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1.
Artigo em Inglês | MEDLINE | ID: mdl-34271060

RESUMO

BACKGROUND: Low epidermal filaggrin (FLG) is a risk factor for atopic dermatitis (AD) and allergic comorbidity. FLG mutations do not fully explain the variation in epidermal FLG levels, highlighting that other genetic loci may also regulate FLG expression. OBJECTIVE: We sought to identify genetic loci that regulate FLG expression and elucidate their functional and mechanistic consequences. METHODS: A genome-wide association study of quantified skin FLG expression in lesional and baseline non(never)-lesional skin of children with AD in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort was conducted. Clustered regularly interspaced short palindromic repeat approaches were used to create isogenic human keratinocytes differing only at the identified variant rs11652075, and caspase recruitment domain family member 14 (CARD14)-deficient keratinocytes for subsequent mechanistic studies. RESULTS: The genome-wide association study identified the CARD14 rs11652075 variant to be associated with FLG expression in non(never)-lesional skin of children with AD. Rs11652075 is a CARD14 expression quantitative trait locus in human skin and primary human keratinocytes. The T variant destroys a functional cytosine-phosphate-guanine site, resulting in reduced cytosine-phosphate-guanine methylation at this site (but not neighboring sites) in TT and CT compared with CC primary human keratinocytes and Mechanisms of Progression of Atopic Dermatitis to Asthma in Children children's skin samples, and rs11652075 increases CARD14 expression in an allele-specific fashion. Furthermore, studies in clustered regularly interspaced short palindromic repeat-generated CC and TT isogenic keratinocytes, as well as CARD14-haplosufficient and deficient keratinocytes, reveal that IL-17A regulates FLG expression via CARD14, and that the underlying mechanisms are dependent on the rs11652075 genotype. CONCLUSIONS: Our study identifies CARD14 as a novel regulator of FLG expression in the skin of children with AD. Furthermore, CARD14 regulates skin FLG homeostasis in an rs11652075-dependent fashion.

2.
Genes (Basel) ; 12(6)2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34071175

RESUMO

Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists.

3.
Artigo em Inglês | MEDLINE | ID: mdl-34062314

RESUMO

BACKGROUND AND AIMS: Esophageal dilation improves dysphagia but not inflammation in eosinophilic esophagitis (EoE) patients. We investigated if dilation modifies the association between symptoms and esophageal eosinophil count (eos/hpf). METHODS: Adults enrolled in a multisite, prospective Consortium of Gastrointestinal Eosinophilic Disease Researchers OMEGA observational study (NCT02523118) completed the symptom-based EoE activity index (EEsAI) patient-reported outcome instrument and underwent endoscopy with biopsies. Patients were stratified based on dilation status as absent, performed ≤1 and >1 year before endoscopy. Assessments included Spearman's correlations of the relationship between symptoms and eos/hpf and linear regression with EEsAI as the outcome, eos/hpf as predictor, and interaction for dilation and eos/hpf. RESULTS: Amongst 100 patients (n=61 male, median age 37 years), 15 and 40 patients underwent dilation ≤1 year and >1 year before index endoscopy, respectively. In non-dilated patients, association between eos/hpf and symptoms was moderate (Rho=0.49, p-value<0.001); for 10 eos/hpf increase, the predicted EEsAI increased by 2.69 (p-value=0.002). In patients dilated ≤1 and >1 year before index endoscopy, this association was abolished (Rho=-0.38, p-value=0.157 for ≤1 year and Rho=0.02, p-value=0.883 >1 year); for 10 eos/hpf increase, the predicted EEsAI changed by -1.64 (p-value=0.183) and 0.78 (p-value=0.494), respectively). Dilation modifies association between symptoms and eos/hpf (p-value=0.005 and p-value=0.187 for interaction terms of eos/hpf and dilation ≤1 year and >1 year before index endoscopy, respectively). CONCLUSION: In non-dilated EoE adults, eos/hpf correlates modestly with symptoms; this correlation was no longer appreciated in dilated patients, and the dilation effects lasted longer than one year. Dilation status should be considered in studies evaluating EoE treatment and for clinical follow-up.

4.
Artigo em Inglês | MEDLINE | ID: mdl-34111451

RESUMO

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is an epithelial-derived cytokine important in initiation of allergic inflammation. Single nucleotide polymorphisms (SNPs) in TSLP are associated with asthma, yet studies have shown inconsistent associations between circulating TSLP and asthma. Studies that integrate the combined effects of TSLP genotype, TSLP mRNA, circulating TSLP levels, and asthma outcome are lacking. OBJECTIVES: This study sought to recruit a novel cohort based on asthma-relevant TSLP SNPs and determine their impact on TSLP mRNA expression and TSLP circulating protein levels, and their individual and combined effects on asthma. METHODS: This study developed an algorithm to prioritize TSLP SNPs and recruited 51 carriers and noncarriers based on TSLP genotypes. TSLP mRNA was quantified in nasal epithelial cells and circulating TSLP levels in plasma. This study determined the associations of defined TSLP risk genotypes and/or TSLP mRNA and protein levels with asthma. RESULTS: TSLP mRNA expression, but not circulating TSLP, was significantly increased in people who are asthmatic compared with in people who are nonasthmatic (P = .007; odds ratio, 1.44). Notably, 90% of children with the defined TSLP risk genotypes and high nasal TSLP mRNA expression (top tertile) had asthma compared with 40% of subjects without risk genotypes and with low TSLP expression (bottom tertile) (P = .024). No association between circulating TSLP and asthma was observed. CONCLUSIONS: Collectively, these data suggest childhood asthma is modified by the combined effects of TSLP genotype and TSLP expression in the nasal epithelium. The increased asthma risk likely manifests when genetic variation enables expression quantitative trait loci in the TSLP locus to elevate TSLP. It is important to consider both biomarkers when factoring asthma risk.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33964299

RESUMO

BACKGROUND: Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective. OBJECTIVE: Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history. METHODS: Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated. RESULTS: The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females. CONCLUSIONS: US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors.

7.
J Am Heart Assoc ; 10(9): e017731, 2021 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-33906374

RESUMO

Background Pediatric cardiomyopathy is a genetically heterogeneous disease with substantial morbidity and mortality. Current guidelines recommend genetic testing in children with hypertrophic, dilated, or restrictive cardiomyopathy, but practice variations exist. Robust data on clinical testing practices and diagnostic yield in children are lacking. This study aimed to identify the genetic causes of cardiomyopathy in children and to investigate clinical genetic testing practices. Methods and Results Children with familial or idiopathic cardiomyopathy were enrolled from 14 institutions in North America. Probands underwent exome sequencing. Rare sequence variants in 37 known cardiomyopathy genes were assessed for pathogenicity using consensus clinical interpretation guidelines. Of the 152 enrolled probands, 41% had a family history of cardiomyopathy. Of 81 (53%) who had undergone clinical genetic testing for cardiomyopathy before enrollment, 39 (48%) had a positive result. Genetic testing rates varied from 0% to 97% between sites. A positive family history and hypertrophic cardiomyopathy subtype were associated with increased likelihood of genetic testing (P=0.005 and P=0.03, respectively). A molecular cause was identified in an additional 21% of the 63 children who did not undergo clinical testing, with positive results identified in both familial and idiopathic cases and across all phenotypic subtypes. Conclusions A definitive molecular genetic diagnosis can be made in a substantial proportion of children for whom the cause and heritable nature of their cardiomyopathy was previously unknown. Practice variations in genetic testing are great and should be reduced. Improvements can be made in comprehensive cardiac screening and predictive genetic testing in first-degree relatives. Overall, our results support use of routine genetic testing in cases of both familial and idiopathic cardiomyopathy. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01873963.

8.
Epigenomics ; 13(8): 613-630, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33820434

RESUMO

Background: Overlap of pathways enriched by single nucleotide polymorphisms and DNA-methylation underlying chronic postsurgical pain (CPSP), prompted pilot study of CPSP-associated methylation quantitative trait loci (meQTL). Materials & methods: Children undergoing spine-fusion were recruited prospectively. Logistic-regression for genome- and epigenome-wide CPSP association and DNA-methylation-single nucleotide polymorphism association/mediation analyses to identify meQTLs were followed by functional genomics analyses. Results: CPSP (n = 20/58) and non-CPSP groups differed in pain-measures. Of 2753 meQTLs, DNA-methylation at 127 cytosine-guanine dinucleotides mediated association of 470 meQTLs with CPSP (p < 0.05). At PARK16 locus, CPSP risk meQTLs were associated with decreased DNA-methylation at RAB7L1 and increased DNA-methylation at PM20D1. Corresponding RAB7L1/PM20D1 blood eQTLs (GTEx) and cytosine-guanine dinucleotide-loci enrichment for histone marks, transcription factor binding sites and ATAC-seq peaks suggest altered transcription factor-binding. Conclusion: CPSP-associated meQTLs indicate epigenetic mechanisms mediate genetic risk. Clinical trial registration: NCT01839461, NCT01731873 (ClinicalTrials.gov).

9.
Clin Exp Allergy ; 51(5): 666-673, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33721370

RESUMO

BACKGROUND: Children with atopic dermatitis (AD) are often sensitized to food and aeroallergens, but sensitization patterns have not been analysed with biologic measures of disease pathogenicity. OBJECTIVE: We sought to define allergen sensitization grouping(s) using unbiased machine learning and determine their associations with skin filaggrin (FLG) and transepidermal water loss (TEWL) (assesses skin barrier integrity), S100A8 and S100A9 expression (assesses skin inflammation) and AD severity. METHODS: We studied 400 children with AD in the Mechanisms of Progression from Atopic Dermatitis to Asthma in Children (MPAACH) cohort to identify groupings of food and aeroallergen sensitizations. MPAACH is a paediatric AD cohort, aged 1-2, recruited through hospital/community settings between 2016 and 2018. We analysed these groupings' associations with AD biomarkers: skin FLG, S100A8 and S100A9 expression, total IgE, TEWL and AD severity. RESULTS: An unbiased machine learning approach revealed five allergen clusters. The most common cluster (N = 131), SPTPEP, had sensitization to peanut, egg and/or pets. Three low prevalence clusters, which included children with allergen sensitization other than peanut, egg or pets, were combined into SPTOther . SPTNEG included children with no sensitization(s). SPTPEP children had higher median non-lesional TEWL (16.9 g/m2 /h) and IgE (90 kU/L) compared with SPTOTHER (8.8 g/m2 /h and 24 kU/L; p = .01 and p < .001) and SPTNEG (9 g/m2 /h and 26 kU/L; p = .003 and p < .001). SPTPEP children had lower median lesional (0.70) and non-lesional (1.09) FLG expression compared with SPTOTHER (lesional: 0.9; p = .047, non-lesional: 1.78; p = .01) and SPTNEG (lesional: 1.47; p < .001, non-lesional: 2.21; p < .001). There were no differences among groupings in S100A8 or S100A9 expression. CONCLUSIONS AND CLINICAL RELEVANCE: In this largely clinic-based cohort of young children with AD, allergic sensitization to peanut, egg, cat or dog was associated with more severe disease and skin barrier function but not markers of cutaneous inflammation. These data need replicating in a population-based cohort but may have important implications for understanding the interaction between AD and allergic sensitization.

10.
J Neurotrauma ; 2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33605167

RESUMO

The present study examined the differential effect of the brain-derived neurotrophic factor (BDNF) Val66Met polymorphism on behavioral adjustment in children with traumatic brain injury (TBI) relative to children with orthopedic injury (OI). Participants were drawn from a prospective, longitudinal study of children who sustained a TBI (n = 69) or OI (n = 72) between 3 and 7 years of age. Parents completed the Child Behavior Checklist (CBCL) at the immediate post-acute period, 6, 12, and 18 months after injury, and an average of 3.5 and 7 years after injury. Longitudinal mixed models examined the BDNF Val66Met allele status (Met carriers vs. Val/Val homozygotes) × injury group (TBI vs. OI) interaction in association with behavioral adjustment. After adjusting for continental ancestry, socioeconomic status, time post-injury, and pre-injury functioning, the allele status × injury group interaction was statistically significant for Internalizing, Externalizing, and Total Behavior problems. Post hoc within-group analysis suggested a consistent trend of poorer behavioral adjustment in Met carriers relative to Val/Val homozygotes in the TBI group; in contrast, the opposite trend was observed in the OI group. These within-group differences, however, did not reach statistical significance. The results support a differential effect of the BDNF Val66Met polymorphism on behavioral adjustment in children with early TBI relative to OI, and suggest that the Met allele associated with reduced activity-dependent secretion of BDNF may impart risk for poorer long-term behavioral adjustment in children with TBI.

11.
Urology ; 153: 147-155, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33592224

RESUMO

OBJECTIVES: To compare toxicity and all-cause mortality for mCRPC patients receiving first line oral systemic therapy prescribed by medical oncologists and urologists. METHODS: Population-based retrospective cohort study of chemotherapy-naïve men aged ≥66 years treated for mCRPC with first-line abiraterone or enzalutamide based on administrative health data (Ontario, Canada, 2012-2017). Primary outcomes were hospitalizations/ER visits for any cause or treatment-related toxicity during first-line mCRPC treatment. Secondary outcome was all-cause mortality. We calculated hazard ratios (HRs) comparing outcomes for different medical specialties using multivariable Cox proportional hazards models. RESULTS: Among 3405 mCRPC patients, 2407 (70.7%) received abiraterone and 998 (29.3%) received enzalutamide. 1786 (52.5%) patients visited the ER or were hospitalized. Men treated by medical oncologists had an increased risk of hospitalization/ER visits (HR1.16, 95%CI 1.03-1.31; P = .02), toxicity-related visits (HR1.34, 95%CI 1.08-1.69; P = .01), and mortality (HR1.16, 95%CI 1.02-1.33; P = .02) compared to urologists. Limited information was available, beyond PSA adjustment and prior treatment, on patient disease burden. CONCLUSION: We observed fewer hospital visits overall and for treatment-related toxicity for mCRPC patients who were prescribed first line abiraterone or enzalutamide by urologists compared to medical oncologists. These differences may result from higher prostate cancer disease burden in patients managed by medical oncologists, and/or other unmeasured differences in patient management between specialties.

12.
J Allergy Clin Immunol ; 147(1): 244-254.e6, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33446329

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic, food antigen-mediated disease characterized by esophageal dysfunction and intraepithelial eosinophil accumulation. OBJECTIVE: We hypothesized that very early onset EoE (V-EoE) would be enriched for early-life and genetic factors and have worse presentation and prognosis than later-onset pediatric EoE (L-EoE). METHODS: We conducted a single-site, retrospective review comparing patients diagnosed at age 12 months or less (V-EoE, n = 57) and age 14 to 18 years (L-EoE, n = 70). These patients underwent medical record, EoE Histology Scoring System, Endoscopic Reference Score, and EoE Diagnostic Panel assessment when sample availability permitted. Genetic association used 2 EoE genotype repositories. Data were analyzed using chi-square tests, t tests, Wilcoxon rank-sum tests, Spearman correlations, cluster analysis, and logistic regression. RESULTS: Among pediatric patients with EoE, diagnosis most commonly occurred within early life (0-24 months, 17%). V-EoE was more likely to attain histologic remission via dietary restriction (P < .0001). Basal zone hyperplasia and eosinophil inflammation were greater in V-EoE (P < .05). Esophageal strictures more commonly occurred in L-EoE (P = .03). V-EoE had lower endoscopic scores (P < .05). Molecular expression was very similar between groups. Cesarean delivery was more common in patients with V-EoE (P = .03). Patients with V-EoE demonstrated enrichment of CAPN14 common genetic variants. CONCLUSIONS: Early-life diagnosis of EoE is a common occurrence. V-EoE responds to standard therapy without early evidence for complications, suggesting a less severe prognosis than hypothesized. Molecular pathogenesis is preserved between V-EoE and L-EoE. Cesarean delivery and CAPN14 genetic variation likely promote earlier disease development.


Assuntos
Calpaína/genética , Esofagite Eosinofílica/genética , Variação Genética , Adolescente , Idade de Início , Calpaína/imunologia , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/patologia , Feminino , Humanos , Masculino , Estudos Retrospectivos
13.
J Child Adolesc Psychopharmacol ; 31(1): 56-62, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32845723

RESUMO

Objective: To determine the effect of CYP2D6 metabolizer status on aripiprazole tolerability in pediatric patients with mood disorders. Methods: We retrospectively reviewed electronic medical record data for 277 patients ≤18 years of age (at the time of CYP2D6 testing) with a mood disorder, receiving oral aripiprazole, and CYP2D6 genotyped as part of routine care. The maximum aripiprazole dose and concomitant medications were extracted from the medical record. The reason for aripiprazole discontinuation was determined to be from side effects (e.g., weight gain, akathisia, GI upset), nonresponse, or other reasons (e.g., financial). Associations with CYP2D6 were analyzed using multivariate linear regression models and chi-square tests. Results: Of the 277 patients (mean age: 14.3 ± 2.4), 57% were normal metabolizers (NMs), 37% were intermediate metabolizers (IMs), 5% were poor metabolizers (PMs), and 1.4% were ultrarapid metabolizers (UMs). A total of 72.2% of the cohort were concomitantly taking a CYP2D6 inhibitor, resulting in phenoconversion. Accounting for phenoconversion resulted in 27% phenoconverted NMs (pNMs), 24% phenoconverted IMs (pIMs), 48% phenoconverted PMs (pPMs), and <1% phenoconverted ultrarapid metabolizers. CYP2D6 pPMs discontinued treatment due to side effects more often than any other CYP2D6 group (67% for pPM, 51% pIM, 57% pNM, chi-square p = 0.024). Body mass index percentile change was associated with the CYP2D6 phenotype (p = 0.038), the time on aripiprazole (p = 0.001), and the number of concomitant CYP2D6 substrates (p = 0.044) in multivariable models. Conclusions: Phenoconverted CYP2D6 metabolizer status is associated with aripiprazole discontinuation. In addition, dose adjustments based on CYP2D6 metabolizer status and concomitant medications could improve aripiprazole treatment outcomes.

14.
Allergy ; 76(1): 302-313, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32640045

RESUMO

BACKGROUND: Atopic dermatitis (AD) patients are often colonized with Staphylococcus aureus, and staphylococcal biofilms have been reported on adult AD skin lesions. The commensal S epidermidis can antagonize S aureus, although its role in AD is unclear. We sought to characterize S aureus and S epidermidis colonization and biofilm propensity and determine their associations with AD severity, barrier function, and epidermal gene expression in the first US early-life cohort of children with AD, the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children (MPAACH). METHODS: The biofilm propensity of staphylococcal isolates was assessed by crystal violet assays. Gene expression of filaggrin and antimicrobial alarmins S100A8 and S100A9 was measured in keratinocyte RNA extracted from skin tape strips. Staphylococcal biofilms sampled from MPAACH skin were visualized using scanning electron microscopy. RESULTS: Sixty-two percent of staphylococcal isolates (sampled from 400 subjects) formed moderate/strong biofilms. Sixty-eight percent of subjects co-colonized with both staphylococcal species exhibited strains that formed cooperative mixed-species biofilms. Scanning electron microscopy verified the presence of staphylococcal biofilms on the skin of MPAACH children. Staphylococcus aureus strains showing higher relative biofilm propensity compared with S epidermidis were associated with increased AD severity (P = .03) and increased lesional and nonlesional transepidermal water loss (P = .01, P = .03). CONCLUSIONS: Our data suggest a pathogenic role for S aureus biofilms in AD. We found that strain-level variation in staphylococcal isolates governs the interactions between S epidermidis and S aureus and that the balance between these two species, and their biofilm propensity, has important implications for AD.


Assuntos
Dermatite Atópica , Infecções Estafilocócicas , Adulto , Biofilmes , Criança , Humanos , Pele , Staphylococcus aureus , Staphylococcus epidermidis/genética
15.
J Asthma ; 58(3): 284-292, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31809667

RESUMO

OBJECTIVE: We previously reported that children exposed to secondhand smoke (SHS) that carried variants in the NAT1 gene had over two-fold higher hair cotinine levels. Our objective was to determine if NAT1 polymorphisms confer increased risk for developing asthma in children exposed to SHS. METHODS: White participants in the Cincinnati Childhood Allergy and Air Pollution Study (n = 359) were genotyped for 10 NAT1 variants. Smoke exposure was defined by hair cotinine and parental report. Asthma was objectively assessed by spirometry and methacholine challenge. Findings were replicated in the Genomic Control Cohort (n = 638). RESULTS: Significant associations between 5 NAT1 variants and asthma were observed in the CCAAPS exposed group compared to none in the unexposed group. There was a significant interaction between NAT1 rs13253389 and rs4921581 with smoke exposure (p = 0.02, p = 0.01) and hair cotinine level (p = 0.048, p = 0.042). Children wildtype for rs4921581 had increasing asthma risk with increasing hair cotinine level, whereas those carrying the NAT1 minor allele had an increased risk of asthma regardless of cotinine level. In the GCC, 13 NAT1 variants were associated with asthma in the smoke-exposed group, compared to 0 in the unexposed group, demonstrating gene-level replication. CONCLUSIONS: Variation in the NAT1 gene modifies asthma risk in children exposed to secondhand-smoke. To our knowledge, this is the first report of a gene-environment interaction between NAT1 variants, smoke exposure, cotinine levels, and pediatric asthma. NAT1 genotype may have clinical utility as a biomarker of increased asthma risk in children exposed to smoke.

16.
Dis Esophagus ; 34(2)2021 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-32766724

RESUMO

Early life exposures have been associated with pediatric eosinophilic esophagitis (EoE), but it is unknown if a similar association is present in adults. We aimed to assess the association between early life risk factors and development of EoE in adulthood. To do this, we conducted a case-control study which was nested within a prospective cohort study of adults undergoing outpatient endoscopy. Cases of EoE were diagnosed per consensus guidelines; controls did not meet these criteria. Subjects and their mothers were contacted to collect information on four key early life exposures: antibiotics taken during the first year of life, Cesarean delivery, preterm delivery (≤37 weeks' gestation), and neonatal intensive care unit (NICU) admission. We calculated the odds of EoE given in each exposure and assessed agreement between subjects and their mothers. For the 40 cases and 40 controls enrolled, we observed a positive association between each of the early life exposures and development of EoE (antibiotics in infancy, OR = 4.64, 95% CI = 1.63-13.2; Cesarean delivery, OR = 3.08, 95% CI = 0.75-12.6; preterm delivery, OR = 2.92, 95% CI = 0.71-12.0; NICU admission, OR = 4.00, 95% CI = 1.01-15.9). Results were unchanged after adjusting for potential confounders, though only early antibiotic use had CIs that did not cross 1.0. Moderate to strong agreement was observed between 54 subject-mother pairs (antibiotics, K = 0.44, P = 0.02; Cesarean delivery, K = 1.0, P < 0.001; preterm delivery, K = 0.80, P < 0.001; NICU, K = 0.76, P < 0.001). In sum, antibiotics in infancy was significantly associated with increased risk of EoE diagnosed in adulthood, while positive trends were seen with other early life factors such as Cesarean delivery, preterm delivery, and NICU admission. This may indicate persistent effects of early life exposures and merits additional study into conserved pathogenic mechanisms.

17.
Am J Med Genet A ; 185(1): 141-149, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33118324

RESUMO

Turner syndrome is associated with an increased risk of aortic aneurysms and dissection. Recent 2017 clinical care guidelines recommend medical therapy to treat aortic dilatation, although whether this slows dilatation is unknown. We aimed to describe a pre-guideline cohort of Turner syndrome patients with aortic dilatation, the rate of dilatation following diagnosis, and post therapy dilatation rates. We conducted a retrospective review of Turner syndrome patients with a dilated aortic root or ascending aorta by current definitions. In total, 40 patients were included with 22 treated patients. Most patients had 45,X karyotype, were white, non-Hispanic, and received both growth hormone and estrogen. Except for hypertension, there were no differences in risk factors among treated and untreated groups. Bicuspid aortic valve was very common. Treatment group patients had significantly more dilated ascending aortas by absolute measurements and aortic size index. In an adjusted model, there was minimal change in aortic measures over time and this was not associated with medication use. In conclusion, in this cohort, Turner syndrome patients with aortic dilatation were more likely to be treated if they had hypertension and if they met multiple dilatation criteria. Further study is needed to establish medical therapy efficacy on dilatation progression.

18.
Clin Exp Allergy ; 51(6): 801-810, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33382170

RESUMO

BACKGROUND: Second-hand smoke (SHS) exposure is associated with paediatric asthma, and oxidative stress is believed to play a role in mediating this association. The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) is important for the defence against oxidative stress. OBJECTIVE: To explore interactions between NFE2L2 genotype and SHS exposure in paediatric asthma risk. METHODS: We used a genotyped subset of patients of European ancestry (N = 669, median age at enrolment = 6.8 years) enrolled in the clinical cohort Greater Cincinnati Pediatric Clinic Repository as the study population, and a population-based paediatric cohort (N = 791) to replicate our findings. History of asthma diagnosis was obtained from medical records, and SHS exposure was obtained from questionnaires. Four NFE2L2 tagging SNPs were included in the analysis, and interactions between SHS and NFE2L2 genotype were evaluated using logistic regression. RESULTS: Three of the analysed SNPs, rs10183914, rs1806649 and rs2886161, interacted significantly with SHS exposure to increase asthma risk (p ≤ .02). The interaction was replicated in an independent cohort for rs10183914 (p = .04). Interactions between SHS exposure and NFE2L2 genotype were also associated with an increased risk of hospitalization (p = .016). In stratified analyses, NFE2L2 genotype was associated with daily asthma symptoms in children with SHS exposure (OR = 3.1; p = .048). No association was found in children without SHS exposure. Examination of publicly available chromatin immunoprecipitation followed by sequencing (ChIP-seq) data sets confirmed the presence of active histone marks and binding sites for particular transcription factors overlapping the coordinates for the significantly associated SNPs. CONCLUSIONS AND CLINICAL RELEVANCE: Our study provides evidence that NFE2L2 genotype interacts with SHS exposure to affect both asthma risk and severity in children and identifies a population of children at increased risk of asthma development.

19.
Nat Commun ; 11(1): 4092, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796837

RESUMO

Single nucleotide polymorphisms (SNPs) in the gene encoding kinesin family member 3A, KIF3A, have been associated with atopic dermatitis (AD), a chronic inflammatory skin disorder. We find that KIF3A SNP rs11740584 and rs2299007 risk alleles create cytosine-phosphate-guanine sites, which are highly methylated and result in lower KIF3A expression, and this methylation is associated with increased transepidermal water loss (TEWL) in risk allele carriers. Kif3aK14∆/∆ mice have increased TEWL, disrupted junctional proteins, and increased susceptibility to develop AD. Thus, KIF3A is required for skin barrier homeostasis whereby decreased KIF3A skin expression causes disrupted skin barrier function and promotes development of AD.


Assuntos
Dermatite Atópica/metabolismo , Cinesina/metabolismo , Pele/metabolismo , Adolescente , Adulto , Alelos , Animais , Criança , Dermatite Atópica/genética , Dermatite Atópica/patologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Cinesina/genética , Masculino , Metilação , Camundongos , Reação em Cadeia da Polimerase em Tempo Real , Pele/patologia , Adulto Jovem
20.
J Pediatr ; 221: 188-195.e1, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32446479

RESUMO

OBJECTIVE: To determine whether the Ghent Criteria (2010) can be reliably used in evaluating preadolescents and adolescents for Marfan syndrome by comparing aortic growth, systemic scores, and anthropometric features in individuals with and without Marfan syndrome. STUDY DESIGN: A retrospective chart review was completed for patients less than 15 years of age referred for Marfan syndrome. Comparisons were made between the first and last visit. Paired t tests were used to compare Ghent systemic scores. Wilcoxon rank-sum test were used to compare age, aortic root z scores, height z scores, and body mass index z scores. Recursive partitioning was used to identify combinations of factors to distinguish Marfan syndrome. RESULTS: In total, 53 individuals met inclusion criteria (29 Marfan syndrome and 24 non-Marfan syndrome). Ghent systemic score increased in the Marfan syndrome group and declined in the non-Marfan syndrome. The non-Marfan syndrome group did not develop progressive aortic root dilation with age. Individuals with Marfan syndrome had higher median height z scores than non-Marfan syndrome, with no difference in median body mass index z score between groups. A combination of aortic root z score above 0.95 and Ghent systemic score above 3 was highly indicative of a Marfan syndrome diagnosis in children less than 15 years of age. CONCLUSION: The Ghent criteria (2010) can be used to reliably exclude a diagnosis of Marfan syndrome in individuals less than 15 years of age. Genetic testing should be used as an aide in confirming or excluding the diagnosis of Marfan syndrome in individuals with an aortic root z score above 0.95 in combination with a Ghent systemic score above 3 at initial visit.


Assuntos
Aorta/diagnóstico por imagem , Síndrome de Marfan/diagnóstico , Adolescente , Estatura , Índice de Massa Corporal , Criança , Ecocardiografia , Fibrilina-1 , Seguimentos , Testes Genéticos , Humanos , Imagem Cinética por Ressonância Magnética , Síndrome de Marfan/genética , Mutação , Estudos Retrospectivos
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