Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis

This review describes how studies on interactions between genetic variants, and environmental factors, mainly smoking, contribute to the understanding of how autoimmunity to post-translationally (citrullinated) proteins/peptides may occur and potentially contribute to certain subsets of rheumatoid arthritis. A main message is that studies on specific immune mechanisms in a complex and heterogeneous disease like RA should be undertaken with the help of results from genetic epidemiology. By those means, it may be possible to identify subsets of RA in a way that in the end allows development and testing of precise and subset-specific interventions against environment as well as genetically defined molecular pathways, in particular those that regulate specific immune responses.     

The molecular epidemiology of parasite infections: tools and applications

Molecular epidemiology, broadly defined, is the application of molecular genetic techniques to the dynamics of disease in a population. In this review, we briefly describe molecular and analytical tools available for molecular epidemiological studies and then provide an overview of how they can be applied to better understand parasitic disease. A range of new molecular tools have been developed in recent years, allowing for the direct examination of parasites from clinical or environmental samples, and providing access to relatively cheap, rapid, high throughput molecular assays. At the same time, new analytical approaches, in particular those derived from coalescent theory, have been developed to provide more robust estimates of evolutionary processes and demographic parameters from multilocus, genotypic data. To date, the primary application of molecular epidemiology has been to provide specific and sensitive identification of parasites and to resolve taxonomic issues, particularly at the species level and below. Population genetic studies have also been used to determine the extent of genetic diversity among populations of parasites and the degree to which this diversity is associated with different host cycles or epidemiologically important phenotypes. Many of these studies have also shed new light on transmission cycles of parasites, particularly the extent to which zoonotic transmission occurs, and on the prevalence and importance of mixed infections with different parasite species or intraspecific variants (polyparasitism). A major challenge, and one which is now being addressed by an increasing number of studies, is to find and utilize genetic markers for complex traits of epidemiological significance, such as drug resistance, zoonotic potential and virulence.     

Genetic control of vectorial competence in Aedes mosquitoes

The transmission of pathogens by arthropods is dependent on the relationships that exist between the pathogen, the invertebrate host (the vector) and the vertebrate host, each of which is influenced by environmental variations. Particular attention is given to the knowledge of intrinsic factors and the mechanisms controlling the ability of vectors to transmit pathogens (viruses or parasites). Polymorphism in the expression of susceptibility to oral infection has been shown to occur among geographical samples of mosquitoes. It has been proven that intraspecific variations in vector competence are controlled by one or more genes and expressed in variable proportions within a mosquito population. Recent advances in molecular biology have facilitated accessibility of nucleic acid sequence data. These new techniques allow one to analyse the genotype distribution within and among populations. Population genetic studies are currently used to understand the evolution of species differentiation and provide indications on genetic relationship among field vector populations. Estimations of gene flow with respect to vector capacity have provided rich insight into vector species complexes. Knowledge of intraspecies variation is important for the understanding of vector transmission, disease epidemiology and disease control. In this article, two examples are presented to illustrate the contribution of population genetic studies to the understanding of epidemiology of arthropod-borne diseases: Aedes polyneniensis, a vector of human lymphatic filariasis and Aedes aegypti, the vector of dengue viruses.     

Schizophrenia genetics at the millennium: cautious optimism

The views expressed here are the personal opinions of the authors and should not be taken to imply agreement or endorsement by the National Institutes of Health or the Federal Government.
As the new millennium approaches, research into the genetic aspects of schizophrenia has already made an impressive start toward an integrated model which is discovering roles for genetic agents, environmental agents and experiences, and chance factors. The best model follows that proposed for understanding such complex diseases as coronary artery disease and diabetes. Genetic information has come from both genetic epidemiology and molecular genetics. Evidence for gene regions on 6p and 8p gives the strongest support for harboring schizophrenia susceptibility genes, based on international collaborative studies that "generally" replicate one another; evidence for regions on 3p, 5q, 9p, 20p, and 22q, while less compelling, will encourage focused work. Determining the steps between the regions and the phenotype will challenge the next generation of scientists.     

Genome-scale approaches to the epigenetics of common human disease

Traditionally, the pathology of human disease has been focused on microscopic examination of affected tissues, chemical and biochemical analysis of biopsy samples, other available samples of convenience, such as blood, and noninvasive or invasive imaging of varying complexity, in order to classify disease and illuminate its mechanistic basis. The molecular age has complemented this armamentarium with gene expression arrays and selective analysis of individual genes. However, we are entering a new era of epigenomic profiling, i.e., genome-scale analysis of cell-heritable nonsequence genetic change, such as DNA methylation. The epigenome offers access to stable measurements of cellular state and to biobanked material for large-scale epidemiological studies. Some of these genome-scale technologies are beginning to be applied to create the new field of epigenetic epidemiology.     

Developmental origin and fate of meso-diencephalic dopamine neurons

Specific vulnerability of substantia nigra compacta neurons as compared to ventral tegmental area neurons, as emphasized in Parkinson's disease, has been studied for many years and is still not well understood. The molecular codes and mechanisms that drive development of these structures have recently been studied through the use of elegant genetic ablation experiments. The data suggested that specific genes at specific anatomical positions in the ventricular zone are crucial to drive development of young neurons into the direction of the dopaminergic phenotype. In addition, it has become clear the these dopaminergic neurons are present in the diencephalon and in the mesencephalon and that they may contain a specific molecular signature that defines specific subsets in terms of position and function. The data indicate that these specific subsets may explain the specific response of these neurons to toxins and genetic ablation.     

The cryptic interplay between systemic lupus erythematosus and infections

The underlying trigger for systemic lupus erythematosus (SLE) has remained elusive, and multiple interacting environmental and genetic factors likely contribute to the onset and perpetuation of the disease. Among environmental influences, infectious agents have been suggested to play a pivotal role in driving autoimmunity pathogenesis via structural or functional molecular mimicry, the expression of proteins that induce cross-reactive responses against self-antigens, and the aberrant activation or apoptosis of different immune system cells in the context of a peculiar genetic background. The increased viral load and changing subsets of lytic or latent viral proteins observed in selected populations with SLE have indicated that common viruses, such as Epstein–Barr virus, parvovirus B19, cytomegalovirus, retroviruses and transfusion-transmitted viruses, might be triggers for this disease. Alternatively, some infectious agents might exert a protective effect from autoimmunity. Existing achievements have not been fully investigated and clarified. Thus, the aim of this review is to analyze the medical literature within the last 15 years regarding the role of infectious agents in the pathogenesis of SLE.     

Genes for atopy and asthma

The genetic basis of atopic diseases is represented by a complex network of interacting genes or common genetic variants rather than a few disease-causing mutations. The individual risk of developing asthma or other atopic diseases is defined by the concert of interaction of these hereditary factors and environmental stimuli. The first decade of asthma genetics has been spent identifying those genetic regions through linkage analysis, which are likely to harbour asthma genes. At the same time, several candidate genes for asthma and atopy have been identified and their variants characterized, some of them even to a level of functional understanding. Rather than adding new candidate regions and genes to the pool of knowledge, the interest in the past year has moved to a more sophisticated statistical evaluation of the given linkage and association data and a more precise definition of so-called 'intermediate phenotypes'. Some of the results are quite surprising and have helped us to understand the underlying pathophysiology. For example, the distinct clinical traits of asthma, such as atopic sensitization or inflammation of the bronchial epithelium, seem to be defined by distinct subsets of predisposing genes. At the same time, the very same subsets of genes might underlie further clinical diseases with similar clinical features. Polymorphisms within IL-4R alpha, which had been shown to be associated with asthma and atopy, have also been shown to be associated with kidney allograft rejection, systemic lupus erythematosus and Crohn's disease. There might thus just be a few asthma and atopy genes. Finally, asthma and atopy genetics has now reached a point of practical application. The genetics of susceptibility to environmental stimuli, pharmacogenetic data, and the advent of new pharmaceutical targets will greatly influence the whole field of asthma and atopy.     

Saliviruses—the first knowledge about a newly discovered human picornavirus

The salivirus, first discovered in the year 2009, is a member of the large and growing family Picornaviridae. At present, the genus Salivirus contains 1 species Salivirus A and 2 genotypes, Salivirus A1 and Salivirus A2. Salivirus has been identified in humans and chimpanzees and may cause acute gastroenteritis in humans, having been detected in 0% to 8.7% of fecal samples collected from gastroenteritis in different human populations. Salivirus is ubiquitous in wastewater of human origin and river water specimens worldwide and represents a potential indicator human RNA virus for monitoring of environmental samples. This review summarizes the current knowledge on saliviruses including discovery, taxonomy, genome structure, and genetic diversity; covers all aspects of infection including epidemiology, molecular epidemiology, clinical feature, host species, environmental characteristics, and laboratory diagnosis; and gives a summary of possible future perspectives.     

Zoonotic potential and molecular epidemiology of Giardia species and giardiasis

Molecular diagnostic tools have been used recently in assessing the taxonomy, zoonotic potential, and transmission of Giardia species and giardiasis in humans and animals. The results of these studies have firmly established giardiasis as a zoonotic disease, although host adaptation at the genotype and subtype levels has reduced the likelihood of zoonotic transmission. These studies have also identified variations in the distribution of Giardia duodenalis genotypes among geographic areas and between domestic and wild ruminants and differences in clinical manifestations and outbreak potentials of assemblages A and B. Nevertheless, our efforts in characterizing the molecular epidemiology of giardiasis and the roles of various animals in the transmission of human giardiasis are compromised by the lack of case-control and longitudinal cohort studies and the sampling and testing of humans and animals living in the same community, the frequent occurrence of infections with mixed genotypes and subtypes, and the apparent heterozygosity at some genetic loci for some G. duodenalis genotypes. With the increased usage of multilocus genotyping tools, the development of next-generation subtyping tools, the integration of molecular analysis in epidemiological studies, and an improved understanding of the population genetics of G. duodenalis in humans and animals, we should soon have a better appreciation of the molecular epidemiology of giardiasis, the disease burden of zoonotic transmission, the taxonomy status and virulences of various G. duodenalis genotypes, and the ecology of environmental contamination.     

Parkinson's disease: Exit toxins,enter genetics

Parkinson's disease was long considered a non-hereditary disorder. Despite extensive research trying to find environmental risk factors for the disease, genetic variants now stand out as the major causative factor. Since a number of genes have been implicated in the pathogenesis it seems likely that several molecular pathways and downstream effectors can affect the trophic support and/or the survival of dopamine neurons, subsequently leading to Parkinson's disease. The present review describes how toxin-based animal models have been valuable tools in trying to find the underlying mechanisms of disease, and how identification of disease-linked genes in humans has led to the development of new transgenic rodent models. The review also describes the current status of the most common genetic susceptibility factors for Parkinson's disease identified up to today.     

UKEMS/Dutch EMS-sponsored workshop on biomarkers of exposure and oxidative DNA damage & 7th GUM-32P-postlabelling workshop, University of Münster, Münster, Germany, 28-29 March 2011

Environmental exposures are a major concern for human cancer. However, the precise contribution of specific risk factors and their interactions, both with each other and with genotype, continue to be difficult to elucidate. The exposome is the comprehensive characterisation of an individual's lifetime exposure history (Wild, C. P. (2009) Environmental exposure measurement in cancer epidemiology. Mutagenesis, 24, 117-125). Unravelling complex environmental and genetic aetiologies in order to plan effective public health interventions demands that both environmental exposures and genetic variations are reliably measured. The development, validation and application of biomarkers of exposure are manifestly critical to the future of cancer epidemiology. The aim of this workshop at the University of Münster was to discuss the current status of exposure biomarkers in cancer molecular epidemiology as well as new findings achieved by applying the methods to studies of mechanisms of human cancer. Day 1 focused on biomarkers of exposure (i.e. carcinogen DNA adducts), effect and susceptibility to gain greater understanding of environmental cancer risks and their modulation. Day 2 focused on the role of oxidative stress and DNA damage in human carcinogenesis including methodologies used for the measurement of oxidatively induced DNA lesions in human cells or tissues and the possible use of these lesions as cancer biomarkers.     

Molecular epidemiology of tick-borne encephalitis

The review presents information on the development of studies into the molecular epidemiology of tick-borne encephalitis (TBE) in Russia and foreign countries. The existence of three major virus genotypes has been established by various techniques, such as genomic fragment sequencing, molecular hybridization using genotype-specific probes, and restriction fragment length polymorphism test. Each of the genotypes prevails in different parts of a natural habitat; the Ural-Siberian genotype (a Siberian subtype) is most commonly encountered. The genetic differences between the strains belonging to different genotypes are great and comparable with differences between some mammalian flaviviruses transmitted by ticks (viruses of a TBE complex). Further studies of the molecular epidemiology of TBE are of importance in understanding the evolution of the causative agent, improving the taxonomy and the classification of flavivuruses, and designing highly effective methods for the specific diagnosis, prevention, and treatment of the disease.     

Molecular epidemiology of tuberculosis: current insights

Molecular epidemiologic studies of tuberculosis (TB) have focused largely on utilizing molecular techniques to address short- and long-term epidemiologic questions, such as in outbreak investigations and in assessing the global dissemination of strains, respectively. This is done primarily by examining the extent of genetic diversity of clinical strains of Mycobacterium tuberculosis. When molecular methods are used in conjunction with classical epidemiology, their utility for TB control has been realized. For instance, molecular epidemiologic studies have added much-needed accuracy and precision in describing transmission dynamics, and they have facilitated investigation of previously unresolved issues, such as estimates of recent-versus-reactive disease and the extent of exogenous reinfection. In addition, there is mounting evidence to suggest that specific strains of M. tuberculosis belonging to discrete phylogenetic clusters (lineages) may differ in virulence, pathogenesis, and epidemiologic characteristics, all of which may significantly impact TB control and vaccine development strategies. Here, we review the current methods, concepts, and applications of molecular approaches used to better understand the epidemiology of TB.     

Genetic dissection of inflammatory bowel disease: unravelling etiology and improving diagnostics

Over the past 10 years, remarkable advances in the mapping and identification of genes involved in susceptibility to inflammatory bowel disease have been witnessed. Most notable among these advances has been the discovery of variants in the CARD15, DLG5, SLC22A4 and SLC22A5 genes, which are associated with increased risk of inflammatory bowel disease or specifically Crohn’s disease. These discoveries have provided critical new insights into the molecular pathophysiology of inflammatory bowel disease and the pathways wherein genetic and environmental factors such as enteric bacterial flora may interact to trigger immune dysregulation and intestinal inflammation. This review will outline the discovery of these inflammatory bowel disease-related genes, describe future prospects for further inflammatory bowel disease gene identification, and consider the impact of a genetic understanding of inflammatory bowel disease on future clinical practice.     

Application of molecular typing to the epidemiology of Streptococcus pneumoniae.

The spread of antibiotic resistance and the development of new vaccines have focused attention on the epidemiology of Streptococcus pneumoniae over recent years. While serotyping and the determination of antibiotic resistance remain primary methods for characterising pneumococci, molecular typing can add greater discrimination and complementary information. Methods based on restriction fragment length polymorphism within total DNA or non-specific polymerase chain reaction provide information representative of the whole genome and can be used to recognise closely related isolates from different sources, whether in the investigation of possible cross infection at the local level or in the investigation of national or international spread of antibiotic resistant strains. Fingerprinting of penicillin binding protein genes adds further information in the analysis of penicillin resistant isolates. The use of a combination of typing methods to analyse both the genome as a whole and specific loci has led to the realisation that pneumococci undergo horizontal gene transfer much more often than most other bacterial species. In particular the spread of penicillin resistance has been characterised by a combination of the spread of epidemic strains, transfer of chromosomal resistance genes from such strains into other genetic backgrounds, and transfer of capsule genes resulting in the switch of serotypes within strains. In the future molecular typing will have an important role in discovering whether widespread vaccination leads to genetic modification of the pneumococcal population causing invasive disease.     

A review of the genetic epidemiology of resistance to parasitic disease and atopic asthma: common variants for common phenotypes?

PURPOSE OF REVIEW: An inverse relationship between resistance to certain parasitic diseases and measures of atopy and asthma has long been observed. A possible explanation is that genetic determinants which confer protection against detrimental worm burdens are the same determinants involved in atopic asthma. The focus of this review is to consider the potential candidate genes that have been elucidated as part of molecular, genomic and genetic studies of parasite biology, host-parasite interactions and classic genetic epidemiology studies on parasitic disease and allergic asthma. RECENT FINDINGS: Comparative studies of the Plasmodium and Schistosoma spp. genomes have revealed a number of proteins that are homologous to humans. A number of linkage and association studies on susceptibility/resistance to parasitic diseases, including malaria and schistosomiasis, overlap with associations that have been identified for susceptibility to atopy and asthma. SUMMARY: In response to parasitic approaches in maintaining survival, the human host has evolved genetic adaptations that minimize severe manifestations of disease, which conversely appear to contribute to allergic disease. A clearer understanding of this process will elucidate the complex pathways and mechanisms involved in these traits.     

Bridging the gap from genetic association to functional understanding: the next generation of mouse models of multiple sclerosis

Multiple sclerosis (MS) is a disabling autoimmune disease of the central nervous system, which affects approximately 0.1% of the population with variable degrees of severity. Disease susceptibility is jointly determined by genetic predisposition and environmental contribution. However, as only a handful of genetic risk factors have been investigated beyond initial genome-wide association studies and environmental factors are largely unidentified, the exact mechanism of how these associations interact remains speculative. Our current understanding of this complex and heterogeneous disease has been advanced by experimental data obtained from animal modeling, with particular focus on the mouse MS model, experimental autoimmune encephalomyelitis. Manipulation of the mouse genome to study genetic risk factors has largely proved informative, but it also has limitations. Integration effects of transgene insertion, gene copy number, and expression variation, as well as differences in regulatory elements between mouse and human, are some of the hurdles faced when using such models to understand human gene variants in mice. Furthermore, as the list of MS disease-associated genetic variants continues to increase, so does the demand to find new approaches to study them. A new generation of humanized mice aims to tighten the gap between mouse and human, such that MS-associated genetic variants can be modeled more physiologically and systematically.     

Molecular pathogenesis, experimental models and new therapeutic strategies for Parkinson's disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by rigidity, bradykinesia, postural instability and resting tremor. The major symptoms are related to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The recent discovery of PARK genes causing familial forms of PD has led to a new approach in the study of the disease. The cause and pathogenesis of PD remains unknown; mitochondrial dysfunction, oxidative damage, endoplasmic reticulum stress, failure of the ubiquitin-proteasome system, environmental factors and genetic predisposition might all be involved. Toxin-induced PD animal models and genetic mouse models that mimic familial PD have contributed to investigating the molecular pathogenesis and treatment of the disease. Recently, neurogenesis in the striatum and subventricular zones in PD animal models have been reported. This review discusses molecular pathogenesis, experimental disease models and recent cell-based therapeutic approaches for PD.