Celiac disease: From genetics to epigenetics

Celiac disease(CeD)is a multifactorial autoimmune disorder spread worldwide.The exposure to gluten,a protein found in cereals like wheat,barley and rye,is the main environmental factor involved in its pathogenesis.Even if the genetic predisposition represented by HLA-DQ2 or HLA-DQ8 haplotypes is widely recognised as mandatory for CeD development,it is not enough to explain the total predisposition for the disease.Furthermore,the onset of CeD comprehend a wide spectrum of symptoms,that often leads to a delay in CeD diagnosis.To overcome this deficiency and help detecting people with increased risk for CeD,also clarifying CeD traits linked to disease familiarity,different studies have tried to make light on other predisposing elements.These were in many cases genetic variants shared with other autoimmune diseases.Since inherited traits can be regulated by epigenetic modifications,also induced by environmental factors,the most recent studies focused on the potential involvement of epigenetics in CeD.Epigenetic factors can in fact modulate gene expression with many mechanisms,generating more or less stable changes in gene expression without affecting the DNA sequence.Here we analyze the different epigenetic modifications in CeD,in particular DNA methylation,histone modifications,non-coding RNAs and RNA methylation.Special attention is dedicated to the additional predispositions to CeD,the involvement of epigenetics in developing CeD complications,the pathogenic pathways modulated by epigenetic factors such as microRNAs and the potential use of epigenetic profiling as biomarker to discriminate different classes of patients.     

The genetics of Graves' disease: HLA and disease susceptibility

To relate genetic variation in Graves' disease (GD) susceptibility to polymorphism at MHC loci, clinical and family studies were undertaken in eastern Hungary. Among 1980 relatives of 534 index patients, 2.9% of siblings, 2.7% of offspring, and 3.0% of parents had GD. HLA haplotype combinations in affected sibling pairs were determined in the present data and combined with data in the literature (12 sibling pairs from Farid 1981, 12 from Chan et al. 1980, and 15 from Sasazuki et al. 1983); 43, 23, and 1 affected sibling pairs shared, respectively, 2, 1, and 0 HLA haplotypes. This distribution is inconsistent with simple dominant inheritance, but is consistent with simple recessive inheritance of HLA-related susceptibility over a range of gene frequencies (0.2-0.4). A frequency of 0.3 gives the best fit and is consistent with penetrance of 7.1% for the recessive susceptibility genotype; the data, however, can accommodate penetrance values up to 16%. The distribution of HLA haplotypes in 33 families related disease susceptibility more strongly to DR than to other loci. The distribution of HLA-B8 genotypes in 256 patients was in close agreement with Hardy-Weinberg equilibrium proportions, also favoring recessive inheritance of MHC-related susceptibility. The probability that an individual will be affected with GD can be predicted, based on sex, HLA genotype, and family history. For example, 14.9% of DR3-positive women with an affected first degree relative are likely to be affected. These predictions can be tested as family data accumulate.     

Fibrinogen and cardiovascular disease: genetics and biomarkers

Several prospective epidemiological studies and clinical observations provided evidence regarding fibrinogen and coronary artery disease (CAD). Many of these studies firmly correlate fibrinogen with CAD. However, it is uncertain whether this relation is causal or reflects genetic variability and residual confounding by other risk factors. Several polymorphisms on fibrinogen chain genes affect its levels, however only few of the genetic variants are associated with increased cardiovascular risk. As regards the role of fibrinogen in myocardial infarction (MI) studies indicate that genetic variations have at best a modest impact on the process resulting in MI. Therefore, the screening of fibrinogen genes might not be useful for the assessment of the risk of MI. However, the findings that specific genotypes lead to specific differences in fibrinogen levels, but may not be linked to cardiovascular risk, complicates the hypothesis of causality of fibrinogen in the pathogenesis of cardiovascular disease.     

胰岛素基因突变:从遗传学和β细胞生物学到临床疾病

近年来,越来越多新的胰岛素基因突变开始吸引人们的注意,已证实突变位于胰岛素基因的非翻译区和前胰岛素原的编码区,包括信号肽、胰岛素链、C肽和A链,以及信号肽酶和激素原转换酶的蛋白水解剪切位点.这些突变影响胰岛细胞中胰岛素合成的不同步骤,引起胰岛素原错误折叠和早发的常染色体显性糖尿病,前胰岛素原基因突变所致的前胰岛素原加工缺陷、胰岛素原错误折叠和内质网应激可能在糖尿病发生、发展中发挥重要作用.     

Helicobacter pylori: host genetics and disease outcomes

Helicobacter pylori infection is the most common chronic bacterial infection worldwide and is associated with divergent clinical outcomes that range from simple asymptomatic gastritis to more serious conditions, such as peptic ulcer disease and gastric cancer. The key determinants of these outcomes are the severity and distribution of H. pylori-induced gastritis. Host genetic factors play an important role in influencing disease risk, but identifying candidate genes is a major challenge that has to stem from a profound understanding of the pathophysiology of the disease. In the case of H. pylori, the most promising candidate genes are ones that attenuate gastric acid secretion and lead to a destructive chronic inflammatory response against the infection. In particular, certain cytokine and innate immune response gene polymorphisms appear to influence risk of gastric cancer and its precursor conditions. There are currently no convincing genetic risk markers for acquisition of H. pylori infection or risk of developing peptic ulcer disease. Future research agendas should focus on identifying the full genetic risk profile for H. pylori-induced gastric neoplasia. This will help to target the population most at risk by directing eradication therapy and closer follow-up to the affected individuals.     

Pattern recognition receptors and the innate immune response to viral infection

The innate immune response to viral pathogens is critical in order to mobilize protective immunity. Cells of the innate immune system detect viral infection largely through germline-encoded pattern recognition receptors (PRRs) present either on the cell surface or within distinct intracellular compartments. These include the Toll-like receptors (TLRs), the retinoic acid-inducble gene I-like receptors (RLRs), the nucleotide oligomerization domain-like receptors (NLRs, also called NACHT, LRR and PYD domain proteins) and cytosolic DNA sensors. While in certain cases viral proteins are the trigger of these receptors, the predominant viral activators are nucleic acids. The presence of viral sensing PRRs in multiple cellular compartments allows innate cells to recognize and quickly respond to a broad range of viruses, which replicate in different cellular compartments. Here, we review the role of PRRs and associated signaling pathways in detecting viral pathogens in order to evoke production of interferons and cytokines. By highlighting recent progress in these areas, we hope to convey a greater understanding of how viruses activate PRR signaling and how this interaction shapes the anti-viral immune response.     

Pediatric inflammatory bowel disease: clinical and molecular genetics

Pediatric-onset inflammatory bowel disease (IBD) is characterized by distinct phenotypic differences compared to adult-onset IBD. This raises the question whether early (pediatric) onset IBD represents the same disease process occurring in adults but merely at an earlier age or does IBD in children have a very different etiology and pathogenesis but with the same clinical presentation as adults. The use of techniques such as whole genome association studies to perform broad, unbiased screening for the contributions of common genetic variations to complex disease has rapidly assisted in the identification of several novel susceptibility loci associated with pediatric-onset Crohn's disease such as IL23R and ATG16L1. These genes join the already confirmed IBD susceptibility genes such as NOD2/CARD15, IBD5, and DLG5. Therefore, there is hope that advances in the field of clinical and molecular genetics will assist in answering the fundamental question of whether pediatric IBD has a different etiology and pathogenesis compared to adult IBD. This review examines the current status of clinical and molecular genetics of pediatric IBD, and highlights the differences between pediatric and adult IBD in disease phenotypes and genotypes. Finally, the future directions of genetic investigations in pediatric IBD are discussed.     

Veno-occlusive disease: cytokines,genetics, and haemostasis

Hepatic veno-occlusive disease (VOD) is a major cause of morbidity and mortality following high dose cytotoxic therapy for stem cell transplantation (SCT). Pre-existing liver damage, SCT-related therapy, and genetic polymorphisms all appear to increase the risk of developing VOD. Studies of biological markers during SCT suggest that cytokines, haemostasis, and hepatic drug metabolism via the glutathione pathway are all involved in the pathogenesis of VOD. Until recently, treatment options were limited and experimental therapies directed at the pathogenesis of the disease were mostly unsuccessful. However, Defibrotide, a relatively new agent that has modulatory effects on vascular endothelium, cytokine release, and haemostasis, has been used with some success in the management and prophylaxis of VOD. In the future, a better understanding of genetic polymorphisms and biological markers which may be important in the pathogenesis of VOD, may enable us to predict which patients are most likely to be affected.     

Nonalcoholic fatty liver disease: from clinical recognition to treatment

Nonalcoholic fatty liver disease (NAFLD) is probably the most common spectrum of metabolic liver disease in the world, encompassing simple steatosis to steatohepatitis, advanced fibrosis, cirrhosis and hepatocellular carcinoma. NAFLD affects a significant part of the general population worldwide. The existing correlation between obesity and NAFLD in combination with the increase in the frequency of obesity in the developed world implies that the incidence and severity of NAFLD will increase in the near future. Newer data support the idea that NAFLD constitutes the more important cause of cryptogenic cirrhosis of the liver and a ground for the development of hepatocellular carcinoma. Liver biopsy remains the most specific and sensitive method to differentiate NAFLD, providing important information on the long-term prognosis of the patients. The ‘two hit’ hypothesis constitutes the currently prevailing theory for the development of NAFLD and nonalcoholic steatohepatitis. The first ‘hit’ is purported to be the increase of free fatty acids in hepatocytes, which results in a decrease of β-oxidation. The second step includes all mechanisms contributing to the development of necroinflammation and fibrosis. Currently, an effective treatment for patients with NAFLD does not exist. Improvement in liver histology remains the primary goal of any therapeutic approach in patients with NAFLD. Viewing NAFLD in the frame of the metabolic syndrome opens the possibility that both the onset of the disease and disease progression could be prevented by changes in lifestyle. Physical exercise and a low calorie diet in combination with the gradual loss of body weight represent the cornerstone for the management of NAFLD patients.     

mtDNA的遗传学特征与心血管疾病

线粒体基因组(mitochondrial DNA,mtDNA)是细胞能量生成的场所。分析显示mtDNA突变通过影响线粒体的氧化应激、能量代谢等方面而参与各种心血管疾病的发生、发展。通过对mtDNA的进一步研究有助于为心血管疾病寻找病因和有效的治疗提供新思路和理论基础。文章简述mtDNA的遗传学特征以及mtDNA突变与心血管疾病(如高血压病、冠心病、心肌病、心律失常等)的关系。     

Molecular genetics and age-related disease.

Maintenance and repair processes are crucial to the pathogenesis of ageing and late-onset disease. Thus, there is increasing recognition of the importance of genetic factors in the development of late-onset conditions such as stroke, Parkinson's disease and osteoporosis, and accumulating evidence for a genetic component in the development of chronic obstructive pulmonary disease. We review the approaches and problems in the genetic investigation of complex disorders in old age, taking chronic obstructive pulmonary disease as an example.     

Autoantibodies to human heart conduction system in Chagas' disease

Destruction of heart tissue in chronic chagasic cardiopathy may be caused by autoimmune recognition of heart tissue. Indirect evidence suggests that there is antigenic cross-reactivity between Trypanosoma cruzi and heart tissue. The objective of this study was to determine whether seric autoantibodies against atrio-ventricular (AV) node and sinus auricular node tissues are markers of chronic cardiopathy condition. We searched for the presence of seric autoantibodies against AV node and sinus auricular node tissues in 25 sera from chronic chagasic cardiopathy patients, 20 sera from non-chagasic cardiopathy patients, 20 sera from indeterminate chagasic subjects, and 20 sera from healthy blood donors as controls. Diagnosis of dilated cardiopathy was established based on the left-ventricular end systolic dimension and cardiothoracic ratio on chest x-radiography and impaired contracting ventricle, and chagasic etiology by demonstration of circulating antibodies using ELISA and IIF. Autoantibody detection against conduction heart tissue was carried out by immunohistochemical test. The tissues were obtained from non-cardiopathy necropsy case. Human sera were diluted at 1:10 in PBS-FSB. Goat antihuman laminin was used as positive control. Autoantibodies were more frequently found in chronic chagasic cardiopathy (20%) compared to non-chagasic cardiopathy (5%) and indeterminate chagasic subjects (5%), pattern staining define interstitial and membrane targets on rich conduction system tissue. In conclusion seric autoantibodies against heart conduction system are not a good markers for chagasic cardiopathy group. Their presence showed no clear association with complex rhythm/conduction aberrations.     

Mechanisms of disease: genetics of Paget's disease of bone and related disorders

Paget's disease of bone (PDB) is a common disorder in which focal abnormalities of increased bone turnover lead to complications such as bone pain, deformity, pathological fractures, and deafness. PDB has a strong genetic component and several susceptibility loci for the disease have been identified by genome-wide scans. Mutations that predispose individuals to PDB and related disorders have been identified in four genes. The rare PDB-like syndromes of familial expansile osteolysis, early-onset familial PDB, and expansile skeletal hyperphosphatasia are caused by insertion mutations in TNFRSF11A, which encodes receptor activator of nuclear factor (NF)kappaB (RANK)-a critical regulator of osteoclast function. Inactivating mutations in TNFRSF11B, which encodes osteoprotegerin (a decoy receptor for RANK ligand) cause idiopathic hyperphosphatasia, and polymorphisms in this gene seem to increase the risk for classical PDB. Mutations of the sequestosome 1 gene (SQSTM1), which encodes an important scaffold protein in the NFkappaB pathway, are a common cause of classical PDB. The rare syndrome of hereditary inclusion body myopathy, PDB, and fronto-temporal dementia is caused by mutations in the valosin-containing protein (VCP) gene. This gene encodes VCP, which has a role in targeting the inhibitor of NFkappaB for degradation by the proteasome. Several additional genes for PDB remain to be discovered, and it seems likely that they will also involve the RANK-NFkappaB signaling pathway or components of the proteasomal processing of this pathway, underscoring the critical importance of this signaling pathway in bone metabolism and bone disease.     

Celiac disease genetics: current concepts and practical applications.

Celiac disease is a multifactorial disease with complex genetics. Both HLA and non-HLA genes contribute to the genetic component, but recent findings suggest that the importance of non-HLA genes might have been overestimated. No susceptibility genes other than HLA-DQ have yet been identified in celiac disease. In contrast to the meager knowledge regarding non-HLA genes, we have acquired a detailed understanding about which HLA genes are predisposing for disease, and how they are involved in the pathogenesis. This knowledge might pave the road for novel treatments for the disease. The role of HLA as a necessary, but not sufficient, genetic factor can moreover be used for diagnostic purposes to exclude a celiac disease diagnosis. The applicability of HLA genotyping is particularly useful for excluding celiac disease in family members or risk groups with fairly unbiased distribution of HLA alleles (ie, patients with Turner syndrome and patients with Down syndrome) and in patients with a clinical suspicion of celiac disease.     

Pediatric fatty liver disease: Role of ethnicity and genetics

Non-alcoholic fatty liver disease (NAFLD) comprehends a wide range of conditions, encompassing from fatty liver or steatohepatitis with or without fibrosis, to cirrhosis and its complications. NAFLD has become the most common form of liver disease in childhood as its prevalence has more than doubled over the past 20 years, paralleling the increased prevalence of childhood obesity. It currently affects between 3% and 11% of the pediatric population reaching the rate of 46% among overweight and obese children and adolescents. The prevalence of hepatic steatosis varies among different ethnic groups. The ethnic group with the highest prevalence is the Hispanic one followed by the Caucasian and the African-American. This evidence suggests that there is a strong genetic background in the predisposition to fatty liver. In fact, since 2008 several common gene variants have been implicated in the pathogenesis of fatty liver disease. The most important is probably the patatin like phospholipase containing domain 3 gene (PNPLA3) discovered by the Hobbs’ group in 2008. This article reviews the current knowledge regarding the role of ethnicity and genetics in pathogenesis of pediatric fatty liver.