Todd M. Everson

Prognostic impact of definitive local therapy of the primary tumor in men with metastatic prostate cancer at diagnosis: A population-based, propensity score analysis

BACKGROUND This study investigated whether definitive local therapy [radical prostatectomy (RP) or brachytherapy (BT)] of the primary tumor improves survival in men with metastatic prostate cancer (PrCA) at diagnosis. METHODS Data on newly diagnosed metastatic PrCA cases (stage IV, N=7858) were obtained from the Surveillance Epidemiology and End Results (SEER) program. Conventional multivariable survival analysis and propensity score analysis were used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (95% CI) comparing men who underwent definitive local therapy of the primary tumor to those who did not. RESULTS After adjusting for sociodemographic and tumor attributes, having RP after diagnosis with metastatic PrCA was associated with 73% (HR=0.27, 95% CI: 0.20-0.38) lower risk of all-cause mortality and 72% (HR=0.28, 95% CI: 0.20-0.39) reduced risk of death from PrCA. Having BT also was associated with 57% (HR=0.43, 95% CI: 0.31-0.59) and 54% (HR=0.46, 95% CI: 0.33-0.64) lower risk of all-cause and PrCA-specific mortality. Similar results were observed in propensity score-adjusted analysis as well as when stratified by age and extent of tumor metastasis. CONCLUSIONS These findings suggest that definitive local therapy improves survival in men with metastatic PrCA at diagnosis. Future work should consider comorbidities, diet, physical activity and smoking status.

Epigenetic mechanisms and models in the origins of asthma.

Purpose of reviewEpigenetic mechanisms have the ability to alter the phenotype without changing the genetic code. The science of epigenetics has grown considerably in recent years, and future epigenetically based treatments or prevention strategies are likely. Epigenetic associations with asthma have received growing interest because genetic and environmental factors have been unable to independently explain the cause of asthma. Recent findingsRecent findings suggest that both the environment and underlying genetic sequence variation influence DNA methylation, which in turn seems to modify the risk conferred by genetic variants for various asthma phenotypes. In particular, DNA methylation may act as an archive of a variety of early developmental exposures, which then can modify the risk related to genetic variants. SummaryCurrent asthma treatments may control the symptoms of asthma but do not modify its natural history. Epigenetic mechanisms and novel explanatory models provide burgeoning approaches to significantly increase our understanding of the initiation and progression of asthma. Due to the inheritance of epigenetics, we anticipate a rapid emergence of critical information that will provide novel treatment strategies for asthma in the current generation and ultimately the prevention of asthma in future generations.

Association of season of birth with DNA methylation and allergic disease

Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long‐lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy.

DNA methylation loci associated with atopy and high serum IgE: a genome-wide application of recursive Random Forest feature selection

BackgroundThe prevalence of allergic diseases are increasing worldwide, emphasizing the need to elucidate their pathogeneses. The aims of this study were to use a two-stage design to identify DNA methylation levels at cytosine–phosphate–guanine (CpG) sites across the genome associated with atopy and high serum immunoglobulin E (IgE), then to replicate our findings in an independent cohort.MethodsAtopy was assessed via skin prick tests and high serum IgE. Methylation levels were measured from whole blood using the Illumina Infinium HumanMethylation450 BeadChip from 18-year-old women (n = 245) and men (n = 122) in the Isle of Wight birth cohort. After data cleaning and processing, and removing probes with possible single nucleotide polymorphisms, DNA methylation levels from 254,460 CpG sites from the 245 women were subjected to recursive Random Forest feature selection for stage 1. The sites selected from stage 1 were tested in stage 2 for associations with atopy and high IgE levels (>200 kU/L) via logistic regression adjusted for predicted cell-type proportions and sex. Sites significantly associated with atopy in stage 2 underwent replication tests in the independent Swedish birth cohort BAMSE (n = 464).ResultsIn stage 1, 62 sites were selected, of which 22 were associated with atopy in stage 2 (P-value range 6.5E−9 to 1.4E−5) and 12 associated with high IgE levels (P-value range 1.1E−5 to 7.1E−4) at the Bonferroni adjusted alpha (0.05/62 = 0.0008). Of the 19 available sites, 13 were replicated.ConclusionsWe identified 13 novel epigenetic loci associated with atopy and high IgE that could serve as candidate loci for future studies; four were within genes with known roles in the immune response (cg04983687 in the body of ZFPM1, cg18219873 in the 5′UTR of PRG2, cg27469152 in the 3′UTR of EPX, and cg09332506 in the body of COPA).

Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: findings from the pregnancy and childhood epigenetics (PACE) consortium

&NA; Pre‐pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta‐analysed the association between pre‐pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother‐newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother‐child pairs), we meta‐analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10‐7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for acausal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well‐powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large‐scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Maternal cadmium, placental PCDHAC1, and fetal development

Cadmium (Cd) is a ubiquitous environmental contaminant implicated as a developmental toxicant, yet the underlying mechanisms that confer this toxicity are unknown. Mother-infant pairs from a Rhode Island birth cohort were investigated for the potential effects of maternal Cd exposure on fetal growth, and the possible role of the PCDHAC1 gene on this association. Mothers with higher toenail Cd concentrations were at increased odds of giving birth to an infant that was small for gestational age or with a decreased head circumference. These associations were strongest amongst those with low levels of DNA methylation in the promoter region of placental PCDHAC1. Further, we found placental PCDHAC1 expression to be inversely associated with maternal Cd, and PCDHAC1 expression positively associated with fetal growth. Our findings suggest that maternal Cd affects fetal growth even at very low concentrations, and some of these effects may be due to the differential expression of PCDHAC1.

Trihalomethane exposure and biomonitoring for the liver injury indicator, alanine aminotransferase, in the United States population (NHANES 1999–2006)

Exposure to trihalomethanes (or THMs: chloroform, bromoform, bromodichloromethane, and dibromochloromethane [DBCM]) formed via drinking water disinfection has been associated with adverse reproductive outcomes and cancers of the digestive or genitourinary organs. However, few studies have examined potential associations between THMs and liver injury in humans, even though experimental studies suggest that these agents exert hepatotoxic effects, particularly among obese individuals. This study examined participants in the National Health and Nutrition Examination Survey (1999-2006, N=2781) to test the hypothesis that THMs are associated with liver injury as assessed by alanine aminotransferase (ALT) activity in circulation. Effect modification by body mass index (BMI) or alcohol consumption also was examined. Associations between blood THM concentrations and ALT activity were assessed using unconditional multiple logistic regression to calculate prevalence odds ratios (ORs) with 95% confidence intervals (CIs) for exposure among cases with elevated ALT activity (men: >40IU/L, women: >30IU/L) relative to those with normal ALT, after adjustment for variables that may confound the relationship between ALT and THMs. Compared to controls, cases were 1.35 times more likely (95% CI: 1.02, 1.79) to have circulating DBCM concentrations exceeding median values in the study population. There was little evidence for effect modification by BMI, although the association varied by alcohol consumption. Among non-drinkers, cases were more likely than controls to be exposed to DBCM (OR: 3.30, 95% CI: 1.37, 7.90), bromoform (OR: 2.88, 95% CI: 1.21, 6.81), or brominated THMs (OR: 4.00, 95% CI: 1.31, 12.1), but no association was observed among participants with low, or moderate to heavy alcohol consumption. Total THM levels exceeding benchmark exposure limits continue to be reported both in the United States and globally. Results from this study suggest a need for further characterization of ALT activity and possibly other hepatic or metabolic diseases in populations with elevated drinking water THM concentrations.

Placental imprinting variation associated with assisted reproductive technologies and subfertility

ABSTRACT Infertility affects one in 6 couples in developed nations, resulting in an increasing use of assisted reproductive technologies (ART). Both ART and subfertility appear to be linked to lower birth weight outcomes, setting infants up for poor long-term health. Prenatal growth is, in part, regulated via epigenetically-controlled imprinted genes in the placenta. Although differences in DNA methylation between ART and control infants have been found, it remains unclear whether these differences are due to the ART procedures or to the underlying parental subfertility and how these methylation differences affect imprinted gene expression. In this study, we examined the expression of 108 imprinted genes in placental tissues from infants born to subfertile parents (n = 79), matched naturally-conceived controls (n = 158), and infants conceived using in vitro fertilization (IVF, n = 18). Forty-five genes were identified as having significantly different expression between the subfertile infants and controls, whereas no significant differences were identified between the IVF and control groups. The expression of 4 genes—IGF2, NAPIL5, PAX8-AS1, and TUBGCP5—was significantly downregulated in the IVF compared with the subfertile group. Three of the 45 genes significantly dysregulated between subfertile and control placentae—GRB10, NDN, and CD44 —were found to have a significant positive correlation between expression and birth weight. Methylation levels for these 3 genes and 4 others—MKRN3, WRB, DHCR24, and CYR61—were significantly correlated with expression. Our findings indicate that epigenetic differences in placentas resulting from IVF pregnancies may be related to the underlying subfertility in parents using IVF rather than the IVF procedure itself.

Maternal exposure to selenium and cadmium, fetal growth, and placental expression of steroidogenic and apoptotic genes

Background Cadmium (Cd) and selenium (Se) antagonistically influence redox balance and apoptotic signaling, with Cd potentially promoting and Se inhibiting oxidative stress and apoptosis. Alterations to placental redox and apoptotic functions by maternal exposure to Cd and Se during pregnancy may explain some of the Cd and Se associations with fetal development. Objectives Investigate associations between Cd and Se concentrations in maternal toenails with placental expression patterns of tumor necrosis factor (TNF) and steroidogenic genes involved in redox reactions and test associations with fetal growth. Methods In a sub‐sample from the Rhode Island Child Health Study (n = 173), we investigated the relationships between: (1) maternal toenail Cd and Se concentrations and fetal growth using logistic regression, (2) Cd and Se interactions with factor scores from placental TNF and steroidogenic expression patterns (RNAseq) using linear models, and (3) TNF and steroidogenic expression factors with fetal growth via analysis of covariance. Results Se was associated with decreased odds of intrauterine growth restriction (IUGR) (OR = 0.27, p‐value = 0.045). Cd was associated with increased odds of IUGR (OR = 1.95, p‐value = 0.13) and small for gestational age (SGA) births (OR = 1.46, p‐value = 0.11), though not statistically significant. Cd and Se concentrations were antagonistically associated with placental TNF and steroidogenic expression patterns, which also differed by birth size. Conclusions Se may act as an antagonist to Cd and as a modifiable protective factor in fetal growth restriction, and these data suggest these effects may be due to associated variations in the regulation of genes involved in placental redox balance and/or apoptotic signaling. HighlightsTested cadmium and selenium associations with fetal growth and gene expression.Maternal selenium associated with decreased odds of intrauterine growth restriction.Cadmium may increase oxidative and apoptotic placental expression patterns.Selenium may decrease oxidative and apoptotic placental expression patterns.

Epigenome-wide association study of placental DNA methylation and maternal exposure to night shift work in the Rhode Island Child Health Study

Objectives Circadian disruption from environmental and occupational exposures can potentially impact health, including offspring health, through epigenetic alterations. Night shift workers experience circadian disruption, but little is known about how this exposure could influence the epigenome of the placenta, which is situated at the maternal-fetal interface. To investigate whether night shift work is associated with variations in DNA methylation patterns of placental tissue, we conducted an epigenome-wide association study (EWAS) of night shift work. Methods CpG specific methylation genome-wide of placental tissue (measured with the Illumina 450K array) from participants (n=237) in the Rhode Island Child Health Study (RICHS) who did (n=53) and did not (n=184) report working the night shift was compared using robust linear modeling, adjusting for maternal age, pre-pregnancy smoking, infant sex, maternal adversity, and putative cell mixture. Results Night shift work was associated with differential methylation in placental tissue, including CpG sites in the genes NAV1, SMPD1, TAPBP, CLEC16A, DIP2C, FAM172A, and PLEKHG6 (Bonferroni-adjusted p<0.05). CpG sites within NAV1, MXRA8, GABRG1, PRDM16, WNT5A, and FOXG1 exhibited the most hypomethylation, while CpG sites within TDO2, ADAMTSL3, DLX2, and SERPINA1 exhibited the most hypermethylation (BH q<0.10). PER1 was the only core circadian gene demonstrating differential methylation. Functional analysis indicated GO-terms associated with cell-cell adhesion. Conclusions Night shift work was associated with differential methylation of the placenta, which may have implications for fetal health and development. Additionally, neuron navigator 1 (NAV1) may play a role in the development of the human circadian system. What is already known about this subject? Night shift work and circadian disruption may play a role in the development and progression of many diseases. However, little is known about how circadian disruption impacts human fetal health and development. What are the new findings? Working the night shift is associated with altered placental methylation patterns, and particularly, neuron navigator 1 (NAV1) may play a role in the development of the human circadian system. How might this impact on policy or clinical practice in the foreseeable future? Night shift work prior to or during pregnancy may alter the placental epigenome, which has implications for fetal health. Further studies are needed to evaluate night shift work as a possible risk factor for gestational diabetes and to evaluate the impact of circadian disruption on fetal health and development.