ABCB4 disease: Many faces of one gene deficiency

Sticová, Eva; Jirsa, M

doi:10.1016/j.aohep.2019.09.010

Cited by 35 publications

(33 citation statements)

References 82 publications

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“…This variant is of low frequency in AA (MAF=1.2%) but virtually absent in EA and ASN. ABCB4, also known as multidrug resistance protein 3 (MDR3), is a compelling candidate gene, as it has been previously implicated in cholestasis, gallbladder disease, and adult biliary fibrosis/cirrhosis [40][41][42] . Finally, for a number of variant gene-pairs, the observed effect on NAFLD risk and the impact of gene expression in the liver was consistent with our understanding of the expected effect given what is known about gene function, suggesting possible relevance as therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Vujkovic¹,

Ramdas²,

Lorenz³

et al. 2021

Preprint

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Nonalcoholic fatty liver disease (NAFLD) is a prevalent, heritable trait that can progress to cancer and liver failure. Using our recently developed proxy definition for NAFLD based on chronic liver enzyme elevation without other causes of liver disease or alcohol misuse, we performed a multi-ancestry genome-wide association study in the Million Veteran Program with 90,408 NAFLD cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance of which 70 were novel, with an additional European-American specific and two African-American specific loci. Twelve of these loci were also significantly associated with quantitative hepatic fat on radiological imaging (n=44,289). Gene prioritization based on coding annotations, gene expression from GTEx, and functional genomic annotation identified candidate genes at 97% of loci. At eight loci, the allele associated with lower gene expression in liver was also associated with reduced risk of NAFLD, suggesting potential therapeutic relevance. Functional genomic annotation and gene-set enrichment demonstrated that associated loci were relevant to liver biology. We expand the catalog of genes influencing NAFLD, and provide a novel resource to understand its disease initiation, progression and therapy.

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Section: Discussionmentioning

confidence: 99%

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Vujkovic¹,

Ramdas²,

Lorenz³

et al. 2021

Preprint

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“…NGS sequencing is also very useful in diagnosis of ABCB4 deficiency due to its heterogeneous clinical presentation ( 23 ). Dröge et al ( 24 ) in the cohort of 427 patients with suspected genetic cholestasis observed that the median age of symptoms onset in PFIC-3 patients was later than in patients with PFIC-1 or PFIC-2.…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders—Single-Center Experience

et al. 2020

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Objective: To evaluate the clinical utility of panel-based NGS in the diagnostic approach of monogenic cholestatic liver diseases. Study design: Patients with diagnosis of chronic cholestatic liver disease of an unknown etiology underwent NGS of targeted genes panel. Group 1 included five patients (prospectively recruited) hospitalized from January to December 2017 while group 2 included seventeen patients (retrospectively recruited) hospitalized from 2010 to 2017 presenting with low-GGT PFIC phenotype (group 2a, 11 patients) or indeterminant cholestatic liver cirrhosis (group 2b, 6 patients). Results: Among 22 patients enrolled into the study, 21 various pathogenic variants (including 11 novel) in 5 different genes (including ABCB11, ABCB4, TJP2, DGUOK, CYP27A1) were identified. The molecular confirmation was obtained in 15 out of 22 patients (68%). In group 1, two out of five patients presented with low-GGT cholestasis, and were diagnosed with BSEP deficiency. Out of three patients presenting with high-GGT cholestasis, one patient was diagnosed with PFIC-3, and the remaining two were not molecularly diagnosed. In group 2a, seven out of eleven patients, were diagnosed with BSEP deficiency and two with TJP-2 deficiency. In group 2b, three out of six patients were molecularly diagnosed; one with PFIC-3, one with CYP27A1 deficiency, and one with DGUOK deficiency. Conclusions: Panel-based NGS appears to be a very useful tool in diagnosis of monogenic cholestatic liver disorders in cases when extrahepatic causes have been primarily excluded. NGS presented the highest diagnosis rate to identify the molecular background of cholestatic liver diseases presenting with a low-GGT PFIC phenotype.

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“…There is a clinical spectrum of diseases associated with ABCB4 deficiency, including ICP and gallbladder disease. 17 Mutations in this gene may help explain the noted association of gallstone disease and ICP. 8 Gamma-glutamyl transferase (GGT) is often elevated with mutations in this gene, though it is uncommonly elevated in ICP.…”

Section: Geneticsmentioning

confidence: 99%

Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management

Roediger

Fleckenstein

2021

Semin Liver Dis

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Intrahepatic cholestasis of pregnancy (ICP) is a common disorder in the second half of pregnancy characterized by pruritus and elevated serum bile acids (BAs) with spontaneous resolution after delivery. ICP carries a risk of adverse effects on the fetus which correlates with the degree of BA elevation. ICP occurs in genetically susceptible women as the reproductive hormones increase during pregnancy. Ursodeoxycholic acid is still considered the first-line treatment for ICP though it is of unproven benefit in preventing adverse effects on the fetus. Fetal complications, such as stillbirth, increase with gestational age, so preterm delivery is generally performed in cases of severe ICP, defined as BA levels above 40 μmol/L. ICP may recur in future pregnancies and is associated with an increased risk for future hepatobiliary, immune mediated, and cardiovascular diseases. Children born of mothers with ICP have normal development but may have a risk for subsequent metabolic disease.

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ABCB4 disease: Many faces of one gene deficiency

Cited by 35 publications

References 82 publications

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

A trans-ancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation

Targeted Next-Generation Sequencing in Diagnostic Approach to Monogenic Cholestatic Liver Disorders—Single-Center Experience

Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management

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