Modifiable Disease Risk Research Articles

Altered Pancreatic Growth and Insulin Secretion in WSB/EiJ Mice

These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies also highlight the role of post-natal growth in determining adult β-cell mass. Mice are important animal models for the study of metabolic physiology and the genetics of complex traits. Wild-derived inbred mouse strains, such as WSB/EiJ (WSB), are unrelated to the commonly studied mouse strains and are valuable tools to identify novel genes that modify disease risk. We have previously shown that in contrast to C57BL/6J (B6) mice, WSB mice fed a high fat diet do not develop hyperinsulinemia or insulin resistance, and had nearly undetectable insulin secretion in response to an intraperitoneal glucose challenge. As hyperinsulinemia may drive obesity and insulin resistance, we examined whether defects in β-cell mass or function could contribute to the low insulin levels in WSB mice. In young WSB mice, β-cell mass was similar to B6 mice. However, we found that adult WSB mice had reduced β-cell mass due to reduced pancreatic weights. Pancreatic sizes were similar between the strains when normalized to body weight, suggesting their pancreatic size is appropriate to their body size in adults, but overall post-natal pancreatic growth was reduced in WSB mice compared to B6 mice. Islet architecture was normal in WSB mice. WSB mice had markedly increased insulin secretion from isolated islets in vitro. These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies suggest that WSB mice may provide novel insight into mechanisms regulating insulin secretion and also highlight the role of post-natal growth in determining adult β-cell mass.

Effectiveness of Structured Interventional Strategy on Knowledge, Attitude and health behavior regarding selected modifiable coronary artery disease risk factors among adolescents in selected schools

Cardiovascular diseases (CVDs) remain the biggest cause of deaths worldwide. Although CVDs typically occur in middle age or later, risk factors are determined to a great extent by behaviours learned in childhood and continued into adulthood. Adolescence provides an opportunity for teenagers to incorporate healthy lifestyle behaviours that will benefit them not only during the teenage years, but also throughout the life span. The aim of the study was to evaluate the effectiveness of structured interventional strategy on knowledge, attitude and health behavior regarding prevention of selected modifiable CAD risk factors among adolescents in selected schools. An experimental (pre-test and post-test) design was adopted for this study. 80 adolescents were randomly assigned to either experimental or control groups. A structured questionnaire, a five point likert scale, and a 4 point rating scale were used. A pre-test was administered followed by (video – assisted teaching). Three post-tests were given. The results revealed that, the overall paired ‘t’ test in experimental group for knowledge was 24.86, for attitude 17.97 and health behavior 27.01 which were highly significant at P<0.001 level. The overall unpaired ‘t’ test for 3 post-test scores on knowledge was 42.39, for attitude 16.93 and for health behavior 39.49 which were highly significant at P<0.001 level. There was no significant correlation between the dependent variables and there was no significant association between pre-test knowledge, attitude and health behavior and selected demographic variables except for dietary patterns.

Tyrosine Phosphatase PTPN22: Multifunctional Regulator of Immune Signaling, Development, and Disease

Inheritance of a coding variant of the protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene is associated with increased susceptibility to autoimmunity and infection. Efforts to elucidate the mechanisms by which the PTPN22-C1858T variant modulates disease risk revealed that PTPN22 performs a signaling function in multiple biochemical pathways and cell types. Capable of both enzymatic activity and adaptor functions, PTPN22 modulates signaling through antigen and innate immune receptors. PTPN22 plays roles in lymphocyte development and activation, establishment of tolerance, and innate immune cell-mediated host defense and immunoregulation. The disease-associated PTPN22-R620W variant protein is likely involved in multiple stages of the pathogenesis of autoimmunity. Establishment of a tolerant B cell repertoire is disrupted by PTPN22-R620W action during immature B cell selection, and PTPN22-R620W alters mature T cell responsiveness. However, after autoimmune attack has initiated tissue injury, PTPN22-R620W may foster inflammation through modulating the balance of myeloid cell-produced cytokines.

Insomnia symptoms and subsequent cardiovascular medication: a register-linked follow-up study among middle-aged employees

Introduction Sleep disturbances have been associated with increased risk of cardiovascular disease outcomes. The associations of insomnia with hypertension and dyslipidemia, the main modifiable cardiovascular disease risk factors, are less studied. We aimed to examine associations of insomnia symptoms with subsequent prescribed medication for hypertension and dyslipidemia. Materials and methods Baseline questionnaire surveys among 40–60-year-old employees of the City of Helsinki, Finland, were conducted in 2000–2002 (N = 6,477, response rate 67%, 78% women) and linked to a national register on prescribed reimbursed medication 5–7 years prior to and 5 years after baseline. The associations between the frequency of insomnia symptoms (difficulties in initiating and maintaining sleep, non-restorative sleep) and hypertension and dyslipidemia medication during the follow-up were analysed using logistic regression analysis (odds ratios (OR) with 95% confidence intervals (CI)). Analyses were adjusted for pre-baseline medication, sociodemographic and work-related factors, health, and health behaviours. Results Frequent insomnia symptoms were reported by 20%. During the 5-year follow-up 32% had hypertension medication and 15% dyslipidemia medication. Adjusting for age, gender, and pre-baseline medication, frequent insomnia symptoms were associated with hypertension medication (OR 1.57, 95% CI 1.23–2.00) and dyslipidemia medication (OR 1.59, 95% CI 1.19–2.12). Occasional insomnia symptoms were also associated with cardiovascular medication, though less strongly. Further adjustments had negligible effects. Conclusion Insomnia should be taken into account in the prevention and management of cardiovascular disease and related risk factors. Acknowledgements The authors have no conflicts of interests to report. This study has been funded with grants from Academy of Finland, Finnish Work Environment Fund, Juho Vainio Foundation, Emil Aaltonen Foundation, and Doctoral Programs in Public Health.

Multiple Copies of MLL Is The Most Commonly Detected Cytogenetic Abnormality In Newly Diagnosed Multiple Myeloma and May Modify Disease Risk

BackgroundMultiple myeloma (MM) is a heterogeneous condition with variable disease course, response to therapy, and survival outcome. Cytogenetics and fluorescent in-situ hybridization (FISH) have identified several recurrent chromosomal aberrations in MM and play important and independent roles in risk stratification (Munshi et al. Blood 2011). However, the pathogenesis of the disorder remains poorly understood. Next-generation sequencing has recently identified that MM involves mutations of genes with roles in protein translation, histone methylation, and blood coagulation (Chapman et al. Nature 2011). Based on the observation that extra copies of MLL, a histone methyltransferase known to regulate the homeotic transcription factor HOXA9 that is highly expressed in MM, is frequently detected in MM, we sought to define the incidence and prognostic significance of excess MLL in MM patients. MethodsWe identified 188 patients with newly diagnosed MM who had cytogenetics and/or FISH performed on initial, pre-treatment bone marrow specimens at Memorial Sloan-Kettering Cancer Center between January 2009 and December 2012. Standard karyotype and FISH were performed as previously described (Cigudosa et al. Blood 1998, Gerritsen et al. Blood 1992). Probes included LSI IgH/FGF3, LSI IgH/CCND1, LSI IgH/MAF, LSI MLL, LSI p53/cep17, LSI13q14.3/13q34, LSI ETV6, LSI CBFB, LSI 1p36/1q25, and LSI 5,9,15 from Abbott Molecular. Fisher's exact test evaluated the association between MLL and selected abnormalities. Kaplan-Meier methodology estimated overall survival from the date of BM evaluation, and survival was compared using a logrank test. ResultsIn unselected bone marrow specimens, abnormalities were detected by karyotype in 17% (27/156) and FISH in 47% (87/186) of patients tested. Hyperdiploidy, which has been associated with longer survival, was identified in 23% (43/187) of patients, while the unfavorable risk abnormalities, including loss of p53, deletion 13q (by karyotype), translocation (4;14) and excess 1q were seen in 8% (15/179), 8% (12/156), 4% (7/176) and 16% (29/178) of patients, respectively. Translocation (11;14) was seen in 4 patients; translocation (14;16) was not identified in any patient. 28% (51/183) of patients had extra copies of MLL, which was the most frequent genetic abnormality identified. Unexpectedly, this abnormality was significantly associated with both favorable (hyperdiploidy, P = <0.001) and unfavorable (deletion 13q, P = 0.043; excess 1q P = 0.001) risk genetics. While having excess MLL had no impact on the overall survival of standard-risk patients, defined as neither hyperdiploid nor with unfavorable genetics (N = 100), patients with poor-risk genetics (N = 46) and extra copies of MLL had a trend toward better survival, P = 0.06 (Figure 1). [Display omitted] ConclusionsKaryotype and FISH studies identified excess MLL as the most frequent cytogenetic abnormality in a large cohort of newly diagnosed MM patients. In patients with MM and unfavorable cytogenetics, the presence of excess MLL may ameliorate some of the adverse impact of associated with these abnormalities. Understanding the functional significance of excess MLL, perhaps as it relates to frequently dysregulated HOXA9 in MM, may provide insight into disease pathogenesis and/or identify drugable targets. Disclosures:No relevant conflicts of interest to declare.

Frequency of Polymorphism -262 C/T in Catalase Gene and Oxidative Damage in Slovak Children With Bronchial Asthma

IntroductionBronchial asthma is a complex disease in which genetic factors, environmental factors and oxidative damage are responsible for the initiation and modulation of disease progression. If antioxidant mechanisms fail, reactive oxygen species damage the biomolecules followed by progression of the disease. Catalase is one of the most important endogenous enzymatic antioxidants. In the present study, we examined the hypothesis that increased oxidative damage and polymorphism in the CAT gene (-262 promoter region, C/T) are associated with childhood bronchial asthma. Patients and methodsGenotyping of the polymorphisms in the CAT gene in healthy (249) and asthmatic children (248) was performed using polymerase chain reaction – restriction fragment length polymorphism. Markers of oxidative damage: content of sulfhydryl groups and thiobarbituric acid-reactive substances were determined by spectrophotometry in children. ResultsThe TT genotype of catalase was more frequent among the asthmatic patients (22.6%) than in healthy children (4.8%) (odds ratio=5.63; 95% confidence interval=2.93–10.81, P<.001). The amount of sulfhydryl groups decreased significantly and conversely, the content of thiobarbituric acid-reactive substances increased significantly in bronchial asthma and in catalase TT genotype compared to other catalase genotypes of this gene. ConclusionsThese results suggest that catalase polymorphism might participate in development of bronchial asthma and in enhanced oxidative damage in asthmatic children. Genetic variation of enzymatic antioxidants may modulate disease risk.

Individual Variation in Lipidomic Profiles of Healthy Subjects in Response to Omega-3 Fatty Acids

IntroductionConflicting findings in both interventional and observational studies have resulted in a lack of consensus on the benefits of ω3 fatty acids in reducing disease risk. This may be due to individual variability in response. We used a multi-platform lipidomic approach to investigate both the consistent and inconsistent responses of individuals comprehensively to a defined ω3 intervention.MethodsThe lipidomic profile including fatty acids, lipid classes, lipoprotein distribution, and oxylipins was examined multi- and uni-variately in 12 healthy subjects pre vs. post six weeks of ω3 fatty acids (1.9 g/d eicosapentaenoic acid [EPA] and 1.5 g/d docosahexaenoic acid [DHA]).ResultsTotal lipidomic and oxylipin profiles were significantly different pre vs. post treatment across all subjects (p=0.00007 and p=0.00002 respectively). There was a strong correlation between oxylipin profiles and EPA and DHA incorporated into different lipid classes (r2=0.93). However, strikingly divergent responses among individuals were also observed. Both ω3 and ω6 fatty acid metabolites displayed a large degree of variation among the subjects. For example, in half of the subjects, two arachidonic acid cyclooxygenase products, prostaglandin E2 (PGE2) and thromboxane B2 (TXB2), and a lipoxygenase product, 12-hydroxyeicosatetraenoic acid (12-HETE) significantly decreased post intervention, whereas in the other half they either did not change or increased. The EPA lipoxygenase metabolite 12-hydroxyeicosapentaenoic acid (12-HEPE) varied among subjects from an 82% decrease to a 5,000% increase.ConclusionsOur results show that certain defined responses to ω3 fatty acid intervention were consistent across all subjects. However, there was also a high degree of inter-individual variability in certain aspects of lipid metabolism. This lipidomic based phenotyping approach demonstrated that individual responsiveness to ω3 fatty acids is highly variable and measurable, and could be used as a means to assess the effectiveness of ω3 interventions in modifying disease risk and determining metabolic phenotype.

Genome-Wide Association Analysis Identifies 3 Common Variants Predisposing to Brugada Syndrome, a Rare Disease with High Risk of Sudden Cardiac Death

Background The Brugada syndrome (BrS) is considered a rare mendelian disorder with autosomal dominant transmission. BrS is associated with an increased risk of sudden cardiac death and specific ECG features consisting of ST-segment elevation in the right precordial leads. Loss-of-function mutations in SCN5A , encoding the pore-forming subunit of the cardiac sodium channel (Na v 1.5), are identified in ~20% of patients. However, studies in families harboring mutations in SCN5A have demonstrated low disease penetrance and, in some instances, absence of the familial SCN5A mutation in some affected members. These observations suggest a more complex inheritance model. Methods To identify common genetic factors modulating disease risk, we conducted a genome-wide association study on 312 individuals with BrS and 1115 ancestry-matched controls. Results Two genomic loci displayed significant association. Replication testing on 2 independent case/control sets from Europe (598/855) and Japan (208/1016) confirmed both associations and revealed a third locus. The cumulative effect of the 3 loci on disease susceptibility was large, with an odds ratio of 21.5 in the presence of more than 4 risk alleles vs less than 2. Two of 3 loci had previously been shown to influence ECG conduction parameters in the general population. The third locus encompasses a transcription factor that has not previously been implicated in cardiac electrical function and arrhythmia. Functional studies in mice heterozygous knockout for this transcription factor identified differences in expression of Na v 1.5 in addition to differences in conduction of the cardiac electrical impulse in the right ventricular outflow tract. Conclusions Our findings (1) indicate that common genetic variation may have a strong impact on predisposition to BrS and (2) identify a new gene involved in the pathogenesis of the disease.

Modifiable cardiovascular risk factors in patients with ankylosing spondylitis

The aim of this study was to evaluate whether modifiable cardiovascular disease (CVD) risk factors, e.g. atherogenic blood lipids, hypertension and lifestyle-related factors such as smoking, diet and physical inactivity, differ among patients with ankylosing spondylitis (AS) in comparison to the general population. Eighty-eight patients diagnosed with AS were identified by analysis of the databases of a previous community intervention programme, the Västerbotten intervention programme. The patients were compared with 351 controls matched for age, sex and study period. These databases include the results of blood samples analysed for cholesterol, triglycerides and plasma glucose, as well as data on hypertension, height, weight, smoking and dietary habits and physical activity. No significant differences were found between patients and controls regarding hypertension, body mass index, physical activity, diet or smoking. Levels of serum triglycerides (p < 0.01) and cholesterol (p < 0.01) were significantly lower in the patient group. Among the patients, the level of triglycerides correlated inversely with the intake of total fat (r s = -0.25, p < 0.05), monounsaturated fats (r s = -0.29, p < 0.05) and positively correlated to the intake of carbohydrates (r s = 0.26, p < 0.05). These associations were not apparent among the controls. In the cohort of AS patients studied, no differences were found regarding the modifiable risk factors for CVD compared with the general population. Hence, the increased presence of CVD in patients with AS may be caused by other factors such as differences in metabolism and medication such as NSAID or the chronic low-grade inflammation present in the disease.

Genome-wide identification of allele-specific effects on gene expression for single and multiple individuals

The analysis of allele-specific gene expression (ASE) is essential for the mapping of genetic variants that affect gene regulation, and for the identification of alleles that modify disease risk. Although RNA sequencing offers the opportunity to measure expression at allele levels, the availability of powerful statistical methods for mapping ASE in single or multiple individuals is limited. We developed a maximum likelihood model to characterize ASE in the human genome. Approximately 17% of genes displayed an allele-specific effect on gene expression in a single individual. Simulations using our model gave a better performance and improved robustness when compared with the binomial test, with different coverage levels, allelic expression fractions and random noise. In addition, our method can identify ASE in multiple individuals, with enhanced performance. This is helpful in understanding the mechanism of genetic regulation leading to expression changes, alternative splicing variants and even disease susceptibility.

Evidence for long-term impact of Pasos Adelante: using a community-wide survey to evaluate chronic disease risk modification in prior program participants.

Effective community-level chronic disease prevention is critical to population health within developed and developing nations. Pasos Adelante is a preventive intervention that aims to reduce chronic disease risk with evidence of effectiveness in US-Mexico residing, Mexican origin, participants. This intervention and related ones also implemented with community health workers have been shown to improve clinical, behavioral and quality of life indicators; though most evidence is from shorter-term evaluations and/or lack comparison groups. The current study examines the impact of this program using secondary data collected in the community 3–6 years after all participants completed the program. A proportional household survey (N = 708) was used that included 48 respondents who indicated they had participated in Pasos. Using propensity score matching to account for differences in program participants versus other community residents (the program targeted those with diabetes and associated risk factors), 148 natural controls were identified for 37 matched Pasos participants. Testing a range of behavioral and clinical indicators of chronic disease risk, logistic regression models accounting for selection bias showed two significant findings; Pasos participants were more physically active and drank less whole milk. These findings add to the evidence of the effectiveness of Pasos Adalente and related interventions in reducing chronic disease risk in Mexican-origin populations, and illustrate the use of innovative techniques for using secondary, community-level data to complement prior evaluation research.

Polymorphism in the TOMM40 gene modifies the risk of developing sporadic inclusion body myositis and the age of onset of symptoms

A polyT repeat in an intronic polymorphism (rs10524523) in the TOMM40 gene, which encodes an outer mitochondrial membrane translocase involved in the transport of amyloid-β and other proteins into mitochondria, has been implicated in Alzheimer’s disease and APOE-TOMM40 genotypes have been shown to modify disease risk and age at onset of symptoms. Because of the similarities between Alzheimer’s disease and sporadic inclusion body myositis (s-IBM), and the importance of amyloid-β and mitochondrial changes in s-IBM, we investigated whether variation in poly-T repeat lengths in rs10524523 also influence susceptibility and age at onset in a cohort of 90 Caucasian s-IBM patients (55 males; age 69.1±9.6). In carriers of APOE ε3/ε3 or ε3/ε4, genotypes with a very long (VL) poly-T repeat were under-represented in s-IBM compared to controls and were associated with a later age at symptom onset, suggesting that these genotypes may be protective. Our study is the first to suggest that polymorphisms in genes controlling mitochondrial function can influence susceptibility to s-IBM and have disease modifying effects. However, further studies in other s-IBM populations are needed to confirm these findings, as well as expression studies of different TOMM40 alleles in muscle tissue.

Alu retrotransposon quantification in the retina and plasma: Mechanism‐based risk assessment in age‐related macular degeneration

AbstractPurpose Alu RNAs are endogenous pathogens in age‐related macular degeneration (AMD). Currently, efforts to develop diagnostic and prognostic tools are limited. Yet, because AMD is a chronic disease, tools to detect pre‐clinical disease and monitor progression are an essential part of an effective and comprehensive therapeutic strategy. We tested plasma Alu RNA as a potential biomarker for AMD. Also, cells can convert Alu RNA into DNA, and as such, we determined Alu DNA content of RPE cells. We also genotyped RPE cells for a panel of known AMD risk single nucleotide polymorphisms, and developed an AMD risk stratification system based on age, genotype, and Alu DNA content.Methods RPE cells were isolated from human donor eyes were harvested within 5‐10 hours after death. RPE cells were grown in cell culture for four passages. DNA was extracted and subjected to genotyping for AMD‐associated SNPs using TaqMan probes. Plasma sample RNA was extracted with Trizol LS and reverse transcribed. qPCR for DNA performed with standard curves of Alu‐specific primers and housekeeping single copy genes; for cDNA, Alu quantified per mL plasma.Results The RPE of AMD donors contain increased quantities of Alu DNA. Our results suggest that Alu DNA content increases as a function of age and disease status, and that genotype also modulates disease risk. Finally, Alu RNA content in plasma was significantly increased in AMD versus age‐matched healthy controls.Conclusion These efforts set the stage for the utilization of plasma Alu RNA quantity as a novel mechanism‐based biomarker in AMD, and also implicate increased Alu DNA burden as a potential mediator of Alu RNA‐induced RPE cell death in AMD.

Frecuencia del polimorfismo -262 C/T en el gen de la catalasa y lesión oxidativa en niños eslovacos con asma bronquial

IntroductionBronchial asthma is a complex disease in which genetic factors, environmental factors and oxidative damage are responsible for the initiation and modulation of disease progression. If antioxidant mechanisms fail, reactive oxygen species damage the biomolecules followed by progression of the disease. Catalase is one of the most important endogenous enzymatic antioxidants. In the present study, we examined the hypothesis that increased oxidative damage and polymorphism in the CAT gene (-262 promoter region, C/T) are associated with childhood bronchial asthma. Patients and methodsGenotyping of the polymorphisms in the CAT gene in healthy (249) and asthmatic children (248) was performed using polymerase chain reaction–restriction fragment length polymorphism. Markers of oxidative damage: content of sulfhydryl groups and thiobarbituric acid-reactive substances were determined by spectrophotometry in children. ResultsThe TT genotype of catalase was more frequent among the asthmatic patients (22.6%) than in healthy children (4.8%) (odds ratio=5.63; 95% confidence interval=2.93–10.81, P<.001). The amount of sulfhydryl groups decreased significantly and conversely, the content of thiobarbituric acid-reactive substances increased significantly in bronchial asthma and in catalase TT genotype compared to other catalase genotypes of this gene. ConclusionsThese results suggest that catalase polymorphism might participate in development of bronchial asthma and in enhanced oxidative damage in asthmatic children. Genetic variation of enzymatic antioxidants may modulate disease risk.

VEGFA, FLT1, KDR and colorectal cancer: Assessment of disease risk, tumor molecular phenotype, and survival

Angiogenesis is essential for tumor progression. Vascular endothelial growth factor (VEGFA) and its receptors 1 (FLT1) and 2 (KDR), have been identified as major mediators of this process. We hypothesized that genetic variation in FLT1 (38 SNPs), KDR (22 SNPS), and VEGFA (11 SNPs) would be associated with colon and rectal cancer development and survival. Data from a case-control study of 1555 colon cancer cases and 1956 controls and 754 rectal cancer cases and 959 controls were used. An adaptive rank truncation product (ARTP), based on 10,000 permutations, was used to determine the statistical significance of the candidate genes and angiogenesis pathway. Based on ARTP results, FLT1 was significantly associated with risk of colon cancer (P(ARTP) = 0.045) and VEGFA was significantly associated with rectal cancer (P(ARTP) = 0.036). After stratifying by tumor molecular subtype, SNP associations observed for colon cancer were: VEGFA rs2010963 with CIMP+ colon tumors; FLT1 rs4771249 and rs7987649 with TP53; FLT1 rs3751397, rs7337610, rs7987649, and rs9513008 and KDR rs10020464, rs11941492, and rs12498529 with MSI+ and CIMP+/KRAS2-mutated tumors. FLT1 rs2296189 and rs600640 were associated with CIMP+ rectal tumors and FLT1 rs7983774 was associated with TP53-mutated rectal tumors. Four SNPs in FLT1 were associated with colon cancer survival while three SNPs in KDR were associated with survival after diagnosis with rectal cancer. Aspirin/NSAID use, smoking cigarettes, and BMI modified the associations. These findings suggest the importance of inflammation and angiogenesis in the etiology of colorectal cancer and that genetic and lifestyle factors may be targets for modulating disease risk.

Meat-Loving Microbes

The importance of the interaction among diet, gut microbiota, and host genetics in modulating disease risk in humans is being increasingly recognized and studied. In this study, Koeth et al examined the interaction between dietary l-carnitine and gut microbiota in promoting atherosclerosis. Previous work from this group identified the metabolite trimethylamine N-oxide (TMAO) as being potentially proatherogenic, with increased plasma TMAO predicting cardiovascular disease (CVD) risk. TMAO is present in some dietary sources, predominately seafood, but is mainly produced by hepatic oxidation of trimethylamine by flavin monooxygenases. Trimethylamine is derived in the gut by the action of bacteria on multiple diet–derived nutrients, including choline, phosphatidylcholine (lecithin), betaine, creatinine, and carnitine, and diffuses into the bloodstream through the intestinal wall. In this study, the authors hypothesized that dietary l-carnitine, found in high concentrations in red meat, promotes atherosclerosis through gut-mediated generation of TMAO. Koeth et al studied both humans and mice to test the relationship between dietary intake of l-carnitine and gut bacteria–mediated production of TMAO, as well as the development of atherosclerosis. Five volunteer omnivores were given an l-carnitine–rich meal (steak, containing ≈180 mg l-carnitine) combined with 250 mg isotope-labeled d3-l-carnitine supplementation. Plasma and urine samples …

Understanding Neurological Disease Mechanisms in the Era of Epigenetics

The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type-specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues.

Gender, sex hormones and pulmonary hypertension.

Most subtypes of pulmonary arterial hypertension (PAH) are characterized by a greater susceptibility to disease among females, although females with PAH appear to live longer after diagnosis. While this “estrogen paradoxȍ of enhanced female survival despite increased female susceptibility remains a mystery, recent progress has begun to shed light upon the interplay of sex hormones, the pathogenesis of pulmonary hypertension, and the right ventricular response to stress. For example, emerging data in humans and experimental models suggest that estrogens or differential sex hormone metabolism may modify disease risk among susceptible subjects, and that estrogens may interact with additional local factors such as serotonin to enhance the potentially damaging chronic effects of estrogens on the pulmonary vasculature. Regardless, it remains unclear why not all estrogenic compounds behave equally, nor why estrogens appear to be protective in certain settings but detrimental in others. The contribution of androgens and other compounds, such as dehydroepiandrosterone, to pathogenesis and possibly treatment must be considered as well. In this review, we will discuss the recent understandings on how estrogens, estrogen metabolism, dehydroepiandrosterone, and additional susceptibility factors may all contribute to the pathogenesis or potentially to the treatment of pulmonary hypertension, by evaluating current human, cell-based, and experimental model data.

Stress: A Possible Link between Genetics, Epigenetics, and Childhood Asthma

Stress: A Possible Link between Genetics, Epigenetics, and Childhood Asthma

Distribution, Determinants, and Normal Reference Values of Thoracic and Abdominal Aortic Diameters by Computed Tomography (from the Framingham Heart Study)

Current screening and detection of asymptomatic aortic aneurysms is based largely on uniform cut-point diameters. The aims of this study were to define normal aortic diameters in asymptomatic men and women in a community-based cohort and to determine the association between aortic diameters and traditional risk factors for cardiovascular disease. Measurements of the diameters of the ascending thoracic aorta (AA), descending thoracic aorta (DTA), infrarenal abdominal aorta (IRA), and lower abdominal aorta (LAA) were acquired from 3,431 Framingham Heart Study (FHS) participants. Mean diameters were stratified by gender, age, and body surface area. Univariate associations with risk factor levels were examined, and multivariate linear regression analysis was used to assess the significance of covariate-adjusted relations with aortic diameters. For men, the average diameters were 34.1 mm for the AA, 25.8 mm for the DTA, 19.3 mm for the IRA, and 18.7mm for the LAA. For women, the average diameters were 31.9 mm for the AA, 23.1mm for the DTA, 16.7 mm for the IRA, and 16.0 mm for the LAA. The mean aortic diameters were strongly correlated (p <0.0001) with age and body surface area in age-adjusted analyses, and these relations remained significant in multivariate regression analyses. Positive associations of diastolic blood pressure with AA and DTA diameters in both genders and pack-years of cigarette smoking with DTA diameter in women and IRA diameter in men and women were observed. In conclusion, average diameters of the thoracic and abdominal aorta by computed tomography are larger in men compared with women, vary significantly with age and body surface area, and are associated with modifiable cardiovascular disease risk factors, including diastolic blood pressure and cigarette smoking.