scholarly journals The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1837
Author(s):  
Rebecca Jeyaraj ◽  
Kirsten McKay Bounford ◽  
Nicola Ruth ◽  
Carla Lloyd ◽  
Fiona MacDonald ◽  
...  
Keyword(s):  
Liver Disease ◽  
Phenotypic Variability ◽  
Bile Secretion ◽  
Disease Associations ◽  
Paediatric Liver Disease ◽  
Causal Variants ◽  
Potential Benefits ◽  
Infantile Cholestasis ◽  
Neonates And Infants ◽  
Patient Subgroups

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.

scholarly journals Genetic and Epigenetic Modifiers of Alcoholic Liver Disease

2018 ◽  
Vol 19 (12) ◽  
pp. 3857 ◽  
Author(s):  
Marica Meroni ◽  
Miriam Longo ◽  
Raffaela Rametta ◽  
Paola Dongiovanni
Keyword(s):  
Liver Disease ◽  
Alcohol Consumption ◽  
Alcoholic Liver Disease ◽  
Complex Disease ◽  
Wide Spectrum ◽  
Association Studies ◽  
Phenotypic Variability ◽  
Genome Wide Association Studies ◽  
Epigenetic Factors ◽  
Excessive Alcohol Consumption

Alcoholic liver disease (ALD), a disorder caused by excessive alcohol consumption is a global health issue. More than two billion people consume alcohol in the world and about 75 million are classified as having alcohol disorders. ALD embraces a wide spectrum of hepatic lesions including steatosis, alcoholic steatohepatitis (ASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). ALD is a complex disease where environmental, genetic, and epigenetic factors contribute to its pathogenesis and progression. The severity of alcohol-induced liver disease depends on the amount, method of usage and duration of alcohol consumption as well as on age, gender, presence of obesity, and genetic susceptibility. Genome-wide association studies and candidate gene studies have identified genetic modifiers of ALD that can be exploited as non-invasive biomarkers, but which do not completely explain the phenotypic variability. Indeed, ALD development and progression is also modulated by epigenetic factors. The premise of this review is to discuss the role of genetic variants and epigenetic modifications, with particular attention being paid to microRNAs, as pathogenic markers, risk predictors, and therapeutic targets in ALD.

Chronic obstructive pulmonary disease

2017 ◽  
Author(s):  
Amina Jaffer ◽  
Anant Patel ◽  
John Hurst
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Phenotypic Variability ◽  
Evidence Base ◽  
Future Research ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Potential Benefits ◽  
Learning Points

This chapter discusses the case of a 70-year-old man with his first presentation of chronic obstructive pulmonary disease. This case is used as a basis to explore and describe the diagnosis, investigation, and management of this condition. The chapter includes the evidence base and relative guidelines that support current practice, as well as highlighting useful learning points and providing expert opinion. The role of lung volume reduction surgery is discussed, and its potential benefits in selected patients highlighted. Phenotypic variability within chronic obstructive pulmonary disease is increasingly recognized, and this is discussed, including the implications on current management and future research.

Investigation of paediatric liver disease

1991 ◽  
Vol 14 (4) ◽  
pp. 531-537 ◽  
Author(s):  
D. Kelly ◽  
A. Green
Keyword(s):  
Liver Disease ◽  
Paediatric Liver Disease

scholarly journals Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls

2015 ◽  
Author(s):  
Mary D Fortune ◽  
Hui Guo ◽  
Oliver Burren ◽  
Ellen Schofield ◽  
Neil M Walker ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Control Design ◽  
Causal Variant ◽  
The Other ◽  
Risk Variants ◽  
Immune Attack ◽  
Disease Associations ◽  
Causal Variants

Identifying whether potential causal variants for related diseases are shared can increase understanding of the shared etiology between diseases. Colocalization methods are designed to disentangle shared and distinct causal variants in regions where two diseases show association, but existing methods are limited by assuming independent datasets. We extended existing methods to allow for the shared control design common in GWAS and applied them to four autoimmune diseases: type 1 diabetes (T1D); rheumatoid arthritis; celiac disease (CEL) and multiple sclerosis (MS). Ninety regions associated with at least one disease. In 22 regions (24%), we identify association to precisely one of our four diseases and can find no published association of any other disease to the same region; some of these may reflect effects mediated by the target of immune attack. Thirty-three regions (37%) were associated with two or more, but in 14 of these there was evidence that causal variants differed between diseases. By leveraging information across datasets, we identified novel disease associations to 12 regions previously associated with one or more of the other three autoimmune disorders. For instance, we link the CEL-associatedFASLGregion to T1D and identify a single SNP, rs78037977, as a likely causal variant. We also highlight several particularly complex association patterns, including theCD28-CTLA4-ICOSregion, in which it appears that three distinct causal variants associate with three diseases in three different patterns. Our results underscore the complexity in genetic variation underlying related but distinct autoimmune diseases and help to approach its dissection.

Non-alcoholic Fatty Liver Disease in Children

2010 ◽  
Vol 06 ◽  
pp. 60
Author(s):  
Melania Manco ◽  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Alcoholic Fatty Liver ◽  
Obesity Epidemic ◽  
The Metabolic Syndrome ◽  
Paediatric Liver Disease ◽  
Excessive Consumption ◽  
Refined Carbohydrates ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of paediatric liver disease. It is the hepatic component of the metabolic syndrome (MetS), being almost always associated with obesity and insulin resistance, and frequently with abnormal triglyceride and/or cholesterol levels, abnormal blood pressure and impaired glucose tolerance. Its increasing prevalence among children and adolescents has been attributed to the obesity epidemic and the modern western lifestyle, with excessive consumption of refined carbohydrates and saturated fats in combination with low levels of physical activity. Key questions need to be answered concerning the potential progression of NAFLD towards more severe forms of liver derangement, the worth of performing biopsies in children with suspected NAFLD and the role played by the disease in promoting and anticipating the onset of cardiovascular disease (CVD) at an unexpectedly early age. The clinical relevance of these questions is undoubted, as NAFLD may cause significantly increased morbidity and mortality in adulthood.

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