Tobacco smoke exposure dramatically alters DNA methylation in blood cells and may mediate smoking-associated complex diseases through effects on immune cell function. However, knowledge of smoking effects in specific leukocyte subtypes is limited. To better characterize smoking–associated methylation changes in whole blood and leukocyte subtypes, we used Illumina 450K arrays and Reduced Representation Bisulfite Sequencing (RRBS) to assess genome-wide DNA methylation. Differential methylation analysis in whole blood DNA from 172 smokers and 81 nonsmokers revealed 738 CpGs, including 616 previously unreported CpGs, genome-wide significantly associated with current smoking (p <1.2x10-7, Bonferroni correction). Several CpGs (MTSS1, NKX6-2, BTG2) were associated with smoking duration among heavy smokers (>22 cigarettes/day, n = 86) which might relate to long-term heavy-smoking pathology. In purified leukocyte subtypes from an independent group of 20 smokers and 14 nonsmokers we further examined methylation and gene expression for selected genes among CD14+ monocytes, CD15+ granulocytes, CD19+ B cells, and CD2+ T cells. In 10 smokers and 10 nonsmokers we used RRBS to fine map differential methylation in CD4+ T cells, CD8+ T cells, CD14+, CD15+, CD19+, and CD56+ natural killer cells. Distinct cell-type differences in smoking-associated methylation and gene expression were identified. AHRR (cg05575921), ALPPL2 (cg21566642), GFI1 (cg09935388), IER3 (cg06126421) and F2RL3 (cg03636183) showed a distinct pattern of significant smoking-associated methylation differences across cell types: granulocytes> monocytes>> B cells. In contrast GPR15 (cg19859270) was highly significant in T and B cells and ITGAL (cg09099830) significant only in T cells. Numerous other CpGs displayed distinctive cell-type responses to tobacco smoke exposure that were not apparent in whole blood DNA. Assessing the overlap between these CpG sites and differential methylated regions (DMRs) with RRBS in 6 cell types, we confirmed cell-type specificity in the context of DMRs. We identified new CpGs associated with current smoking, pack-years, duration, and revealed unique profiles of smoking-associated DNA methylation and gene expression among immune cell types, providing potential clues to hematopoietic lineage-specific effects in disease etiology.
Nuclear factor- (erythroid-derived 2) like 2 (NFE2L2, NRF2) is a key transcriptional activator of the antioxidant response pathway and is closely related to erythroid transcription factor NFE2. Under oxidative stress, NRF2 heterodimerizes with small Maf proteins and binds cis-acting enhancer sequences found near oxidative stress response genes. Using the dietary isothiocyanate sulforaphane (SFN) to activate NRF2, chromatin immunoprecipitation sequencing (ChIP-seq) identified several hundred novel NRF2-mediated targets beyond its role in oxidative stress. Activated NRF2 bound the antioxidant response element (ARE) in promoters of several known and novel target genes involved in iron homeostasis and heme metabolism, including known targets FTL and FTH1, as well as novel binding in the globin locus control region. Five novel NRF2 target genes were chosen for followup: AMBP, ABCB6, FECH, HRG-1 (SLC48A1), and TBXAS1. SFN-induced gene expression in erythroid K562 and lymphoid cells were compared for each target gene. NRF2 silencing showed reduced expression in lymphoid, lung, and hepatic cells. Furthermore, stable knockdown of NRF2 negative regulator KEAP1 in K562 cells resulted in increased NQO1, AMBP, and TBXAS1 expression. NFE2 binding sites in K562 cells revealed similar binding profiles as lymphoid NRF2 sites in all potential NRF2 candidates supporting a role for NRF2 in heme metabolism and erythropoiesis.
Aim: Hemophilia A is a genetic, chronic disorder classified by deficient or defective coagulation factor VIII (FVIII) that puts those affected at risk for spontaneous bleeding episodes, which lead to joint damage and chronic pain over time. Currently, most severe hemophilia A patients are treated with prophylactic FVIII, which requires costly and frequent infusions and lifelong adherence to medication. A gene therapy (valoctocogene roxaparvovec) is currently in development for the treatment of severe hemophilia A. This model assessed the potential cost-effectiveness of treating patients with valoctocogene roxaparvovec rather than prophylactic therapy. Materials and methods: We developed an individual-based, state-transition microsimulation model for assessing the likely cost-effectiveness of valoctocogene roxaparvovec compared to prophylactic FVIII. Men aged 30 with severe hemophilia A were modeled over a lifetime horizon, and costs were reported from the perspective of the United States health care system. Through microsimulation, patient-level heterogeneity was captured in starting weight, starting Pettersson score (PS), durability of valoctocogene roxaparvovec, and annual bleed rate (ABR). Results: The model projects that treatment with single-administration valoctocogene roxaparvovec would be cost-saving to people with hemophilia A at a price point comparable to other currently available gene therapy products due to its potential to reduce FVIII utilization, direct medical costs, lifetime bleeds, and accumulated joint damage. Limitations: The model relies upon evidence-based assumptions for clinical inputs due to limited data availability. Such uncertainty was mitigated by modeling heterogeneity across the population, specifically with regards to long-term gene therapy durability, lifetime bleed rates, and joint damage progression. Conclusion: Valoctocogene roxaparvovec was found to be cost-saving-on average by about $6.8 million per patient-and more effective than prophylactic therapy for treatment of hemophilia A. The comparative benefit of gene therapy was observed across a broad range of simulated patients that were representative of the real-world severe hemophilia A population.
Generalized and partial lipodystrophy are rare and complex diseases with progressive clinical and humanistic burdens stemming from selective absence of subcutaneous adipose tissue which causes reduced energy storage capacity and a deficiency of adipokines such as leptin. Treatment options were limited before leptin replacement therapy (metreleptin) became available. This retrospective study evaluates both clinical and humanistic consequences of the disease and treatment. Chart data were abstracted from a cohort of metreleptin-treated patients with generalized and partial lipodystrophy (n=112) treated at the US National Institutes of Health. To quantify the quality of life consequences of the lipodystrophy disease attributes recorded in chart data, a discrete choice experiment was completed in 6 countries (US, n=250; EU, n=750). Resulting utility decrements were used to estimate the quality adjusted life-year consequences of changes in lipodystrophy attribute prevalence before and after metreleptin. In addition to metabolic impairment, patients with generalized and partial lipodystrophy experienced a range of lipodystrophy consequences, including liver abnormality (94%), hyperphagia (79%), impaired physical appearance (77%), kidney abnormality (63%), reproductive dysfunction (80% of females of reproductive age), and pancreatitis (39%). Improvement was observed in these attributes following initiation of metreleptin. Quality adjusted life-year gains associated with 12 months of treatment with metreleptin were estimated at 0.313 for generalized and 0.117 for partial lipodystrophy, reducing the gap in quality of life between untreated lipodystrophy and perfect health by approximately 59% and 31%, respectively. This study demonstrates that metreleptin is associated with meaningful clinical and quality of life improvements.
Objective: To evaluate the effects of metreleptin in distinct subgroups of patients with generalized lipodystrophy (GL) and partial lipodystrophy (PL), using multivariate linear regression modeling to account for the role of patients' baseline usage of concomitant glucose and lipid-lowering medications and other covariates on their outcomes. Materials and methods: A post-hoc statistical analysis of two published single-arm, interventional, phase 2 clinical trials at NIH was conducted. Concomitant medication use was assessed for the clinical trial population using prescription fill data, measured at baseline and the post-one year following metreleptin initiation. Pre-specified co-primary efficacy endpoints measured were change from baseline in HbA1c at month 12, and the percent change from baseline in fasting serum triglycerides (TG) at month 12. Descriptive and statistical analyses were conducted for the overall population, the separate populations with GL and PL, and additional PL subgroups defined by baseline metabolic markers of elevated HbA1c and elevated fasting TG. Results: As previously reported, improvement in HbA1c and fasting TG from baseline to 12 months on metreleptin were observed in the overall population (mean change À1.57 percentage points and median change À37.9%, respectively) and subgroups. For both HbA1c and TG, baseline levels were significant predictors of changes after metreleptin. After considering baseline characteristics such as disease type, age, sex, and baseline HbA1c, baseline insulin use was not found to be a significant predictor of HbA1c improvement following metreleptin initiation. Similar results were seen for TG levels, with the use of any lipid-lowering medications at baseline not found to be a significant predictor of reductions in fasting TG levels. Conclusions: Patients treated with metreleptin experienced statistically significant improvement in metabolic markers of glycemic and hypertriglyceridemic control-e.g. HbA1c and triglyceride levelsacross various subgroups after controlling for baseline characteristics and concomitant medication usage.
Cost-effectiveness analyses often inform healthcare reimbursement decisions. The preferred measure of effectiveness is the quality adjusted life year (QALY) gained, where the quality of life adjustment is measured in terms of utility. Areas covered: We assessed the availability and variation of utility values for health states associated with advanced or metastatic non-small cell lung cancer (NSCLC) to identify values appropriate for cost-effectiveness models assessing alternative treatments. Our systematic search of six electronic databases (January 2000 to August 2015) found the current literature to be sparse in terms of utility values associated with NSCLC, identifying 27 studies. Utility values were most frequently reported over time and by treatment type, and less frequently by disease response, stage of disease, adverse events or disease comorbidities. Expert commentary: In response to rising healthcare costs, payers increasingly consider the cost-effectiveness of novel treatments in reimbursement decisions, especially in oncology. As the number of therapies available to treat NSCLC increases, cost-effectiveness analyses will play a key role in reimbursement decisions in this area. Quantifying the relationship between health and quality of life for NSCLC patients via utility values is an important component of assessing the cost effectiveness of novel treatments.
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