Genetic epidemiology of irritable bowel syndrome

Irritable bowel syndrome(IBS) is the most common functional gastrointestinal disorder characterized by presence of abdominal pain or discomfort associated with altered bowel habits. It has three main subtypes- constipation predominant IBS(C-IBS),diarrhea predominant IBS(D-IBS) and IBS with mixed featuresof both diarrhea as well as constipation(M-IBS). Its pathophysiology and underlying mechanisms remain elusive. It is traditionally believed that IBS is a result of multiple factors including hypersensitivity of the bowel,altered bowel motility,inflammation and stress. Initial studies have shown familial aggregation of IBS suggesting shared genetic or environmental factors. Twin studies of IBS from different parts of world have shown higher concordance rates among monozygotic twins than dizygotic twins,and thus suggesting a genetic component to this disorder. Multiple studies have tried to link single-nucleotide polymorphisms(SNPs) to IBS but there is little evidence that these SNPs are functional. Various molecules have been studied and investigated by the researchers. Serotonin,a known neurotransmitter and a local hormone in the enteric nervous system,has been most extensively explored. At this time,the underlying gene pathways,genes and functional variants linked with IBS remain unknown and the promise of genetically-determined risk prediction and personalize medicine remain unfulfilled. However,molecular biological technologies continue to evolve rapidly and genetic investigations offer much promise in the intervention,treatment and prevention of IBS.     

Mechanisms Underlying Visceral Hypersensitivity in Irritable Bowel Syndrome

Visceral hypersensitivity is currently considered a key pathophysiological mechanism involved in pain perception in large subgroups of patients with functional gastrointestinal disorders, including irritable bowel syndrome (IBS). In IBS, visceral hypersensitivity has been described in 20%–90% of patients. The contribution of the central nervous system and psychological factors to visceral hypersensitivity in patients with IBS may be significant, although still debated. Peripheral factors have gained increasing attention following the recognition that infectious enteritis may trigger the development of persistent IBS symptoms, and the identification of mucosal immune, neural, endocrine, microbiological, and intestinal permeability abnormalities. Growing evidence suggests that these factors play an important role in pain transmission from the periphery to the brain via sensory nerve pathways in large subsets of patients with IBS. In this review, we will report on recent data on mechanisms involved in visceral hypersensitivity in IBS, with particular attention paid to peripheral mechanisms.     

Role of environmental pollution in irritable bowel syndrome

Irritable bowel syndrome (IBS), with the prevalence of 10%-20 % of the population has become an emerging problem worldwide. IBS is a functional gastrointestinal (GI) disorder characterized by abdominal pain or discomfort and altered bowel habits. The etiology of IBS contains genetic, psychological, and immunological factors, and has not been fully elucidated; of note, recent studies also point at environmental pollution and its role in the development of functional GI diseases. In this review we focus on several environmental factors, such as bacterial contamination, air pollution, radiation and even stress as potential triggers of IBS. We discuss associated disturbances in homeostasis, such as changes in intestinal microbiome and related pathophysiological mechanisms. Based on the effect of environmental factors on the GI tract, we also propose novel targets in IBS treatment.     

Gender and racial differences in nonalcoholic fatty liver disease

Due to the worldwide epidemic of obesity, nonalcoholic fatty liver disease(NAFLD) has become the most com-mon cause of elevated liver enzymes. NAFLD represents a spectrum of liver injury ranging from simple steato-sis to nonalcoholic steatohepatitis(NASH) which may progress to advanced fibrosis and cirrhosis. Individuals with NAFLD, especially those with metabolic syndrome, have higher overall mortality, cardiovascular mortality, and liver-related mortality compared with the general population. According to the population-based studies, NAFLD and NASH are more prevalent in males and in Hispanics. Both the gender and racial ethnic differences in NAFLD and NASH are likely attributed to interaction between environmental, behavioral, and genetic fac-tors. Using genome-wide association studies, several genetic variants have been identified to be associated with NAFLD/NASH. However, these variants account for only a small amount of variation in hepatic steatosis among ethnic groups and may serve as modifiers of the natural history of NAFLD. Alternatively, these variants may not be the causative variants but simply markers representing a larger body of genetic variations. In this article, we provide a concise review of the gender and racial differences in the prevalence of NAFLD and NASHin adults. We also discuss the possible mechanisms for these disparities.     

The genetics of vasculitides

Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Beh?et's disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date.     

Twin studies used to prove that the comorbidity of major depressive disorder with IBS is NOT influenced by heredity

Twin studies have traditionally been used to assess the heritability of diseases such as irritable bowel syndrome (IBS) by comparing concordance rates in monozygotic twins (identical genetic endowment) to dizygotic twins (half of genes shared). Wojczynski et al. used twins in a novel way-they studied monozygotic twins who were discordant for IBS (but who shared identical genes) to show that the comorbidity of IBS with major depressive disorder could NOT be due to genetic influences. This paradigm provides the most rigorous method for separating genetic from environmental influences and should be adopted by other researchers. However, the authors' conclusion that major depressive disorder and IBS are part of the same pathophysiological process is questioned on the basis of (a) incomplete co-occurrence of IBS and major depressive disorder (13-45% co-occurrence) and (b) lack of specificity-the authors show that chronic widespread pain (related to fibromyalgia) and chronic fatigue are also strongly associated with IBS. This study provides precise, generalizable estimates from a large population-based study for the comorbidity of IBS with major depressive disorder, chronic widespread pain, and chronic fatigue.     

Irritable bowel syndrome:Emerging paradigm in pathophysiology

Irritable bowel syndrome(IBS)is one of the most common gastrointestinal disorders,characterized by abdominal pain,bloating,and changes in bowel habits.These symptoms cannot be explained by structural abnormalities and there is no specific laboratory test or biomarker for IBS.Therefore,IBS is classified as a functional disorder with diagnosis dependent on the history taking about manifested symptoms and careful physical examination.Although a great deal of research has been carried out in this area,the pathophysiology of IBS is complex and not completely understood.Multiple factors are thought to contribute to the symptoms in IBS patients;altered gastrointestinal motility,visceral hypersensitivity,and the brain-gut interaction are important classical concepts in IBS pathophysiology.New areas of research in this arena include inflammation,postinfectious low-grade inflammation,genetic and immunologic factors,an altered microbiota,dietary factors,and enteroendocrine cells.These emerging studies have not shown consistent results,provoking controversy in the IBS field.However,certain lines of evidence suggest that these mechanisms are important at least a subset of IBS patients,confirming that IBS symptoms cannot be explained by a single etiological mechanism.Therefore,it is important to keep in mind that IBS requires a more holistic approach to determining effective treatment and understanding the underlying mechanisms.     

Significance of genetic polymorphisms in patients with nonalcoholic fatty liver disease

Because of recent advances in genetic research such as genome-wide association studies, the underlying genetic mechanisms of nonalcoholic fatty liver disease (NAFLD) pathophysiology have been elucidated. Here, we present a review of the current literature on the impact of genetic polymorphisms in patients with NAFLD. These genetic polymorphisms, which regulate lipid metabolism, glucose metabolism, and the renin-angiotensin system, are involved in NAFLD onset, steatosis, inflammation, fibrosis, and hepatocellular carcinoma (HCC). Among these genetic polymorphisms, many studies and meta-analyses have demonstrated that position 148 (rs738409 C/G) of the patatin-like phospholipase domain-containing protein (PNPLA3) is a genetic factor associated with NAFLD pathophysiological features, such as hepatic fat level, hepatic inflammation, fibrosis, and HCC. However, the impact of genetic polymorphisms on NAFLD pathophysiology appears to differ among ethnic groups. Therefore, further studies with larger sample sizes are needed for each ethnic group.     

Genetics of irritable bowel syndrome

Irritable bowel syndrome (IBS) is one of the most common diagnoses made by gastroenterologists and primary care providers alike, and yet the underlying mechanism remains poorly understood. Family and twin studies suggest that IBS may have a genetic basis. Several candidate gene association studies have been performed, but thus far, they have failed to clearly identify an "IBS gene." Epidemiological studies are needed to facilitate phenotype definition and identify relevant environment risk factors that will need to factor in gene and environment interactions in all future genetic studies. As genetic research in IBS is relatively nascent, much opportunity, as well as many challenges, exists in identifying the genes responsible for IBS.     

Sleep and its Relationship to Racial and Ethnic Disparities in Cardiovascular Disease

There are substantial racial/ethnic disparities in cardiovascular disease in the U.S., but few mechanisms have emerged as feasible intervention targets. A growing body of research suggests that racial/ethnic differences in sleep deficiency, including extreme sleep duration, sleep-disordered breathing, and insomnia, may help explain disparities in cardiovascular disease. However, little is known about the mechanisms underlying racial/ethnic disparities in sleep. In this article, we review the extant literature on sleep and cardiovascular outcomes (eg, hypertension, stroke, cardiovascular disease) and racial/ethnic differences in these relations. We also discuss possible mechanisms that might help explain racial/ethnic sleep disparities, including neighborhood disadvantage, psychosocial and occupational stressors, acculturation, and treatment access and adherence. More research is needed to establish causal linkages among race/ethnicity, sleep, and these mechanisms, but existing evidence suggests that targeting these factors in interventions may reduce racial/ethnic sleep disparities and improve primary prevention of cardiovascular disease among all racial/ethnic groups.     

Genetischer Hintergrund der Vaskulitiden

Genetic association studies have been of great value in the past by contributing to the understanding of pathophysiological mechanisms of chronic inflammatory and autoimmune diseases. Many genetic risk factors have been identified which confer susceptibility for one or several (autoimmune) disease(s). Using a candidate-gene approach, the first genetic risk factors and polymorphisms of vasculitides have been identified. Due to the rarity of autoimmune vasculitides often only small sample numbers have been generated and analysed, leading to inconsistent results. Furthermore, differences in ethnic background may complicate analysis. Only few of the detected risk factors have been reliably replicated in larger cohorts, such as the association of the PTPN22*620W allele with WG and MPA, the deficiency allele Pi*Z of the alpha1 antitrypsin gene and the HLA-DPB*04041 allele with WG and the HLA-DRB3/DRB4 with CSS. Genome-wide association studies (GWAS) offer the advantage of screening the whole genome for risk factors rather than relying on disease models postulated by the investigator; however, they require even larger sample sizes. Initial results from GWA studies are available for Beh?et??s disease and Kawasaki syndrome, which identified new genetic associations but require replication, especially since some of the identified risk factors could not be linked to pathophysiological pathways to date.     

Irritable bowel syndrome: epidemiology, natural history, health care seeking and emerging risk factors

IBS is a common condition, affecting approximately 3% to 15% of the general population based on various diagnostic criteria. There seem to be differences in disease epidemiology between the eastern and the western world. As data from larger Asian epidemiological studies begin to surface,however, such differences appear to be less marked. The proportion of IBS patients who consult a physician for their symptoms is around 50%.Psychological factors and the presence and duration of abdominal pain are all significant predictors for health care seeking. The natural history of IBS is characterized by frequent fluctuation of symptoms and by an overlap with other functional GI disorders, some of which share a number of risk factors for IBS. Unnecessary abdominal surgery is performed in a high proportion of IBS sufferers. Along with the established role for psychosocial conditions in IBS, other risk factors are emerging. Evidence for postinfectious IBS is mounting, but the clinical usefulness of characterizing such patients remains unclear. Food sensitivities are frequently present in IBS, but more well-conducted trials of avoidance diets and desensitization are needed. Finally,genetic markers in IBS are an increasing focus of attention, but the amount of phenotypic variance explained by genetic variability remains to be established.     

Environmental versus genetic risk factors for irritable bowel syndrome: clinical and therapeutic implications

The pathogenesis of irritable bowel syndrome (IBS) has traditionally been based on the biopsychosocial model that emphasizes that the symptom manifestations of IBS and consulting behavior are influenced at least in part by psychological processes. However, there has been increasing interest in trying to identify and unravel potential molecular mechanisms in IBS, and this endeavor has been driven by some evidence that there is a true genetic contribution to IBS. IBS does aggregate in families, and the concordance of IBS is twice as great in monozygotic compared with dizygotic twins in most, but not all, studies. A number of genetic polymorphisms have been associated with IBS but most remain to be independently confirmed, and unknown gene-environment interactions probably remain essential for the disorder to manifest. As we become better able to specify the phenotypes within IBS, it seems likely that increasingly relevant gene associations that have implications for testing and treatment will rapidly be identified. IBS probably represents a collection of several organic diseases, some of which may have a genetic component; the biopsychosocial model, although important, may represent a gross oversimplification of the underlying molecular pathogenesis.     

Functional findings in irritable bowel syndrome

The pathophysiology of IBS is complex and still incompletely known. Both central and peripheral factors, including psychosocial factors, abnormal GI motility and secretion, and visceral hypersensitivity, are thought to contribute to the symptoms of IBS. Several studies have demonstrated altered GI motor function in IBS patients and the pattern differs between IBS subgroups based on the predominant bowel pattern. Few studies have so far addressed GI secretion in IBS, but there are some evidence supporting altered secretion in the small intestine of IBS patients. Visceral hypersensitivity is currently considered to be perhaps the most important pathophysiological factor in IBS. Importantly, several external and internal factors can modulate visceral sensitivity, as well as GI motility, and enhanced responsiveness within the GI tract to for instance stress and nutrients has been demonstrated in IBS patients. Today IBS is viewed upon as a disorder of dysregulation of the so-called brain-gut axis, involving abnormal function in the enteric, autonomic and/or central nervous systems, with peripheral alterations probably dominating in some patients and disturbed central processing of signals from the periphery in others.     

Acupuncture-moxibustion in treating irritable bowel syndrome: How does it work?

Irritable bowel syndrome (IBS) is a functional intestinal disease characterized by abdominal pain or discomfort and altered bowel habits. It has drawn great attention because of its high prevalence, reoccurring symptoms, and severe influence on patients’ lives. Many clinical studies have demonstrated the efficacy of acupuncture-moxibustion in treating IBS. Increasing attention has been paid to research regarding the action mechanisms of acupuncture-moxibustion for IBS, and the adoption of modern techniques has achieved some progress. This article reviews the latest advances among action mechanism studies from the perspectives of gastrointestinal motility, visceral hypersensitivity, the brain-gut axis, the neuroendocrine system, and the immune system. It is shown that acupuncture-moxibustion can effectively regulate the above items, and thus, this treatment should have a high efficacy in the treatment of IBS. This article also identifies existing problems in current mechanism research and raises several ideas for future studies. Further revelations regarding these action mechanisms will promote the application of acupuncture-moxibustion in treating IBS.     

Genetic determination of irritable bowel syndrome

Irritable bowel syndrome （IBS） is a common functional gastrointestinal disorder. According to the Rome m criteria, IBS is defined as recurrent abdominal pain or discomfort for at least 3 d per month during the previous 3 mo associated with two or more of the following symptoms： improvement with defecation, onset associated with a change in the frequency of stool and/or onset associated with a change in form or appearance of stool. There is growing evidence regarding the genetic contribution in IBS, however the precise etiology of IBS is still unknown. The evaluation of the genetic influence is based on twin studies, familial aggregation and genetic epidemiological investigations. Most studies showed a concordance for IBS significantly greater in monozygotic than in dizygotic twins. The majority of the studies have shown that familial aggregation may represent exposures to a similar environment, as well as the influence of genetic factors. Whereas no specific gene has been identified in association with IBS, recent studies have noticed the importance of polymorphisms in the promoter region of the serotonin reuptake transporter gene, G-protein beta 3 subunit gene （C825T）, cholecystokinin receptor （CCKAR gene 779T〉C）, and high-producer tumor necrosis factor genotype. Further studies are necessary to determine how genetic factors influence the clinical manifestations and therapeutical response in IBS patients.     

PNPLA3基因多态性与非酒精性脂肪性肝病关系的研究进展

非酒精性脂肪性肝病(NAFLD)已成为西方发达国家慢性肝病的首要病因,在我国已成为仅次于慢性病毒性肝炎的第二大肝病.但是其发病机制尚不清楚,目前仍然没有有效的治疗方式,有研究指出NAFLD与遗传、环境、精神心理因素有关,而且接触相似危险因素的个体间NAFLD的发病率差异较大,疾病进程亦不尽相同,这一事实提示遗传因素及基因多态性与NAFLD发病及进程有关.全基因组关联研究发现PNPLA3(patatin - like phospholipase domain containing 3)基因多态性与NAFLD的遗传易感性及进展有着密切的联系.本综述主要从PNPLA3的结构特征、PNPLA3基因的生物学特征及PNPLA3基因多态性与NAFLD的相关性几个方面进行探讨,从而有利于NAFLD发病机制的阐明,对NAFLD的预防和治疗提供可能.     

Doctor-patient interaction for irritable bowel syndrome in primary care: a systematic perspective

BACKGROUND AND AIMS: Irritable bowel syndrome (IBS) is defined by specific validated symptom criteria and encompasses several different underlying pathophysiological mechanisms that express a common set of symptoms. However, IBS is poorly understood by patients. We aimed to explore how a diagnosis of IBS affects the interaction between patients and their physicians. METHODS: A comprehensive literature search for studies in the English language addressing this issue was conducted using Medline, PubMed, Cochrane Database, Psychinfo, Cinahl, Embase, Web of Science and manual recursive search of reference lists. Investigators reviewed and abstracted data from articles fulfilling our inclusion criteria: primary care patients, all ages, gender and ethnic groups diagnosed with IBS by a general practitioner (GP). RESULTS: Retrieval of 121 articles generated only four that met inclusion criteria. Research methods of three studies relied solely on qualitative subjective, anecdotal patient narratives, a bias in favor of patients' negative opinion, absence of objective physician diagnostic criteria, pre-testing questions for two studies, follow-up and patient verification of accounts for accuracy. The fourth study included objective physician diagnostic criteria, quantitative measures, a pre-testing questionnaire, and both patient and doctor perspectives. There was a disparity between patient and GP perception regarding the nature, severity and consequences of IBS in primary care, leading patients to perceive this interaction as one of dissatisfaction. The fourth study revealed GP management of IBS mostly meets patient's expectations areas of concern centered on etiology, diagnostic criteria and dietary advice. Disparity seems to lie with the physician, who needs to provide more trust, knowledge, and sympathy, create rapport and be forthcoming with information, while keeping information simple and understandable. Patient dissatisfaction stems from the actual information provided and how this is communicated. CONCLUSIONS: There is evidence that some IBS patients in primary care experience dissatisfaction and negative attitudes in GP interactions. Future research should take into account personality attributes and cross-situational stability in addition to methodological implications of studies. GPs may be the first avenue for IBS patients to vent their frustration, and appropriate education programs for optimal management of patients with IBS are needed in primary care.     

Relationship between infectious gastroenteritis and irritable bowel syndrome

A newly recognized causative factor in a subset of patients with irritable bowel syndrome (IBS) is called post-infectious IBS (PI-IBS). IBS symptoms frequently develop after an acute episode of infectious gastroenteritis. Several studies have been made in our understanding of the concept of PI-IBS. Recent studies suggest that transient or chronic gastrointestinal inflammation may play a role in IBS pathogenesis. PI-IBS can be regarded as a natural experiment model in which an insult in the form of an infective disease impacts on subjects with underlying genetic and psychosocial predispositions who then develop IBS. IBS is likely to be a complex trait wherein variability in clinical presentation is partially explained by heterogeneity in underlying genetic and environmental risk factors for PI-IBS. Further studies on PI-IBS are needed to understand the pathophysiology of functional gastrointestinal disorders and to develop new promising management for such patients.     

Racial/Ethnic Residential Segregation,Obesity, and Diabetes Mellitus

Persistent racial/ethnic disparities in obesity and type 2 diabetes mellitus seen in the US are likely due to a combination of social, biological, and environmental factors. A growing number of studies have examined the role of racial/ethnic residential segregation with respect to these outcomes because this macro-level process is believed to be a fundamental cause of many of the factors that contribute to these disparities. This review provides an overview of findings from studies of racial/ethnic residential segregation with obesity and diabetes published between 2013 and 2015. Findings for obesity varied by geographic scale of the segregation measure, gender, ethnicity, and racial identity (among Hispanics/Latinos). Recent studies found no association between racial/ethnic residential segregation and diabetes prevalence, but higher segregation of Blacks was related to higher diabetes mortality. Implications of these recent studies are discussed as well as promising areas of future research.