Differential Environmental Exposures Research Articles

One Size Does Not Fit All: The Case for Translational Medicine.

Therapy for inflammatory bowel diseases (IBD) has developed during recent years. Despite the availability of new therapeutic modalities, overall therapy success remains modest, and complete remission is usually achieved and maintained in approximately 30% of patients only. This observation can be explained by a number of reasons. First, the involvement of multiple genetic loci combined with differential environmental exposures suggests that IBD represent a continuum of disorders rather than distinct homogeneous disease entities. This diversity is translated into different disease course patterns, wherein some patients experience quiescent disease whereas others suffer from a relentless disease course. Hence, basic disease pathogenesis sets the stage for differential treatment responses. To date, IBD therapy is based on immunosuppression which does not take basic disease variability into account. Treatments are prescribed based on statistical considerations related to the response of the average patient in clinical trials rather than on personal considerations. Treatment outcomes can potentially be improved if physiologic considerations are integrated into the drug selection process. In one approach, drugs can be targeted at known patient dysfunctional processes such as in the case of patients carrying autophagy-related genetic polymorphisms being treated with rapamycin, a drug that inhibits mTOR inhibitor and enhances autophagy. Another alternative would be to use a systems approach to perform unsupervised, high-throughput screening in order to derive predictive treatment biomarkers and mechanistic insights associated with response to specific drug therapy. Additional predictive markers for drug safety are needed as well. Caveats and directions for needed future studies are outlined.

Could epigenetics help explain racial disparities in chronic pain?

African Americans disproportionately suffer more severe and debilitating morbidity from chronic pain than do non-Hispanic Whites. These differences may arise from differential exposure to psychosocial and environmental factors such as adverse childhood experiences, racial discrimination, low socioeconomic status, and depression, all of which have been associated with chronic stress and chronic pain. Race, as a social construct, makes it such that African Americans are more likely to experience different early life conditions, which may induce epigenetic changes that sustain racial differences in chronic pain. Epigenetics is one mechanism by which environmental factors such as childhood stress, racial discrimination, economic hardship, and depression can affect gene expression without altering the underlying genetic sequence. This article provides a narrative review of the literature on epigenetics as a mechanism by which differential environmental exposure could explain racial differences in chronic pain. Most studies of epigenetic changes in chronic pain examine DNA methylation. DNA methylation is altered in the glucocorticoid (stress response) receptor gene, NR3C1, which has been associated with depression, childhood stress, low socioeconomic status, and chronic pain. Similarly, DNA methylation patterns of immune cytokine genes have been associated with chronic stress states. Thus, DNA methylation changes may play an essential role in the epigenetic modulation of chronic pain in different races with a higher incidence of epigenetic alterations contributing to more severe and disabling chronic pain in African Americans.

Genome-wide profiling of normal gastric mucosa identifies Helicobacter pylori- and cancer-associated DNA methylome changes.

The large geographic variations in the incidence of gastric cancer (GC) are likely due to differential environmental exposures, in particular to Helicobacter pylori (H. pylori) infection. We aimed to investigate the impact of H. pylori on the epigenome in normal gastric mucosa and methylation changes associated with cancer risk independent of H. pylori. A discovery set of normal gastric mucosa from GC cases (n = 42) and controls (n = 42), nested in a large case-control study and stratified by H. pylori status, were subjected to genome-wide methylation profiling. Single-nucleotide polymorphism arrays from peripheral blood leukocytes were used to conduct methylation quantitative trait loci (mQTL) analysis. A validation set of gastric mucosa samples (n = 180) was used in the replication phase. We found 1,924 differentially methylated positions (DMPs) and 438 differentially methylated regions (DMRs) associated with H. pylori infection, most of which were hypermethylated. Significant methylation alterations identified in the initial set were successfully replicated. Furthermore, the H. pylori-associated DMP/Rs showed marked stability ('epigenetic memory') after H. pylori clearance. Interestingly, we found 152 DMRs associated with cancer risk independent of the H. pylori status in normal gastric mucosa. The methylation score derived from three biomarkers was a strong predictor of GC. Finally, the mQTL analysis indicated that the H. pylori- and cancer-specific methylation signatures were minimally affected by genetic variation. The comprehensively characterized methylome changes associated with H. pylori infection and GC risk in our study might serve as potential biomarkers for early cancer progression in tumour-free gastric mucosa.

SURVEY OF GROSS AND HISTOPATHOLOGIC FINDINGS IN TWO WINTERING SUBPOPULATIONS OF SANDHILL CRANES ( ANTIGONE CANADENSIS).

: Sandhill Cranes ( Antigone canadensis) of the midcontinent population (MCP) and Rocky Mountain population (RMP) are migratory game birds with stable populations that travel between Canada and the southern US and Mexico. In the winters of 2012-14, we performed gross and histologic examinations of 43 hunter-harvested Sandhill Cranes in Texas (MCP) and New Mexico (RMP) to assess the impact of disease on populations. Lesions were significantly more common in the MCP relative to the RMP, likely reflecting differential environmental exposure to pathogens and parasites. Grossly, liver nodules and esophageal granulomas were present in 8-39% of birds. In feces from over half of birds, we found coccidian oocysts with mitochondrial gene sequences identical to those of Eimeria gruis and Eimeria reichenowi previously obtained from sympatric Whooping Cranes ( Grus americana). Over one-quarter of birds had liver and cardiac lesions suggestive of disseminated visceral coccidiosis. We documented proliferative colitis due to Cryptosporidium in a wild Sandhill Crane. Additionally, several endoparasites were found in histologic sections from several cranes, including a bird with respiratory trematodiasis and two birds with Tetrameres sp. in the proventriculus associated with ductal ectasia. In addition to describing lesions and parasites that impact Sandhill Crane health, these pathology data may also be relevant for the conservation of endangered Whooping Cranes using a surrogate species approach.

Cytogenetic Profile in 7209 Indian Patients with <i>de novo</i> Acute Leukemia: A Single Centre Study from India

Background: Cytogenetics is one of the most important diagnostic parameters in the classification of acute leukemia. Recurrent chromosomal aberrations in acute leukemia have provided insights into the molecular mechanism of leukemogenesis. The variable frequencies of recurrent cytogenetic markers due to ethical/racial differences have been reported from Western and some Asian countries. Objective: We report cytogenetic data of largest cohort of 7209 adult and pediatric patients with de novo acute leukemia (AL) to determine the prevalence of various cytogenetic sub groups and compare with the Western and Asian population. Material & Methods: The AL patients included 2609 AML (adult: 2042, pediatric: 567), 3708 B-cell-precursor (BCP)-ALL (adult: 1300, pediatric: 2408) and 892 cases of T-ALL (adult: 480, pediatric: 412). Cytogenetic studies included conventional karyotyping and FISH using panel of probes. Results: The incidence of t(8;21) was high, comparable to other Asian countries. In comparison to our series and Western population, t(15;17) was more prevalent in Chinese population. Cytogenetic profiling of BCP-ALL revealed low prevalence of ETV6/RUNX1 in ours as well as other Asian population. The MLL aberrations in BCP-ALL and TLX1 & TLX3 aberrations in T-ALL occurred less frequently in our series as compared with Western population. Conclusion: The present study with a large cohort showed the heterogeneity of AL that involved various factors, such as age, gender and prevalence of distinct cytogenetic subgroups. Our data in comparison with other population based studies revealed differential distribution of some cytogenetic sub-groups indicating geographic heterogeneity due to differential environmental exposure which probably influenced underlying genetic susceptibility.

Differential environmental exposure among non-Indigenous Canadians as a function of sex/gender and race/ethnicity variables: a scoping review.

To determine the extent, range and types of studies of differential environmental chemical exposures among non-Indigenous Canadians as a function of sex/gender and race/ethnicity. Computerized database searches were performed from November to December 2013 using Medline, Embase, CAB Abstracts, Proquest and Scopus to identify relevant studies of environmental exposures among non-Indigenous adults aged ≥18 years in Canada published between 1993 and 2013. Articles were identified for full-text review based on a screening of titles and abstracts and were excluded during this initial review if they focused on environmental exposures in the following populations: 1) Indigenous populations, 2) individuals <15 years of age, 3) pregnant women and associated negative birth outcomes, or 4) non-Canadian populations. Articles were also excluded if the primary focus was on exposures to environmental tobacco smoke, non-chemical occupational hazards, infectious diseases, noise and/or radiation. A full-text review of 78 identified articles systematically assessed how sex/gender and race/ethnicity were considered. Although 59% of studies stratified results by sex, less than half of these offered any explanation of differential exposures. Eighteen of the 78 studies (23%) used terms related to race/ethnicity in their participant descriptions. Of the studies that conducted subgroup analyses of exposure results by race/ethnicity (n=15), a total of 8 also included subgroup analysis by sex. Overall, 3 of the 78 (3%) articles reviewed analyzed environmental exposures as a function of sex/gender and race/ethnicity. The role of sex/gender and race/ethnicity in influencing environmental exposure levels among non-Indigenous Canadians has not been adequately addressed to date.

Meta-analysis of mismatch repair polymorphisms within the cogent consortium for colorectal cancer susceptibility.

In the last four years, Genome-Wide Association Studies (GWAS) have identified sixteen low-penetrance polymorphisms on fourteen different loci associated with colorectal cancer (CRC). Due to the low risks conferred by known common variants, most of the 35% broad-sense heritability estimated by twin studies remains unexplained. Recently our group performed a case-control study for eight Single Nucleotide Polymorphisms (SNPs) in 4 CRC genes. The present investigation is a follow-up of that study. We have genotyped six SNPs that showed a positive association and carried out a meta-analysis based on eight additional studies comprising in total more than 8000 cases and 6000 controls. The estimated recessive odds ratio for one of the SNPs, rs3219489 (MUTYH Q338H), decreased from 1.52 in the original Swedish study, to 1.18 in the Swedish replication, and to 1.08 in the initial meta-analysis. Since the corresponding summary probability value was 0.06, we decided to retrieve additional information for this polymorphism. The incorporation of six further studies resulted in around 13000 cases and 13000 controls. The newly updated OR was 1.03. The results from the present large, multicenter study illustrate the possibility of decreasing effect sizes with increasing samples sizes. Phenotypic heterogeneity, differential environmental exposures, and population specific linkage disequilibrium patterns may explain the observed difference of genetic effects between Sweden and the other investigated cohorts.

Programming of DNA methylation in type 2 diabetes

Programming of DNA methylation in type 2 diabetes

Naive antibody gene-segment frequencies are heritable and unaltered by chronic lymphocyte ablation

A diverse antibody repertoire is essential for an effective adaptive immune response to novel molecular surfaces. Although past studies have observed common patterns of V-segment use, as well as variation in V-segment use between individuals, the relative contributions to variance from genetics, disease, age, and environment have remained unclear. Using high-throughput sequence analysis of monozygotic twins, we show that variation in naive V(H) and D(H) segment use is strongly determined by an individual's germ-line genetic background. The inherited segment-use profiles are resilient to differential environmental exposure, disease processes, and chronic lymphocyte depletion therapy. Signatures of the inherited profiles were observed in class switched germ-line use of each individual. However, despite heritable segment use, the rearranged complementarity-determining region-H3 repertoires remained highly specific to the individual. As it has been previously demonstrated that certain V-segments exhibit biased representation in autoimmunity, lymphoma, and viral infection, we anticipate our findings may provide a unique mechanism for stratifying individual risk profiles in specific diseases.

Invited commentary

The Swedish Twin Registry, which is administered by the Department of Medical Epidemiology and Biostatistics at Karolinska Institute in Stockholm, Sweden, is the largest in the world, containing approximately 86,000 twin pairs. This robust registry was begun in the 1960s by two Swedish investigators, Lars Friberg and Rune Cederlöf, who utilized twin information dating back to 1886 to study risk factors for cancer and cardiovascular diseases while controlling for the genetic propensity to disease. The Registry links easily with the National Patient Registry, which has data on all public inpatient care in Sweden, to identify particular disease processes such as abdominal aortic aneurysms (AAA). The current study, by Wahgren and colleagues, utilizes information gained from this population-based monozygotic and dizygotic twin data. This study is unique in its characterization of the genetic and environmental influences on the development of AAA. Dr Wahgren has provided the most complete and convincing epidemiologic evidence to date for the existence of heritable contributions to aneurysm formation. The major findings of this study are that concordances (identical genetic traits) and correlations (agreement in continuously varying traits) are higher in monozygotic twins than in dizygotic twins, indicating true genetic effects. Data from this study demonstrated that the identical twin of a monozygotic twin with an AAA has a 24% chance of having an AAA. Alternatively stated, the twin has a risk of AAA that is 71 times greater than if the first twin did not have an AAA. Interestingly, gender was not influential, most likely because of the small number of women in the study. Twin births are relatively uncommon, as they represent only 3% of all births in the United States. However, much data can be gained from the study of the presence or absence of complex traits and coexisting environmental influences in this small cohort. We know that environmental factors such as smoking, nutrition, dyslipidemia, infections, and random factors (toxic exposure, spontaneous mutations) may contribute to AAA formation. The twin model is unique in that several key assumptions are made including equivalent environmental exposure and removal of the influence of age. Of the 265 concordant twin pairs (both affected with AAA) in the Swedish Registry, genetic effects accounted for 70% and nonshared environmental effects accounted for the other 30% (no effect from similar or shared environmental effects) of the phenotypic variance. It is well known that first-degree relatives, particularly siblings of AAA patients, have an increased risk for AAA. By studying concordant and discordant twins, these investigators have removed doubts about age variability or differential environmental exposures occurring in childhood and early adulthood. Still, the population in Sweden may be different than more heterogenous populations that exist elsewhere in the world, limiting the value of this study. The government of Sweden provides equal access to medical care and basic education. Even so, inequalities exist where health status may be a function of socioeconomic standing. However, for Sweden and the United States, as well as other countries, this study provides convincing evidence for genetic contributions to AAA development and perhaps evidence for a stronger role in screening siblings of affected persons. Furthermore, Sweden's robust data repository remains an invaluable resource for the scientific study of disease processes in the twin population and is an example for others to follow. Genetic and environmental contributions to abdominal aortic aneurysm development in a twin populationJournal of Vascular SurgeryVol. 51Issue 1PreviewThe contribution of hereditary and environmental factors to the development of abdominal aortic aneurysms (AAAs) is still partly unknown. The aim of this study was to analyze the role of these factors in a large population-based sample of twins. Full-Text PDF Open Archive

Neonatal Nutritional Interventions in the Prevention of Type 1 Diabetes

After completing this article, readers should be able to: 1. Outline the current concepts of the pathogenesis of type 1 diabetes (T1D) with regard to dietary triggers and genetic susceptibility. 2. Discuss the evidence, both epidemiologic and that derived from studies of animal models, that supports the association between infant feeding practices and T1D. 3. Describe the roles for intestinal immunity and permeability in supporting the hypothetical model of cow milk protein mediation of T1D autoimmunity. 4. Delineate the goals and rationale for prospective clinical trials evaluating neonatal nutrition and the development of T1D. 5. List the putative dietary modulators of T1D. Type 1 diabetes (T1D), a disease that has unacceptably high morbidity and mortality, is increasing in incidence, prompting the redoubling of efforts toward its prevention. Progress toward prevention and cure relies on elucidation of the disease’s pathogenesis, which, to date, has remained poorly defined. The defining features of T1D, insulin deficiency and hyperglycemia, result from an immune-mediated destruction of insulin-secreting beta cells in the pancreatic islets. The loss of beta cell mass is believed to be gradual for most individuals, accounting for the sometimes prolonged asymptomatic periods of autoimmunity preceding overt diabetes (Fig. 1). Indeed, the chronic autoimmune nature of the disease is well established, as is the genetic predisposition. Specific associations with molecules of the human lymphocyte antigen (HLA) define both susceptibility to and protection from T1D. However, T1D is a polygenic disorder with more than 20 loci associated with susceptibility or resistance to the disease, of which the HLA may account for less than 50% of the genetic predisposition. Genetics clearly comprises a major component of the development of T1D, but the interaction between the environment and the immune system abnormalities is believed to weigh heavily in disease development. Indeed, trends in T1D incidence, both geographic and temporal, suggest a strong …

Differential environmental exposure alters NMDA but not AMPA receptor subunit expression in nucleus accumbens core and shell

Environmentally enriched (EE) rats show neurobehavioral differences relative to less stimulated, socially isolated (SI) littermates. Although experience-dependent cortical changes are presumed to underlie learning differences in these differentially housed animals, EE rats show reduced reward-seeking behavior and altered cytoarchitecture and dopaminergic function in the nucleus accumbens (NAcc), a brain area involved in adaptive, goal-directed activity. Given that glutamate and its interaction with dopamine regulate motivational and associative processing in this brain region, we assessed expression of the NR1 subunit of the N-methyl- d-aspartate (NMDA) receptor and the GluR1 subunit of the α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in the NAcc core and shell of EE and SI rats. Our results indicate fewer intensely stained NR1 immunopositive neurons in both core and shell of EE relative to SI rats. No such differences were observed in GluR1 staining. These results suggest that environmental experience alters NMDA but not AMPA receptor expression in NAcc. Increased expression of the NR1 subunit in the NAcc of SI rats may augment impulsivity and reward-seeking behavior relative to EE rats.

Discordant MZ Twins With Cleft Lip and Palate: A Model for Identifying Genes in Complex Traits

AbstractMonozygotic (MZ) twins may be discordant for complex traits due to differential environmental exposure in utero, epigenetic variability in imprinting, X chromosome inactivation, or stochastic effects. Occasionally MZ twins may be discordant for chromosomal and single gene disorders due to somatic mosaicism. For complex traits, which are due to the interactive effects of multiple genes and environmental factors, the affected twin of a discordant MZ pair offers the possibility for identifying somatic mutations in candidate genes. DNA sequencing of candidate genes in discordant MZ twins can identify those rare etiologic mutational events responsible for the different phenotypes since the confounding effects of common single nucleotide polymorphisms are eliminated, as DNA sequences should be identical in MZ pairs. In this report we describe the extensive DNA sequencing of 18 candidate genes in a sample of MZ and dizygotic (DZ) twins with nonsyndromic cleft lip with or without cleft palate. We were unable to identify any somatic differences in approximately 34 Kb of DNA sequenced in 13 MZ pairs, for a total of approximately 900 Kb of sequence comparisons, supporting the hypothesis that nonetiologic posttwinning mutations are rare. While no etiologic variants were identified in this study, sequence comparisons of discordant MZ twins can serve as a tool for identifying etiologic mutations in clefting and other complex traits.

Discordant MZ Twins With Cleft Lip and Palate: A Model for Identifying Genes in Complex Traits

Monozygotic (MZ) twins may be discordant for complex traits due to differential environmental exposure in utero, epigenetic variability in imprinting, X chromosome inactivation, or stochastic effects. Occasionally MZ twins may be discordant for chromosomal and single gene disorders due to somatic mosaicism. For complex traits, which are due to the interactive effects of multiple genes and environmental factors, the affected twin of a discordant MZ pair offers the possibility for identifying somatic mutations in candidate genes. DNA sequencing of candidate genes in discordant MZ twins can identify those rare etiologic mutational events responsible for the different phenotypes since the confounding effects of common single nucleotide polymorphisms are eliminated, as DNA sequences should be identical in MZ pairs. In this report we describe the extensive DNA sequencing of 18 candidate genes in a sample of MZ and dizygotic (DZ) twins with nonsyndromic cleft lip with or without cleft palate. We were unable to identify any somatic differences in approximately 34 Kb of DNA sequenced in 13 MZ pairs, for a total of approximately 900 Kb of sequence comparisons, supporting the hypothesis that nonetiologic posttwinning mutations are rare. While no etiologic variants were identified in this study, sequence comparisons of discordant MZ twins can serve as a tool for identifying etiologic mutations in clefting and other complex traits.

Are Asian and Pacific Islander Children Overlooked for Health Risks?

As the number of Asian and Pacific Islander (API) American children increases, emerging health disparities become evident, indicating several contributing factors with powerful implications for environmental risk assessment. Differential environmental exposures and social, economic, and cultural influences contribute to the vulnerability observed in these groups. This article presents an overview of the major environmental constraints faced by the API community and proposes a research agenda and protocol for translational research sensitive to this population. As health inequities are increasingly recognized among APIs, there is an urgent need for the government and the scientific research community to better coordinate health research, data collection, and epidemiological studies on this macroethnic group in order to develop more culturally informed pediatric environmental risk assessments.

Specific chromosomal changes in patients with acute nonlymphocytic leukemia from India

We analysed forty consecutive patients with acute nonlymphocytic leukemia (ANLL) using methotrexate cell synchronization and 24 h-unstimulated cultures of bone marrow cells to determine the incidence of chromosomal aberrations and the association of specific anomalies with FAB morphological subtypes, in an Indian population. All patients demonstrated an abnormal karyotypic pattern. The specific chromosomal changes viz., t(9;22), t(8;21), t(15;17), t/del(11q), 12p- were found in M 1(3/5), M2(8/15), M3(8/8), M4(1/1) M5(2/4) and M2Ba(1/1) (M2 with Basophilia) patients. Abnormalities of 11q were also noted in two M2 patients showing monocytic involvement. A translocation involving chromosomes 6 and 9 was seen in one patient with M1 and two patients with M2. An inv(16) was observed in M1 (one case), M2 (two cases) and M6 (one case). A del(16) was noted in an M4 case. Although t(9;22) is frequently associated with M1 patients, it was also detected in M2 (two patients) and M4 (one patient). Among all the FAB specific anomalies described above, t(8;21) and t(15;17) were observed only in M2 and M3 patients, respectively. Interestingly, one M2 patient had two independent clones, one with t(8;21) and t(9;11). Deletion or translocation involving 11q was found in a Ph positive M4 patient. New structural rearrangements such as t(1;7) (q32;q36) in association with t(8;21), and t(14;22) (q32;q11) in association with del(11)(q23) were detected in a M2 and a M5 patient, respectively. In conclusion, our studies have revealed that the incidence of FAB specific abnormalities viz., t(8;21); t(15;17), t(9;22), t/del(11q) and also other recurrent anomalies viz., -7/7q-, +8 is much higher in our patients, as compared with other countries. This difference may be attributed to the influence of differential environmental exposure to unknown carcinogenic agents.

Plasticity of GFAP-immunoreactive astrocyte size and number in visual cortex of rats reared in complex environments

Previous studies have indicated effects of postweaning rearing environment complexity on astrocyte nuclei. This study examined the effects of rearing for 10, 30 or 67 days in a complex (EC), social (SC) or individual cage (IC) environment upon glial fibrillary acidic protein (GFAP) immunoreactive astrocytes of the occipital cortex. EC rats exposed to their environment for 30 days or longer had a greater surface density of astrocytic processes (Sv) than SC or IC rats. The greater surface density of EC cortical astrocytes appeared to be due to an increase in the mean size of astrocytes after 30 days of differential environmental exposure. After 67 days of environmental exposure, however, the greater Sv appeared to be due to an increase in the number of astrocytes. Astrocytic plasticity appears to develop rather slowly during exposure to a complex environment and appears to involve two stages. The first stage is a hypertrophy of existing astrocytes and the second stage involves proliferation or retarded death of astrocytes. These changes may be related to brain information processing since astrocytes are known modulators of synaptic activity and may possibly serve as regulators of synaptic density.

Serum Protein Electrophoretic Fractions Among Negro and White Subjects in Evans County, Georgia

Patterns of serum albumin and globulin fractions in Negro and white subjects by age, race, sex and social class are presented. Strength of association of these proteins with certain physiological variables is shown. It appears likely that the serum albumin difference observed among older Negro male and white subjects has been environmentally determined (? factors). A difference in the pattern of alpha2 and beta globulin concentration among Negro and white subjects was observed. The reason for the racial differences in the average concentration of the latter proteins is not clear from an analysis of the available data. Negro subjects in Evans County had a significantly higher serum gamma globulin concentration than did white subjects. The latter finding was not explained by a differential occurrence of disease or a differential environmental exposure as judged by social class comparisons, personal examinations and a knowledge of the comnmunity ecology. The implication is that genetic factors may be a stronger determinant of the racial difference in total circulating gamma globulin concentration. The frequency distribution of gamma globulin among Negro male and female subjects was bimodal. The reason for this pattern was not evident in the data gathered. Studies are contemplated which will be designed to examine further the observations and questions outlined herein.