Role of genetics in the diagnosis and prognosis of Crohn's disease

Considering epidemiological, genetic and immunological data, we can conclude that the inflammatory bowel diseases are heterogeneous disorders of multifactorial etiology in which hereditability and environment interact to produce the disease. It is probable that patients have a genetic predisposition for the development of the disease coupled with disturbances in immunoregulation. Several genes have been so far related to the diagnosis of Crohn's disease. Those genes are related to innate pattern recognition receptors, to epithelial barrier homeostasis and maintenance of epithelial barrier integrity, to autophagy and to lymphocyte differentiation. So far, the most strong and replicated associations with Crohn's disease have been done with NOD2, IL23R and ATG16L1 genes. Many genes have so far been implicated in prognosis of Crohn's disease and many attempts have been made to classify genetic profiles in Crohn's disease. CARD15 seems not only a susceptibility gene, but also a disease-modifier gene for Crohn's disease. Enriching our understanding on Crohn's disease genetics is important but when combining genetic data with functional data the outcome could be of major importance to clinicians.     

Neuro-Behçet Disease,Neuro-Sweet Disease,and Spectrum Disorders

Behçet disease and its related disorder, Sweet disease, are multifactorial disorders whose susceptibility loci have been identified in the genes of various immunological factors aside from human leukocyte antigens. The neurological involvement of these diseases, including encephalitis, myelitis, and meningitis, referred to as neuro-Behçet disease (NBD) and neuro-Sweet disease (NSD) respectively, is sometimes difficult to diagnose, especially when the characteristic mucocutaneous symptoms do not precede neurological symptoms or when characteristics of both diseases are present in a single patient. NBD and NSD constitute a spectrum of diseases that are differentiated according to the combination of risk factors, including the genetic background. Encephalitis, myelitis, and meningitis similar to NBD or NSD can be diagnosed as spectrum disorders, even if the characteristic mucocutaneous symptoms fail to be detected. Understanding these conditions as a disease spectrum may help elucidate the disease pathogenesis and assist in the development of therapeutic agents.     

Viruses, autophagy genes, and Crohn's disease

The etiology of the intestinal disease Crohn's disease involves genetic factors as well as ill-defined environmental agents. Several genetic variants linked to this disease are associated with autophagy, a process that is critical for proper responses to viral infections. While a role for viruses in this disease remains speculative, accumulating evidence indicate that this possibility requires serious consideration. In this review, we will examine the three-way relationship between viruses, autophagy genes, and Crohn's disease and discuss how host-pathogen interactions can mediate complex inflammatory disorders.     

Dissecting the genetic heterogeneity of gallbladder stone formation

Gallstone disease affects almost 20% of individuals in Westernized countries. As its incidence in the developing countries is rising considerably, currently, it is the second most common gastroenterological condition worldwide. Gallstone formation is driven by an interaction between genetic and environmental risk factors. Previous studies have demonstrated that the genetic background accounts for ~25% of the total disease risk. Linkage and case-control studies of candidate genes and recent genome-wide studies have identified multiple lithogenic genes, in particular the hepatocanalicular cholesterol transporter ABCG5/G8 and the bilirubin conjugating enzyme UGT1A1, as major genetic determinants of gallstones in humans. In this review, we summarize the recent findings related to the genetics of cholelithiasis, update the "inventory" of human lithogenic genes, and relate the genetic studies to the pathobiologic background of the disease. In closing, future applications of genetic testing for gallstone carriers and asymptomatic family members are addressed.     

The new genetics and chronic obstructive pulmonary disease

Epidemiological and family studies provide evidence for genetic factors contributing to chronic obstructive airways disease (COPD) susceptibility. Studies to date have focused on candidate genes implicated in the pathogenesis of the disease. In general, many of these studies have been underpowered or have not been extensive enough in investigating the full extent of genetic variation in these genes. This has resulted in conflicting data with potential false positives or findings that have not been replicated. More recently, larger studies and extensive coverage of candidate genes have implicated genetic variants that may contribute to the disease. The use of unbiased genome-wide association studies offer the prospect of identifying new genes involved in COPD susceptibility and genetic modifiers of disease phenotypes. There is cause for optimism as a number of major complex diseases have been successfully tackled in this way. The review will highlight what has been achieved by genetic studies to date, some of the related problems and the future impact of high throughput technologies such as genome-wide association studies on our understanding of the genetic basis of COPD.     

原发性高尿酸血症及痛风易感基因研究进展

原发性高尿酸血症及痛风为多基因遗传性疾病.近期对该病进行的全基因组关联分析(GWAS)发现了多个与尿酸排泄及痛风发病相关的基因,为该病的病因学研究、疾病风险预测及防治提供了新思路.本文就此作一综述.

Abstract：

Primary hyperuricemia and gout are multifactorial conditions with strong genetic components. recently genome-wide association studies (GWAS) have revealed that several genes are related to primary hyperuricemia and gout which offers a thought for the research into the etiology, disease risk prediction, and prevention and treatment of this disease.     

Genetic Backgrounds of Asthma and COPD

Asthma and COPD are complex diseases with strong genetic and environmental components. These common pulmonary diseases have both different and similar clinical features. Molecular genetic techniques are being used to improve understanding of these common late onset disorders. Recently, several genes and genetic loci associated with increased susceptibility to asthma and COPD have been described. Many of these genes are expressed in the lung tissues, indicating that events in lung tissues might drive disease processes. Lung tissues are rich sources of innate danger signals, and an increased understanding of how the lung tissues communicate with the immune system to maintain healthy tissue might provide new insights into the pathogenesis of chronic inflammatory lung diseases in which injury and repair are in disequilibrium. Given that the innate immune system is at the interface between the airways and environmental insults, genetic polymorphisms in genes related to the innate immune system are likely to affect susceptibility to both asthma and CopD. In addition, some findings from genetic studies provide molecular support for the point of view proposed in the Dutch hypothesis regarding the relationship between asthma and COPD, which highlights the complexity of the pathways that can induce small airway disease and suggests that there is a continuum between asthma and COPD.     

Inflammatory bowel disease:Pathogenesis

Inflammatory bowel disease(IBD),including Crohn’s disease and ulcerative colitis,is characterized by chronic relapsing intestinal inflammation.It has been a worldwide health-care problem with a continually increasing incidence.It is thought that IBD results from an aberrant and continuing immune response to the microbes in the gut,catalyzed by the genetic susceptibility of the individual.Although the etiology of IBD remains largely unknown,it involves a complex interaction between the genetic,environmental or microbial factors and the immune responses.Of the four components of IBD pathogenesis,most rapid progress has been made in the genetic study of gut inflammation.The latest internationally collaborative studies have ascertained 163susceptibility gene loci for IBD.The genes implicated in childhood-onset and adult-onset IBD overlap,suggesting similar genetic predispositions.However,the fact that genetic factors account for only a portion of overall disease variance indicates that microbial and environmental factors may interact with genetic elements in the pathogenesis of IBD.Meanwhile,the adaptive immune response has been classically considered to play a major role in the pathogenesis of IBD,as new studies in immunology and genetics have clarified that the innate immune response maintains the same importance in inducing gut inflammation.Recent progress in understanding IBD pathogenesis sheds lights on relevant disease mechanisms,including the innate and adaptive immunity,and the interactions between genetic factors and microbial and environmental cues.In this review,we provide an update on the major advances that have occurred in above areas.     

Significant conservation of synthetic lethal genetic interaction networks between distantly related eukaryotes

Synthetic lethal genetic interaction networks define genes that work together to control essential functions and have been studied extensively in Saccharomyces cerevisiae using the synthetic genetic array (SGA) analysis technique (ScSGA). The extent to which synthetic lethal or other genetic interaction networks are conserved between species remains uncertain. To address this question, we compared literature-curated and experimentally derived genetic interaction networks for two distantly related yeasts, Schizosaccharomyces pombe and S. cerevisiae. We find that 23% of interactions in a novel, high-quality S. pombe literature-curated network are conserved in the existing S. cerevisiae network. Next, we developed a method, called S. pombe SGA analysis (SpSGA), enabling rapid, high-throughput isolation of genetic interactions in this species. Direct comparison by SpSGA and ScSGA of approximately 220 genes involved in DNA replication, the DNA damage response, chromatin remodeling, intracellular transport, and other processes revealed that approximately 29% of genetic interactions are common to both species, with the remainder exhibiting unique, species-specific patterns of genetic connectivity. We define a conserved yeast network (CYN) composed of 106 genes and 144 interactions and suggest that this network may help understand the shared biology of diverse eukaryotic species.     

Genetics of chronic obstructive pulmonary disease

Variability in the susceptibility to develop chronic obstructive pulmonary disease (COPD) is related to both genetic and environmental factors. COPD is likely a genetically complex disease, but severe alpha 1-antitrypsin (AAT) deficiency [e.g., protease inhibitor (PI) Z] remains the only proven genetic risk factor for COPD. Even among PI Z individuals, substantial variability in lung function is observed, suggesting that genetic modifiers may influence the expression of lung disease in severe AAT deficiency. The variable development of COPD in smokers without alpha 1-antitrypsin deficiency and the familial aggregation of lung function measurements also suggest the presence of genetic influences on lung function growth and decline leading to COPD. Many candidate gene loci have been investigated as potential COPD genetic determinants by case-control genetic association studies. However, inconsistent results of these association studies have been frequent. Genetic heterogeneity and population stratification are two potential reasons for the conflicting findings between association studies. Linkage analysis studies have recently been published that may identify regions of the genome that contain COPD susceptibility genes. Future investigations of genetic influences in COPD should consider the use of family-based designs for association studies and the study of positional candidate genes within regions of linkage.     

Molecular genetics of essential hypertension

Hypertension is a major public health problem in the developing as well as in developed countries due to its high prevalence and its association with coronary heart disease, renal disease, stroke, peripheral vascular disease, and related disorders. Essential hypertension (EH) is the most common diagnosis in this disease, suggesting that a monocausal etiology has not been identified. However, a number of risk factors associated with EH have also been identified such as age, sex, demographic, environmental, genetic, and vascular factors. Recent advances in molecular biological research had achieved clarifying the molecular basis of Mendelian hypertensive disorders. Molecular genetic studies have now identified mutations in several genes that cause Mendelian forms of hypertension in humans. However, none of the single genetic variants has emerged from linkage or association analyses as consistently related to the blood pressure level in every sample and in all populations. Besides, a number of polymorphisms in candidate genes have been associated with differences in blood pressure. The most prominent candidate has been the polymorphisms in the renin–angiotensin–aldosterone system. In total, EH is likely to be a polygenic disorder that results from inheritance of a number of susceptibility genes and involves multiple environmental determinants. These determinants complicate the study of blood pressure variations in the general population. The complex nature of the hypertension phenotype makes large-scale studies indispensable, when screening of familial and genetic factors was intended. In this review, recent genetic studies exploring the molecular basis of EH, including different molecular pathways, are highlighted.     

Immunogenetics of autoantibodies and autoimmune diseases

The genetic contribution to the development of autoimmune disease is most likely complex. Along with loci controlling histocompatibility antigens and T-cell receptor proteins, genes that encode autoreactive immunoglobulins may have an important role in the pathogenesis of rheumatoid arthritis and related autoimmune diseases. Although much previous work in this area has concentrated on human monoclonal paraproteins and autoimmune mouse strains, the studies reviewed here examine immunoglobulin genes in the normal human population and normal mouse strains as well as in patients with autoimmune disease. Taken together, these studies suggest that genetic control of the expression of autoimmunity in rheumatoid arthritis and related autoimmune disorders is complex and most likely involves multiple gene loci.     

Genetics of chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a complex disease with multifactorial background, based on the interaction of environmental and genetic factors. Environmental factors are clearly related to the development of the disease. However, family and twin studies suggested genetics factors to be one of the important determinants for the development of COPD. Different approaches have been used to identify genes of interest. Genomewide linkage analysis found areas of interest on different chromosomes, with some genes located in this regions being identified and replicated as susceptibility genes. Numerous of candidate genes that could be linked to disease pathogenesis have been implicated in COPD genetics. However, the candidate gene approach is often limited by inconsistent results in other study populations. Recently, a combination of different methods is used giving more evidence for some candidate genes, including TGFß-1, Surfactant, SERPINE2 and microsomal epoxide hydrolase. In the future ongoing exact phenotype definition, combination of several approaches, genome-wide association studies and animal model genetics will lead to new insights into the genetics of COPD, with epigenetic factors needs to be further investigated and considered in concert with genetic findings.     

Genetic aspects of inflammatory bowel disease: How far have we come, and where are we heading?

Crohn's disease and ulcerative colitis are related complex genetic disorders, with gene—gene and gene—environment interactions that are critical to their pathogenesis. Multiple genetic loci have been implicated through genome-wide searches. Of these, a locus on Crohn's disease has been definitively established in the pericentromeric region of chromosome 16. Multiple candidate gene studies have been forwarded, and functionally significant variants in immuneassociated genes will provide additional insight. Characterization of the genetic variation responsible for causing inflammatory bowel disease will result in development of novel therapeutic approaches as well as in tailoring of specific therapies to individual patients based on their specific molecular pathogenesis.     

Pathophysiology of AAA: Heredity vs Environment

Abdominal aortic aneurysm (AAA) has a complex pathophysiology, in which both environmental and genetic factors play important roles, the most important being smoking. The recently reported falling prevalence rates of AAA in northern Europe and Australia/New Zeeland are largely explained by healthier smoking habits. Dietary factors and obesity, in particular abdominal obesity, are also of importance. A family history of AAA among first-degree relatives is present in approximately 13% of incident cases. The probability that a monozygotic twin of a person with an AAA has the disease is 24%, 71 times higher than that for a monozygotic twin of a person without AAA. Approximately 1000 SNPs in 100 candidate genes have been studied, and three genome-wide association studies were published, identifying different diverse weak associations. An example of interaction between environmental and genetic factors is the effect of cholesterol, where genetic and dietary factors affect levels of both HDL and LDL. True epigenetic studies have not yet been published.     

Osteoporosis and gene polymorphism

Osteoporosis is a multifactorial disease for which genetic and environmental factors are determinants. We have been conducting a candidate-gene approach in which polymorphisms of many bone metabolism related genes have been examined in the association study with bone mineral density and fracture incidence. However, the contribution of each gene is small and the major genetic determinants of BMD have not elucidated. Recently, a genome-wide systematic approach has been conducted to find the responsible genes using a genome-wide list of single nucleotide polymorphisms (SNPs). So far, several genes with higher statistical power have been screened out with this approach. The accumulating information of genome science will help understand the pathogenesis of osteoporosis and find the useful ways for the prevention and the treatment of this disease.     

Genetics in osteoarthritis

Osteoarthritis is a degenerative articular pathology with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. In spite of the multifactorial nature of this pathology, from years 50 one knows that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidates genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this pathology are not known, however, which seems clear is that levels of expression of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthitis.     

Update on the genetics of inflammatory bowel disease

Crohn’s disease and ulcerative colitis are related genetic disorders. Epidemiologic studies suggest that both disorders are caused by a complex interplay of genetic and environmental factors. Genetic linkage studies identify the general chromosomal locations of disease susceptibility genes, and a number of genetic linkages have been reported in inflammatory bowel disease (IBD). Most notable among these linkage regions has been the linkage in the pericentromeric region of chromosome 16, IBD1, among families multiply affected with Crohn’s disease. Recent studies have established that at least three coding region variants in the Nod2 gene are responsible for the linkage findings here, and Nod2 therefore represents the first definitively established gene contributing to the pathogenesis of IBD. The implications of these findings for advancing our understanding of Crohn’s disease are discussed.     

Nonconventional genetic risk factors for cardiovascular disease

Despite numerous advances made in identifying the genes for rare mendelian forms of cardiovascular disease (CVD), relatively little is known about the common, complex forms at the genetic level. Moreover, most genes that have been associated with CVD, whether they are single gene forms or more common forms of the disease, have primarily been involved in biochemical pathways related to what are considered “conventional” risk factors. However, recent genetic studies have begun to identify genes and pathways associated with CVD that would not be considered to underlie conventional risk factors. In this review, we discuss the evidence for this latter notion based on recent linkage and association studies in humans. As an example, we also illustrate how a combination of mouse and human genetics led to identification of the 5-lipoxygenase pathway for CVD, with potentially important implications for its treatment and diagnosis. We conclude with a discussion of the prospects for identifying CVD genes in the future and for potentially developing more effective therapeutic strategies.