Bradley E. Aouizerat

Abstract

Background: Historically, models to describe disease were exclusively nature-based or nurture-based. Current theoretical models for complex conditions such as cardiovascular disease acknowledge the importance of both biologic and nonbiologic contributors to disease. A critical feature is the occurrence of interactions between numerous risk factors for disease. The interaction between genetic (i.e. biologic, nature) and environmental (i.e. non-biologic, nurture) causes of disease is an important mechanism for understanding both the etiology and public health impact of cardiovascular disease. Objectives: The purpose of this paper is to describe theoretical underpinnings of gene–environment interactions, models of interaction, methods for studying gene–environment interactions, and the related concept of interactions between epigenetic mechanisms and the environment. Discussion: Advances in methods for measurement of genetic predictors of disease have enabled an increasingly comprehensive understanding of the causes of disease. In order to fully describe the effects of genetic predictors of disease, it is necessary to place genetic predictors within the context of known environmental risk factors. The additive or multiplicative effect of the interaction between genetic and environmental risk factors is often greater than the contribution of either risk factor alone.

Abstract

UNLABELLED: The Hedgehog (HH)-signaling pathway mediates several processes that are deregulated in patients with metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome generally correlate. Therefore, we hypothesized that the level of HH-pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and HH-pathway activation, immunohistochemistry was performed on liver biopsies from a large, well-characterized cohort of NAFLD patients (n = 90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased HH activity (evidenced by accumulation of HH-ligand-producing cells and HH-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each P < 0.0001), supporting a relationship between HH-pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both P < 0.03). In addition, various clinical parameters that have been linked to histologically advanced NAFLD, including increased patient age (P < 0.005), body mass index (P < 0.002), waist circumference (P < 0.0007), homeostatic model assessment of insulin resistance (P < 0.0001), and hypertension (P < 0.02), correlated with hepatic HH activity.CONCLUSION: In NAFLD patients, the level of hepatic HH-pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the HH-signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with metabolic syndrome.

Abstract

Purpose The purposes of this study were to identify distinct subgroups of patients based on self-reported sleep disturbance prior to through 6 months after breast cancer surgery and evaluate for differences in demographic, clinical, and symptom characteristics among these latent classes. Methods Women (n0398) who underwent unilateral breast cancer surgery were enrolled prior to surgery. Patients completed measures of functional status, sleep disturbance (i.e., General Sleep Disturbance Scale (GSDS); higher scores indicate higher levels of sleep disturbance), fatigue, attentional fatigue, depressive symptoms, and anxiety prior to surgery and monthly for 6 months. Results Three distinct classes of sleep disturbance trajectories were identified using growth mixture modeling. The high sustained class (55.0%) had high and the low sustained class (39.7%) had low GSDS scores prior to surgery that persisted for 6 months. The decreasing class (5.3%) had high GSDS score prior to surgery that decreased over time. Women in the high sustained class were significantly younger, had more comorbidity and poorer function, and were more likely to report hot flashes compared to the low sustained class. More women who underwent mastectomy or breast reconstruction were in the decreasing class. Decreasing and high sustained classes reported higher levels of physical fatigue, attentional fatigue, depressive symptoms, and anxiety compared to the low sustained class. Conclusions A high percentage of women has significant sleep disturbance prior to surgery that persists during subsequent treatments (i.e., radiation therapy and chemotherapy). Clinicians need to perform routine assessments and initiate appropriate interventions to improve sleep prior to and following surgery.

Abstract

Study purposes were to determine the prevalence of persistent pain in the breast; characterize distinct persistent pain classes using growth mixture modeling; and evaluate for differences among these pain classes in demographic, preoperative, intraoperative, and postoperative characteristics. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the pain classes, were evaluated. Patients (n = 398) were recruited prior to surgery and followed for 6 months. Using growth mixture modeling, patients were classified into no (31.7%), mild (43.4%), moderate (13.3%), and severe (11.6%) pain groups based on ratings of worst breast pain. Differences in a number of demographic, preoperative, intraoperative, and postoperative characteristics differentiated among the pain classes. In addition, patients in the moderate and severe pain classes reported higher preoperative levels of depression, anxiety, and sleep disturbance than the no pain class. Findings suggest that approximately 25% of women experience significant and persistent levels of breast pain in the first 6 months following breast cancer surgery. Perspective: Persistent pain is a significant problem for 25% of women following surgery for breast cancer. Severe breast pain is associated with clinically meaningful decrements in functional status and quality of life.

Abstract

Objectives: This study assessed the prevalence of insomnia symptoms among women with and without HIV-infection and examined factors associated with insomnia. Design: Participants (n = 1682) were enrolled in the Women's Interagency HIV Study (WIHS); 69% were infected with HIV. This was a crosssectional analysis of data from standardized interviewer-administered instruments and physical/gynecological exams. Analysis focused on sociodemographics, sleep measures, depressive symptoms, drug use, alcohol consumption, medications, and HIV-related clinical variables. Women were classified as having symptoms of insomnia if they reported either difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening ≥ 3 times a week in the past 2 weeks. Results: Overall, HIV-infected women were 17% more likely to endorse insomnia symptoms than uninfected women (OR = 1.17, 95% CI: 1.04-1.34, P < 0.05). The adjusted prevalence of insomnia symptoms varied by HIV status and age groups. Among women ages 31-40 years, those with HIV infection were 26% more likely to endorse insomnia symptoms than their counterparts (OR = 1.26, 95% CI: 1.01-1.59, P < 0.05). No significant differences were observed in the likelihood of reporting insomnia symptoms based on HIV treatment type. Multivariate-adjusted regression analyses showed that depression was the most consistent and significant independent predictor of the likelihood of reporting insomnia symptoms across all age strata. Conclusions: Insomnia symptoms are common among both HIV-infected and uninfected women. Prevalence of insomnia did not vary significantly by HIV status, except among younger women. Younger women with HIV infection are at greater risk for experiencing insomnia symptoms.

Abstract

Context: Sleep disturbance is a significant problem in oncology patients. Objectives: To examine how actigraphy and self-report ratings of sleep disturbance changed over the course of and after radiation therapy (RT); investigate whether specific patient, disease, and symptom characteristics predicted the initial levels and/or the characteristics of the trajectories of sleep disturbance; and compare predictors of subjective and objective sleep disturbance. Methods: Patients (n = 73) completed self-report questionnaires that assessed sleep disturbance, fatigue, depressive symptoms, anxiety, and pain before the initiation of RT through four months after the completion of RT. Wrist actigraphy was used as the objective measure of sleep disturbance. Hierarchical linear modeling was used for data analyses. Results: Mean wake after sleep onset was 11.9% and mean total score on the General Sleep Disturbance Scale was 45. More than 85% of the patients had an abnormally high number of nighttime awakenings. Substantial interindividual variability was found for both objective and subjective measures of sleep disturbance. Body mass index predicted baseline levels of objective sleep disturbance. Comorbidity, evening fatigue, and depressive symptoms predicted baseline levels of subjective sleep disturbance, and depressive symptoms predicted the trajectory of subjective sleep disturbance. Conclusion: Different variables predicted sleep disturbance using subjective and objective measures. The slightly elevated wake after sleep onset found may be an underestimation of the degree of sleep disturbance when it is evaluated in the context of the high number of nighttime awakenings and patient's perception of poor sleep quality and quantity.

Abstract

Hepcidin regulation is linked to both iron and inflammatory signals and may influence iron loading in nonalcoholic steatohepatitis (NASH). The aim of this study was to examine the relationships among HFE genotype, serum hepcidin level, hepatic iron deposition, and histology in nonalcoholic fatty liver disease (NAFLD). Single-nucleotide polymorphism genotyping for C282Y (rs1800562) and H63D (rs1799945) HFE mutations was performed in 786 adult subjects in the NASH Clinical Research Network (CRN). Clinical, histologic, and laboratory data were compared using nonparametric statistics and multivariate logistic regression. NAFLD patients with C282Y, but not H63D mutations, had lower median serum hepcidin levels (57 versus 65 ng/mL; P = 0.01) and higher mean hepatocellular (HC) iron grades (0.59 versus 0.28; P < 0.001), compared to wild-type (WT) subjects. Subjects with hepatic iron deposition had higher serum hepcidin levels than subjects without iron for all HFE genotypes (P < 0.0001). Hepcidin levels were highest among patients with mixed HC/reticuloendothelial system cell (RES) iron deposition. H63D mutations were associated with higher steatosis grades and NAFLD activity scores (odds ratio [OR], ≥1.4; 95% confidence interval [CI]: >1.0, ≤2.5; P ≤ 0.041), compared to WT, but not with either HC or RES iron. NAFLD patients with C282Y mutations had less ballooning or NASH (OR, ≤0.62; 95% CI: >0.39, <0.94; P ≤ 0.024), compared to WT subjects. Conclusions: The presence of C282Y mutations in patients with NAFLD is associated with greater HC iron deposition and decreased serum hepcidin levels, and there is a positive relationship between hepatic iron stores and serum hepcidin level across all HFE genotypes. These data suggest that body iron stores are the major determinant of hepcidin regulation in NAFLD, regardless of HFE genotype. A potential role for H63D mutations in NAFLD pathogenesis is possible through iron-independent mechanisms.

Abstract

Vitamin E was recently shown to improve hepatic histology in a randomized controlled trial of pioglitazone or vitamin E for nonalcoholic steatohepatitis (PIVENS). The current study utilized samples collected in the PIVENS trial to identify: (1) baseline metabolomic profiles that could identify who would respond to vitamin E treatment and (2) end of treatment metabolomic profiles reflective of histologic improvement. A comprehensive analysis of metabolomics profiles (n = 547) quantified by mass spectrometry was performed in vitamin E responders (n = 16), vitamin E non-responders (n = 15), and placebo responders (n = 15). At baseline, phenyl-propionic acid (Odds ratio: 29.4, p<0.01), indole-propionic acid levels (Odds ratio: 16.2, p<0.01) were directly associated with a subsequent histologic response to vitamin E treatment whereas γ-carboxyethylhydroxychroman (CEHC) levels were inversely related to histologic response. Adjusting for baseline values by analysis of covariance, the end of treatment levels of gamma-glutamyl leucine (Fold change: 0.82, p<0.02) and gamma-glutamyl valine (Fold change: 0.8, p<0.03) were significantly lower in vitamin E responders compared to non-responders. The levels of gamma-glutamyl transpeptidase were not significantly different across the two groups. Subjects receiving placebo who demonstrated a histologic improvement also demonstrated lower levels of gamma-glutamylated amino acids (leucine, valine and isoleucine) compared to vitamin E non-responders. These data provide exploratory proof that there are measurable differences in the metabolic profile of subjects who are likely (vs unlikely) to respond to vitamin E treatment for NASH and in those experiencing histologic improvement (vs no improvement) on treatment and support further studies to validate these biomarkers.

Abstract

Hereditary haemorrhagic telangiectasia (HTT) is a vascular dysplasia syndrome caused by mutations in transforming growth factor-β/bone morphogenetic protein pathway genes, ENG and ACVRL1. HTT shows considerable variation in clinical manifestations, suggesting environmental and/or genetic modifier effects. Strain-specific penetrance of the vascular phenotypes of Eng+/- and Tgfb1-/- mice provides further support for genetic modification of transforming growth factor-β pathway deficits. We previously identified variant genomic loci, including Tgfbm2, which suppress prenatal vascular lethality of Tgfb1-/- mice. Here we show that human polymorphic variants of PTPN14 within the orthologous TGFBM2 locus influence clinical severity of HTT, as assessed by development of pulmonary arteriovenous malformation. We also show that PTPN14, ACVRL1 and EFNB2, encoding EphrinB2, show interdependent expression in primary arterial endothelial cells in vitro. This suggests an involvement of PTPN14 in angiogenesis and/or arteriovenous fate, acting via EphrinB2 and ACVRL1/activin receptor-like kinase 1. These findings contribute to a deeper understanding of the molecular pathology of HTT in particular and to angiogenesis in general.

Abstract

UNLABELLED: The PIVENS (Pioglitazone versus Vitamin E versus Placebo for the Treatment of Nondiabetic Patients with Nonalcoholic Steatohepatitis [NASH]) trial demonstrated that pioglitazone and vitamin E improved liver histology to varying degrees, but the mechanisms are unknown. We conducted a study to examine the changes in adipose tissue insulin resistance (Adipo-IR) during the PIVENS trial and its relationship to histological endpoints. Adipo-IR (fasting nonesterified fatty acids [NEFAs] × fasting insulin) was calculated at baseline and after 16 and 96 weeks of therapy. Compared to placebo, the baseline Adipo-IR was not different in either the vitamin E group (P = 0.34) or the pioglitazone group (P = 0.29). Baseline Adipo-IR was significantly associated with fibrosis score (P = 0.02), but not with other histological features or nonalcoholic fatty liver disease (NAFLD) activity score (NAS). After 16 weeks, compared to placebo, the pioglitazone group had a significant reduction in Adipo-IR (-15.7 versus -1.91; P = 0.02), but this effect did not persist at 96 weeks (-3.25 versus -4.28; P = 0.31). Compared to placebo, Adipo-IR in the vitamin E group did not change significantly either after 16 weeks (P = 0.70) or after 96 weeks (P = 0.85). Change in Adipo-IR at week 16 was not associated with changes in any histological parameters at week 96, but improvement in Adipo-IR at week 96 was significantly associated with improvement in ballooning (P = 0.03), fibrosis (P = 0.004), and NAS (P = 0.01).CONCLUSION: Vitamin E improved liver histology independent of changes in Adipo-IR, and pioglitazone treatment acutely improved Adipo-IR, but this was not sustained. Changes in Adipo-IR were associated with changes in liver histology, including fibrosis.