Multidrug resistance protein 3 R652G may reduce susceptibilityto idiopathic infant cholestasis

Chen, Xiuqi; Wang, Lin-Lin; Shan, Qing-Wen; Tang, Qing; Lian, Shu-Jun

doi:10.3748/wjg.15.5855

Cited by 3 publications

References 15 publications

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Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

Zöllner,

Finer,

Linton

et al. 2023

Sci Rep

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This study assessed the contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people. Five genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency < 5%. Variants were filtered, and annotated to perform rare variant burden analysis, protein structure, and modelling analysis in-silico. Out of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were mostly heterozygous unless specified. 90 were novel and of those variants, 22 were considered likely pathogenic and 9 pathogenic. We identified variants in volunteers with gallstone disease (n = 31), intrahepatic cholestasis of pregnancy (ICP, n = 16), cholangiocarcinoma and cirrhosis (n = 2). Fourteen novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. The rare variant burden was significantly increased in ABCB11. Protein modelling demonstrated variants that appeared to likely cause significant structural alterations. This study highlights the significant genetic burden contributing to cholestatic liver disease. Novel likely pathogenic and pathogenic variants were identified addressing the underrepresentation of diverse ancestry groups in genomic research.

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Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

Zöllner,

Finer,

Linton

et al. 2023

Sci Rep

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Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

Zöllner¹,

Finer

Linton

et al. 2022

Preprint

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ObjectivesThis study aimed to assess contribution of five genes previously known to be involved in cholestatic liver disease in British Bangladeshi and Pakistani people in the United Kingdom as they are an understudied genetic ancestry group with high rates of parental relatedness and disproportionate disease burden.MethodsFive genes (ABCB4, ABCB11, ATP8B1, NR1H4, TJP2) were interrogated by low/mid whole exome sequencing data of 5236 volunteers. Included were non-synonymous or loss of function (LoF) variants with a minor allele frequency <5%. Variants were filtered and annotated. Variants associated with a phenotype or predicted to be likely pathogenic (LP) underwent protein structure and modelling analysis.ResultsOut of 314 non-synonymous variants, 180 fulfilled the inclusion criteria and were heterozygous. 90 were novel and unique to this cohort and not previously reported in the GnomAD database. Of those novel variants, 22 were considered LP and 9 pathogenic. We identified variants associated with gallstone disease (n=31), intrahepatic cholestasis of pregnancy (ICP, n=16), cholangiocarcinoma and cirrhosis (n=2). Fourteen heterozygous novel LoF variants were identified: 7 frameshift, 5 introduction of premature stop codon and 2 splice acceptor variants. A total of 73 variants underwent protein modelling. The study identified 10 variants that resulted in predicted significant structural damage at a protein level, of which 4 were unique to this cohort.ConclusionsThis study identified novel LP and pathogenic variants. We provide further insight into rare variants associated with ICP, cholangiocarcinoma, and gallstone disease. This study highlights the importance of studying diverse ancestry groups in genomic research.WHAT IS KNOWNCholestatic liver diseases encompass a broad range of conditions.Intrahepatic cholestasis of pregnancy (ICP) is the commonest gestational liver disease.Genetic and environmental factors contribute to the aetiology of cholestatic disease.South Asian populations are disproportionally affected.WHAT IS NEW HEREExome sequencing analysis in a British South Asian population discovered new genetic mutations.Pathogenic variants were identified that increase risk to cholestatic liver disease.Novel variants that contribute to ICP were identified.

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Effect of drug transporter pharmacogenetics on cholestasis

Dietrich

Geier

2014

Expert Opinion on Drug Metabolism & Toxicology

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Polymorphisms in transporter genes are frequent. For clinically relevant cholestatic syndromes, it often requires a combination of genetic variants or acquired triggers such as pregnancy or drug treatment. In combination with other pathogenetic aspects, genetic variants in drug transporters may contribute to our understanding of not only cholestatic diseases such as primary sclerosing cholangitis or primary biliary cirrhosis, but also the natural course of chronic liver disease in general.

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Multidrug resistance protein 3 R652G may reduce susceptibilityto idiopathic infant cholestasis

Cited by 3 publications

References 15 publications

Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

Effect of drug transporter pharmacogenetics on cholestasis

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