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

Abstract

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.

Clinical outcomes of ABCB4 heterozygosity in infants and children with cholestatic liver disease

“…The use of population‐based data can have limitations such as lack of individual level data and ancestry as well as technical artifacts that arise from differences in sequencing platforms and data processing 32 . A control population will allow for the calculation of mutational burden and statistical significance of rare variants 33 …”

“…32 A control population will allow for the calculation of mutational burden and statistical significance of rare variants. 33…”