Socioeconomic inequalities in early adulthood disrupt the immune transcriptomic landscape via upstream regulators

Disparities in socio-economic status (SES) predict many immune system-related diseases, and previous research documents relationships between SES and the immune cell transcriptome. Drawing on a bioinformatically-informed network approach, we situate these findings in a broader molecular framework by examining the upstream regulators of SES-associated transcriptional alterations. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a nationally representative sample of 4543 adults in the United States. Results reveal a network—of differentially expressed genes, transcription factors, and protein neighbors of transcription factors—that shows widespread SES-related dysregulation of the immune system. Mediational models suggest that body mass index (BMI) plays a key role in accounting for many of these associations. Overall, the results reveal the central role of upstream regulators in socioeconomic differences in the molecular basis of immunity, which propagate to increase risk of chronic health conditions in later-life

Whole body exposure of mice to secondhand smoke induces dose-dependent and persistent promutagenic DNA adducts in the lung

Secondhand smoke (SHS) exposure is a known risk factor for lung cancer in lifelong nonsmokers. However, the underlying mechanism of action of SHS in lung carcinogenesis remains elusive. We have investigated, using the (32)P-postlabeling assay, the genotoxic potential of SHS in vivo by determining the formation and kinetics of repair of DNA adducts in the lungs of mice exposed whole body to SHS for 2 or 4 months (5h/day, 5 days/week), and an ensuing one-month recovery period. We demonstrate that exposure of mice to SHS elicits a significant genotoxic response as reflected by the elevation of DNA adduct levels in the lungs of SHS-exposed animals. The increases in DNA adduct levels in the lungs of SHS-exposed mice are dose-dependent as they are related to the intensity and duration of SHS exposure. After one month of recovery in clean air, the levels of lung DNA adducts in the mice exposed for 4 months remain significantly higher than those in the mice exposed for 2 months (P<0.0005), levels in both groups being significantly elevated relative to controls (P<0.00001). Our experimental findings accord with the epidemiological data showing that exposure to smoke-derived carcinogens is a risk factor for lung cancer; not only does the magnitude of risk depend upon carcinogen dose, but it also becomes more irreversible with prolonged exposure. The confirmation of epidemiologic data by our experimental findings is of significance because it strengthens the case for the etiologic involvement of SHS in nonsmokers' lung cancer. Identifying the etiologic factors involved in the pathogenesis of lung cancer can help define future strategies for prevention, early detection, and treatment of this highly lethal malignancy

Psychological distress and unsatisfied need for psychosocial support in adolescent and young adult cancer patients during the first year following diagnosis

Purpose Identifying at‐risk adolescent and young adult (AYA) cancer patients and referring them to age‐appropriate psychosocial support services may be instrumental in reducing psychological distress and promoting psychosocial adaptation. The purpose of this study is to identify trajectories of clinically significant levels of distress throughout the first year following diagnosis and to distinguish factors, including supportive care service use, that predict the extent to which AYAs report distress. Methods In this prospective multisite study, 215 AYAs aged 15–39 years were assessed for psychological distress and psychosocial support service use within the first 4 months of diagnosis and again 6 and 12 months later. On the basis of distress scores, respondents were assigned to one of four distress trajectory groups (Resilient, Recovery, Delayed, and Chronic). Multiple logistic regression analyses examined whether demographics, clinical variables, and reports of unsatisfied need for psychosocial support were associated with distress trajectories over 1 year. Results Twelve percent of AYAs reported clinically significant chronic distress throughout the first 12 months following diagnosis. An additional 15% reported delayed distress. Substantial proportions of AYAs reported that needs for information (57%), counseling (41%), and practical support (39%) remained unsatisfied at 12 months following diagnosis. Not getting counseling needs met, particularly with regard to professional mental health services, was observed to be significantly associated with distress over time. Conclusions Substantial proportions of AYAs are not utilizing psychosocial support services. Findings suggest the importance of identifying psychologically distressed AYAs and addressing their needs for mental health counseling throughout a continuum of care. Copyright © 2014 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109318/1/pon3533.pd

MicroRNA profiling reveals marker of motor neuron disease in ALS models

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder marked by the loss of motor neurons (MNs) in the brain and spinal cord, leading to fatally debilitating weakness. Because this disease predominantly affects MNs, we aimed to characterize the distinct expression profile of that cell type to elucidate underlying disease mechanisms and to identify novel targets that inform on MN health during ALS disease time course. microRNAs (miRNAs) are short, noncoding RNAs that can shape the expression profile of a cell and thus often exhibit cell-type-enriched expression. To determine MN-enriched miRNA expression, we used Cre recombinase-dependent miRNA tagging and affinity purification in mice. By defining thein vivomiRNA expression of MNs, all neurons, astrocytes, and microglia, we then focused on MN-enriched miRNAs via a comparative analysis and found that they may functionally distinguish MNs postnatally from other spinal neurons. Characterizing the levels of the MN-enriched miRNAs in CSF harvested from ALS models of MN disease demonstrated that one miRNA (miR-218) tracked with MN loss and was responsive to an ALS therapy in rodent models. Therefore, we have used cellular expression profiling tools to define the distinct miRNA expression of MNs, which is likely to enrich future studies of MN disease. This approach enabled the development of a novel, drug-responsive marker of MN disease in ALS rodents.SIGNIFICANCE STATEMENTAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease in which motor neurons (MNs) in the brain and spinal cord are selectively lost. To develop tools to aid in our understanding of the distinct expression profiles of MNs and, ultimately, to monitor MN disease progression, we identified small regulatory microRNAs (miRNAs) that were highly enriched or exclusive in MNs. The signal for one of these MN-enriched miRNAs is detectable in spinal tap biofluid from an ALS rat model, where its levels change as disease progresses, suggesting that it may be a clinically useful marker of disease status. Furthermore, rats treated with ALS therapy have restored expression of this MN RNA marker, making it an MN-specific and drug-responsive marker for ALS rodents.</jats:p

Prevalence and predictors of post‐traumatic stress symptoms in adolescent and young adult cancer survivors: a 1‐year follow‐up study

Objectives Post‐traumatic stress symptoms (PTSS) have been identified as a meaningful indicator of distress in cancer survivors. Distinct from young adult survivors of childhood cancer, young people diagnosed with cancer as adolescents and young adults (AYAs) face unique psychosocial issues; however, there is little published research of PTSS in the AYA population. This study examines prevalence and predictors of PTSS among AYAs with cancer. Methods As part of a longitudinal study of AYAs with cancer, 151 patients aged 15–39 years completed mailed surveys at 6 and 12 months post‐diagnosis. Severity of PTSS was estimated at 6 and 12 months post‐diagnosis. Multiple regression analyses were conducted to investigate the predictive effects of socio‐demographic and clinical characteristics on changes in PTSS over time. Results At 6 and 12 months, respectively, 39% and 44% of participants reported moderate to severe levels of PTSS; 29% had PTSS levels suggestive of post‐traumatic stress disorder. No significant differences in severity of PTSS between 6 and 12 months were observed. Regression analyses suggested that a greater number of side effects were associated with higher levels of PTSS at 6 months. Currently receiving treatment, having surgical treatment, diagnosis of a cancer type with a 90–100% survival rate, remaining unemployed/not in school, and greater PTSS at 6 months were associated with higher levels of PTSS at 12 months. Conclusions Post‐traumatic stress symptoms were observed as early as 6 months following diagnosis and remained stable at 12‐month follow‐up. The development of early interventions for reducing distress among AYA patients in treatment is recommended. Copyright © 2012 John Wiley & Sons, Ltd.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99033/1/pon3217.pd

Discovery of a novel CHD7 CHARGE syndrome variant by integrated omics analyses

Chromodomain helicase DNA-binding protein 7 (CHD7) pathogenic variants are identified in more than 90% of infants and children with CHARGE (Coloboma of the iris, retina, and/or optic disk; congenital Heart defects, choanal Atresia, Retardation of growth and development, Genital hypoplasia, and characteristic outer and inner Ear anomalies and deafness) syndrome. Approximately, 10% of cases have no known genetic cause identified. We report a male child with clinical features of CHARGE syndrome and nondiagnostic genetic testing that included chromosomal microarray, CHD7 sequencing and deletion/duplication analysis, SEMA3E sequencing, and trio exome and whole-genome sequencing (WGS). We used a comprehensive clinical assessment, genome-wide methylation analysis (GMA), reanalysis of WGS data, and CHD7 RNA studies to discover a novel variant that causes CHD7 haploinsufficiency. The 7-year-old Hispanic male proband has typical phenotypic features of CHARGE syndrome. GMA revealed a CHD7-associated epigenetic signature. Reanalysis of the WGS data with focused bioinformatic analysis of CHD7 detected a novel, de novo 15 base pair deletion in Intron 4 of CHD7 (c.2239-20_2239-6delGTCTTGGGTTTTTGT [NM_017780.3]). Using proband RNA, we confirmed that this novel deletion causes CHD7 haploinsufficiency by disrupting the canonical 3′ splice site and introducing a premature stop codon. Integrated genomic, epigenomic, and transcriptome analyses discovered a novel CHD7 variant that causes CHARGE syndrome

Agrin function associated with ocular development is a target of ethanol exposure in embryonic zebrafish

Alcohol (ethanol) is a teratogen known to affect the developing eyes, face and brain. Among the ocular defects in fetal alcohol spectrum disorder (FASD) are microphthalmia and optic nerve hypoplasia. Employing zebrafish as an FASD model provides an excellent system to analyze the molecular basis of prenatal ethanol exposure-induced defects since embryos can be exposed to ethanol at defined developmental stages and affected genetic pathways can be examined. We have previously shown that disruption of agrin function in zebrafish embryos produces microphthalmia and optic nerve hypoplasia

Socioeconomic inequalities in molecular risk for chronic diseases observed in young adulthood

Many common chronic diseases of aging are negatively associated with socioeconomic status (SES). This study examines whether inequalities can already be observed in the molecular underpinnings of such diseases in the 30s, before many of them become prevalent. Data come from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a large, nationally representative sample of US subjects who were followed for over two decades beginning in adolescence. We now have transcriptomic data (mRNA-seq) from a random subset of 4,543 of these young adults. SES in the household-of-origin and in young adulthood were examined as covariates of a priori -defined mRNA-based disease signatures and of specific gene transcripts identified de novo . An SES composite from young adulthood predicted many disease signatures, as did income and subjective status. Analyses highlighted SES-based inequalities in immune, inflammatory, ribosomal, and metabolic pathways, several of which play central roles in senescence. Many genes are also involved in transcription, translation, and diverse signaling mechanisms. Average causal-mediated effect models suggest that body mass index plays a key role in accounting for these relationships. Overall, the results reveal inequalities in molecular risk factors for chronic diseases often decades before diagnoses and suggest future directions for social signal transduction models that trace how social circumstances regulate the human genome

Genomic risk scores and oral contraceptive-associated ischemic stroke risk: a call for collaboration

BackgroundOral contraceptives (OCs) are generally safe but vascular risk factors increase OC-associated ischemic stroke risk. We performed a case-control study to evaluate whether a genomic risk score for ischemic stroke modifies OC-associated ischemic stroke risk.MethodsThe Genetics of Early-Onset Stroke study includes 332 premenopausal women (136 arterial ischemic stroke cases and 196 controls) with data on estrogen-containing OC use within 30 days before the index event (for cases) or interview (for controls). Using a previously validated genetic risk score (metaGRS) for ischemic stroke based on 19 polygenic risk scores for stroke and stroke-associated risk factors, we stratified our combined case-control sample into tertiles of genomic risk. We evaluated the association between OC use and ischemic stroke within each tertile. We tested if the association between OC use and ischemic stroke depended on the genomic risk of stroke using logistic regression with an OC use × metaGRS interaction term. These analyses were performed with and without adjustment for smoking, hypertension, diabetes, coronary heart disease, and body mass index.ResultsAfter adjustment for vascular risk factors, the odds ratio of OC use was 3.2 (1.7–6.3) overall and increased from the lower, middle, and upper tertile of genomic risk from 1.6 (0.5–5.4) to 2.5 (0.08–8.2) to 13.7 (3.8–67.3) respectively, and a p-value for interaction of 0.001.ConclusionsOur results suggest that genomic profile may modify the OC-associated ischemic stroke risk. Larger studies are warranted to determine whether a genomic risk score could be clinically useful in reducing OC-associated ischemic stroke