed that the C allele on 8q23.3 (rs16892766) was significantly associated with advanced-stage tumors (odds ratio [OR], 1.48; 95% confidence interval [CI], 1.15-1.90; P value = 4.9 x 10(-3)). The G allele on 8q24.21 (rs6983267) was more common in patients with a familial history of CRC (OR, 2.02; 95% CI, 1.35-3.03; P value = 3.9 x 10(-4)). The combination of rs6983267 on 8q24.21 and rs9929218 on 16q22.2 was associated with a history of colorectal adenoma (carriers of GG and AA, respectively; OR, 2.28; 95% CI, 1.32-3.93; P = 5.0 x 10(-4)). CONCLUSIONS: CRC susceptibility variants at 8q23.3, 8q24.21, and 16q22.2 appear to be associated with cancer phenotype. These findings might be used to develop screening and surveillance strategies.

Association of NTRK3 and its interaction with NGF suggest an altered cross-regulation of the neurotrophin signaling pathway in eating disorders.

Eating disorders (EDs) are complex psychiatric diseases that include anorexia nervosa and bulimia nervosa, and have higher than 50% heritability. Previous studies have found association of BDNF and NTRK2 to ED, while animal models suggest that other neurotrophin genes might also be involved in eating behavior. We have performed a family-based association study with 151 TagSNPs covering 10 neurotrophin signaling genes: NGFB, BDNF, NTRK1, NGFR/p75, NTF4/5, NTRK2, NTF3, NTRK3, CNTF and CNTFR in 371 ED trios of Spanish, French and German origin. Besides several nominal associations, we found a strong significant association after correcting for multiple testing (P = 1.04 x 10(-4)) between ED and rs7180942, located in the NTRK3 gene, which followed an overdominant model of inheritance. Interestingly, HapMap unrelated individuals carrying the rs7180942 risk genotypes for ED showed higher levels of expression of NTRK3 in lymphoblastoid cell lines. Furthermore, higher expression of the orthologous murine Ntrk3 gene was also detected in the hypothalamus of the anx/anx mouse model of anorexia. Finally, variants in NGFB gene appear to modify the risk conferred by the NTRK3 rs7180942 risk genotypes (P = 4.0 x 10(-5)) showing a synergistic epistatic interaction. The reported data, in addition to the previous reported findings for BDNF and NTRK2, point neurotrophin signaling genes as key regulators of eating behavior and their altered cross-regulation as susceptibility factors for EDs.

Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis.

Attention-deficit and hyperactivity disorder (ADHD) is a common childhood disorder with a substantial genetic component. However, the extent to which epigenetic mechanisms play a role in the etiology of the disorder is unknown. We performed epigenome-wide association studies (EWAS) within the Pregnancy And Childhood Epigenetics (PACE) Consortium to identify DNA methylation sites associated with ADHD symptoms at two methylation assessment periods: birth and school age. We examined associations of both DNA methylation in cord blood with repeatedly assessed ADHD symptoms (age 4-15 years) in 2477 children from 5 cohorts and of DNA methylation at school age with concurrent ADHD symptoms (age 7-11 years) in 2374 children from 9 cohorts, with 3 cohorts participating at both timepoints. CpGs identified with nominal significance (p < 0.05) in either of the EWAS were correlated between timepoints (ρ = 0.30), suggesting overlap in associations; however, top signals were very different. At birth, we identified nine CpGs that predicted later ADHD symptoms (p < 1 × 10-7), including ERC2 and CREB5. Peripheral blood DNA methylation at one of these CpGs (cg01271805 in the promoter region of ERC2, which regulates neurotransmitter release) was previously associated with brain methylation. Another (cg25520701) lies within the gene body of CREB5, which previously was associated with neurite outgrowth and an ADHD diagnosis. In contrast, at school age, no CpGs were associated with ADHD with p < 1 × 10-7. In conclusion, we found evidence in this study that DNA methylation at birth is associated with ADHD. Future studies are needed to confirm the utility of methylation variation as biomarker and its involvement in causal pathways.

Boundary sequences stabilize transgene expression from subtle position effects in retroviral vectors.

Transgene expression shut-down, attenuation and/or variability from integrated retroviral vectors pose a major obstacle to gene therapy trials involving hematopoietic cells. We have undertaken a systematic assessment of the behavior of different configurations containing IFN-beta SAR and/or 5'HS4 beta-globin insulator sequences within a gammaretroviral vector optimized for high-level expression, focusing on the long-term achievement of stable, homogeneous transgene expression in the successfully transduced cells. Introduction of these cis regulatory elements did not perturb virus production and stability. Conversely, the SAR/5'HS4 insulator combination appeared to increase the homogeneity of EGFP expression in mass cultures. Furthermore, a clonal analysis of the dispersion of EGFP expression revealed that the IFN-SAR/5'HS4 insulator dyad was particularly effective in reducing the variability of transgene expression when both sequences were placed in opposite orientations within the retroviral backbone. These results may prove useful for the design of more stable retroviral expression cassettes able to counteract chromosomal position effects.

Early-Life Environmental Exposures and Blood Pressure in Children.

BACKGROUND: Growing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously. OBJECTIVES: This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. METHODS: Systolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously. RESULTS: Decreases in systolic BP were observed with facility density (ß change for an interquartile-range increase in exposure: -1.7 mm Hg [95% confidence interval (CI): -2.5 to -0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (-1.4 mm Hg [95% CI: -2.6 to -0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: -1.6 mm Hg [95% CI: -2.4 to -0.7 mm Hg]), hexachlorobenzene (-1.5 mm Hg [95% CI: -2.4 to -0.6 mm Hg]), and mono-benzyl phthalate (-0.7 mm Hg [95% CI: -1.3 to -0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (-1.4 mm Hg [95% CI: -2.3 to -0.5 mm Hg]) and child DDE concentrations (-1.1 mm Hg [95% CI: -1.9 to -0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: -0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]). CONCLUSIONS: This study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children.

Restricted transgene persistence after lentiviral vector-mediated fetal gene transfer in the pregnant rabbit model.

BACKGROUND: Prenatal gene transfer may enable early causal intervention for the treatment or prevention of many devastating diseases. Nevertheless, permanent correction of most inherited disorders requires a sustained level of expression from the therapeutic transgene, which could theoretically be achieved with integrating vectors. METHODS: Rabbit fetuses received 8.5 x 10(6) HIV-based recombinant lentivirus particles containing the enhanced green fluorescent protein (EGFP) transgene by intrahepatic, intra-amniotic or intraperitoneal injection at 22 days of gestation. Provirus presence and transgene expression in rabbit tissues were evaluated at both 1.5 and 16 weeks post-in utero intervention by polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively. Moreover, we assessed persistence of EGFP by immunohistochemistry. Enzyme-linked immunosorbent assays confirmed the development of antibodies specific against both the viral vector and the reporter protein. RESULTS: Regardless of the route of administration employed, lentiviral vector-based in utero gene transfer was safe and reached 85% of the intervened fetuses at birth. However, the integrated provirus frequency was significantly reduced to 50% of that in young rabbits at 16 weeks post-treatment. In these animals, EGFP expression was evident in many tissues, including cytokeratin 5-rich basal cells from stratified and pseudostratified epithelia, suggesting that the lentiviral vector might have reached progenitor cells. Conversely, we identified the presence of immune-inflammatory infiltrates in several EGFP-expressing tissues. Moreover, almost 70% of the lentiviral vector-treated rabbits elicited a humoral immune response against the viral envelope and/or the EGFP. CONCLUSIONS: At two-thirds gestational age, the adaptive immune system of the rabbit appears a relevant factor limiting transgene persistence and expression following lentiviral vector-mediated in utero gene transfer.

The first in vivo multiparametric comparison of different radiation exposure biomarkers in human blood.

The increasing risk of acute large-scale radiological/nuclear exposures of population underlines the necessity of developing new, rapid and high throughput biodosimetric tools for estimation of received dose and initial triage. We aimed to compare the induction and persistence of different radiation exposure biomarkers in human peripheral blood in vivo. Blood samples of patients with indicated radiotherapy (RT) undergoing partial body irradiation (PBI) were obtained soon before the first treatment and then after 24 h, 48 h, and 5 weeks; i.e. after 1, 2, and 25 fractionated RT procedures. We collected circulating peripheral blood from ten patients with tumor of endometrium (1.8 Gy per fraction) and eight patients with tumor of head and neck (2.0-2.121 Gy per fraction). Incidence of dicentrics and micronuclei was monitored as well as determination of apoptosis and the transcription level of selected radiation-responsive genes. Since mitochondrial DNA (mtDNA) has been reported to be a potential indicator of radiation damage in vitro, we also assessed mtDNA content and deletions by novel multiplex quantitative PCR. Cytogenetic data confirmed linear dose-dependent increase in dicentrics (p < 0.01) and micronuclei (p < 0.001) in peripheral blood mononuclear cells after PBI. Significant up-regulations of five previously identified transcriptional biomarkers of radiation exposure (PHPT1, CCNG1, CDKN1A, GADD45, and SESN1) were also found (p < 0.01). No statistical change in mtDNA deletion levels was detected; however, our data indicate that the total mtDNA content decreased with increasing number of RT fractions. Interestingly, the number of micronuclei appears to correlate with late radiation toxicity (r2 = 0.9025) in endometrial patients suggesting the possibility of predicting the severity of RT-related toxicity by monitoring this parameter. Overall, these data represent, to our best knowledge, the first study providing a multiparametric comparison of radiation biomarkers in human blood in vivo, which have potential for improving biological dosimetry.

In-utero and childhood chemical exposome in six European mother-child cohorts.

BACKGROUND: Harmonized data describing simultaneous exposure to a large number of environmental contaminants in-utero and during childhood is currently very limited. OBJECTIVES: To characterize concentrations of a large number of environmental contaminants in pregnant women from Europe and their children, based on chemical analysis of biological samples from mother-child pairs. METHODS: We relied on the Early-Life Exposome project, HELIX, a collaborative project across six established population-based birth cohort studies in Europe. In 1301 subjects, biomarkers of exposure to 45 contaminants (i.e. organochlorine compounds, polybrominated diphenyl ethers, per- and polyfluoroalkyl substances, toxic and essential elements, phthalate metabolites, environmental phenols, organophosphate pesticide metabolites and cotinine) were measured in biological samples from children (6-12 years) and their mothers during pregnancy, using highly sensitive biomonitoring methods. RESULTS: Most of the exposure biomarkers had high detection frequencies in mothers (35 out of 45 biomarkers with >90% detected) and children (33 out of 45 biomarkers with >90% detected). Concentrations were significantly different between cohorts for all compounds, and were generally higher in maternal compared to children samples. For most of the persistent compounds the correlations between maternal and child concentrations were moderate to high (Spearman Rho > 0.35), while for most non-persistent compounds correlations were considerably lower (Spearman Rho < 0.15). For mercury, PFOS and PFOA a considerable proportion of the samples of both mothers and their children exceeded the HBM I value established by The Human Biomonitoring Commission of the German Federal Environment Agency. DISCUSSION: Although not based on a representative sample, our study suggests that children across Europe are exposed to a wide range of environmental contaminants in fetal life and childhood including many with potential adverse effects. For values exceeding the HBM I value identification of specific sources of exposure and reducing exposure in an adequate way is recommended. Considerable variability in this "chemical exposome" was seen between cohorts, showing that place of residence is a strong determinant of one's personal exposome. This extensive dataset comprising >100,000 concentrations of environmental contaminants in mother-child pairs forms a unique possibility for conducting epidemiological studies using an exposome approach.

Inter-population variability of DEFA3 gene absence: correlation with haplotype structure and population variability.

BACKGROUND: Copy number variants (CNVs) account for a significant proportion of normal phenotypic variation and may have an important role in human pathological variation. The alpha-defensin cluster on human chromosome 8p23.1 is one of the better-characterized CNVs, in which high copy number variability affecting the DEFA1 and DEFA3 genes has been reported. Moreover, the DEFA3 gene has been found to be absent in a significant proportion of control population subjects. CNVs involving immune genes, such as alpha-defensins, are possibly contributing to innate immunity differences observed between individuals and influence predisposition and susceptibility to disease. RESULTS: We have tested the DEFA3 absence in 697 samples from different human populations. The proportion of subjects lacking DEFA3 has been found to vary from 10% to 37%, depending on the population tested, suggesting differences in innate immune function between populations. Absence of DEFA3 was correlated with the region's haplotype block structure. African samples showed a higher intra-populational variability together with the highest proportion of subjects without DEFA3 (37%). Association analysis of DEFA3 absence with 136 SNPs from a 100-kb region identified a conserved haplotype in the Caucasian population, extending for the whole region. CONCLUSION: Complexity and variability are essential genomic features of the alpha-defensin cluster at the 8p23.1 region. The identification of population differences in subjects lacking the DEFA3 gene may be suggestive of population-specific selective pressures with potential impact on human health.

The IL-4 rs2070874 polymorphism may be associated with the severity of recurrent viral-induced wheeze.

BACKGROUND: Childhood recurrent wheezing and consequently asthma corresponds to various phenotypes. Our aim was to link genetic variants of asthma candidate genes to the phenotypes of early onset wheezing. STUDY DESIGN: We included very young consecutive children presenting with recurrent wheezing who had been evaluated for the severity of wheezing, associated atopic comorbidities, and tested for biomarkers of atopy and inflammation. All were genotyped for 16 single nucleotide polymorphisms (SNPs) linked with asthma or atopy. An unsupervised hierarchical bottom-up method was used for clustering the phenotypes and a multinomial logistic regression was performed for each individual SNP. RESULTS: We replicated the three phenotypes previously described Trousseau Asthma Program in 317 children aged 21.5 ± 7.9 months: cluster 1 (nonatopic uncontrolled severe wheeze), n = 207, a severe viral-induced wheeze, cluster 2 (atopic multiple trigger wheeze), n = 61, with multiple allergic comorbidities, and cluster 3 (episodic viral wheeze), n = 49, a mild viral-induced wheeze. The TT-genotype of the IL-4 rs2070874 polymorphism was significantly associated with the nonatopic uncontrolled severe wheeze compared to the episodic viral wheeze (OR 7.9; CI95% [2.5-25.3]; P = 0.001). CONCLUSION: Association between the TT-genotype of IL-4 rs2070874 polymorphism and a severe phenotype of viral-induced wheeze further underlines the role IL-4 plays in the inflammation pathway leading to viral respiratory infections.

Detectable clonal mosaicism in blood as a biomarker of cancer risk in Fanconi anemia.

Detectable clonal mosaicism for large chromosomal events has been associated with aging and an increased risk of hematological and some solid cancers. We hypothesized that genetic cancer predisposition disorders, such as Fanconi anemia (FA), could manifest a high rate of chromosomal mosaic events (CMEs) in peripheral blood, which could be used as early biomarkers of cancer risk. We studied the prevalence of CMEs by single-nucleotide polymorphism (SNP) array in 130 FA patients' blood DNA and their impact on cancer risk. We detected 51 CMEs (4.4-159 Mb in size) in 16 out of 130 patients (12.3%), of which 9 had multiple CMEs. The most frequent events were gains at 3q (n = 6) and 1q (n = 5), both previously associated with leukemia, as well as rearrangements with breakpoint clustering within the major histocompatibility complex locus (P = 7.3 × 10-9). Compared with 15 743 age-matched population controls, FA patients had a 126 to 140 times higher risk of detectable CMEs in blood (P < 2.2 × 10-16). Prevalent and incident hematologic and solid cancers were more common in CME carriers (odds ratio [OR] = 11.6, 95% confidence interval [CI] = 3.4-39.3, P = 2.8 × 10-5), leading to poorer prognosis. The age-adjusted hazard risk (HR) of having cancer was almost 5 times higher in FA individuals with CMEs than in those without CMEs. Regarding survival, the HR of dying was 4 times higher in FA individuals having CMEs (HR = 4.0, 95% CI = 2.0-7.9, P = 5.7 × 10-5). Therefore, our data suggest that molecular karyotyping with SNP arrays in easy-to-obtain blood samples could be used for better monitoring of bone marrow clonal events, cancer risk, and overall survival of FA patients.

Computational analysis of multimorbidity between asthma, eczema and rhinitis.

BACKGROUND: The mechanisms explaining the co-existence of asthma, eczema and rhinitis (allergic multimorbidity) are largely unknown. We investigated the mechanisms underlying multimorbidity between three main allergic diseases at a molecular level by identifying the proteins and cellular processes that are common to them. METHODS: An in silico study based on computational analysis of the topology of the protein interaction network was performed in order to characterize the molecular mechanisms of multimorbidity of asthma, eczema and rhinitis. As a first step, proteins associated to either disease were identified using data mining approaches, and their overlap was calculated. Secondly, a functional interaction network was built, allowing to identify cellular pathways involved in allergic multimorbidity. Finally, a network-based algorithm generated a ranked list of newly predicted multimorbidity-associated proteins. RESULTS: Asthma, eczema and rhinitis shared a larger number of associated proteins than expected by chance, and their associated proteins exhibited a significant degree of interconnectedness in the interaction network. There were 15 pathways involved in the multimorbidity of asthma, eczema and rhinitis, including IL4 signaling and GATA3-related pathways. A number of proteins potentially associated to these multimorbidity processes were also obtained. CONCLUSIONS: These results strongly support the existence of an allergic multimorbidity cluster between asthma, eczema and rhinitis, and suggest that type 2 signaling pathways represent a relevant multimorbidity mechanism of allergic diseases. Furthermore, we identified new candidates contributing to multimorbidity that may assist in identifying new targets for multimorbid allergic diseases.