255 research outputs found

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

    Get PDF
    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

    Relationship of Paroxysmal Atrial Tachyarrhythmias to Volume Overload

    Get PDF
    BACKGROUND: Clinical experience suggests that atrial tachyarrhythmias (ATs) are a frequent comorbidity in heart failure patients with left ventricular systolic dysfunction and that volume overload may increase AT susceptibility. However, substantiating this apparent relationship in free-living patients is difficult. Recently, certain implantable cardioverter-defibrillators provide, by measuring transpulmonary electric bioimpedance, an index of intrathoracic fluid status (OptiVol index [OI]). The goal of this study was to determine whether periods of greater intrathoracic fluid congestion (as detected by OI) correspond with increased AT event frequency. METHODS AND RESULTS: This analysis retrospectively assessed the relation between AT events and OI estimate of volume overload in patients with left ventricular systolic dysfunction and OI-capable implantable cardioverter-defibrillators. OI values were stratified into 3 levels: group 1, \u3c40; group 2, 40 to 60; and group 3, \u3e60. An OI threshold-crossing event was defined as OI \u3e or = 60, a value previously associated with clinically significant volume overload. Findings in 59 patients (mean left ventricular ejection fraction, 24%) with 225 follow-up visits (mean, 3.8 visits per patient) were evaluated. AT prevalence was 73%. AT frequency (percent of patients visits with at least 1 episode of AT since previous device interrogation) was greater in group 3 versus group 1 (P=0.0342). Finally, in terms of temporal sequence, AT episodes preceded OI threshold-crossing event in 43% of incidences, followed threshold-crossing event in 29%, and was simultaneous or indeterminate in the remainder. CONCLUSIONS: These findings not only support the view that worsening pulmonary congestion is associated with increased AT frequency in patients with left ventricular dysfunction but also suggest that AT events may be responsible for triggering episodic pulmonary congestion more often than previously suspected

    Complex nature of SNP genotype effects on gene expression in primary human leucocytes

    Get PDF
    <p>Abstract</p> <p>Background</p> <p>Genome wide association studies have been hugely successful in identifying disease risk variants, yet most variants do not lead to coding changes and how variants influence biological function is usually unknown.</p> <p>Methods</p> <p>We correlated gene expression and genetic variation in untouched primary leucocytes (n = 110) from individuals with celiac disease – a common condition with multiple risk variants identified. We compared our observations with an EBV-transformed HapMap B cell line dataset (n = 90), and performed a meta-analysis to increase power to detect non-tissue specific effects.</p> <p>Results</p> <p>In celiac peripheral blood, 2,315 SNP variants influenced gene expression at 765 different transcripts (< 250 kb from SNP, at FDR = 0.05, <it>cis </it>expression quantitative trait loci, eQTLs). 135 of the detected SNP-probe effects (reflecting 51 unique probes) were also detected in a HapMap B cell line published dataset, all with effects in the same allelic direction. Overall gene expression differences within the two datasets predominantly explain the limited overlap in observed <it>cis</it>-eQTLs. Celiac associated risk variants from two regions, containing genes <it>IL18RAP </it>and <it>CCR3</it>, showed significant <it>cis </it>genotype-expression correlations in the peripheral blood but not in the B cell line datasets. We identified 14 genes where a SNP affected the expression of different probes within the same gene, but in opposite allelic directions. By incorporating genetic variation in co-expression analyses, functional relationships between genes can be more significantly detected.</p> <p>Conclusion</p> <p>In conclusion, the complex nature of genotypic effects in human populations makes the use of a relevant tissue, large datasets, and analysis of different exons essential to enable the identification of the function for many genetic risk variants in common diseases.</p

    Structural insights into RNA processing by the human RISC-loading complex.

    Get PDF
    Targeted gene silencing by RNA interference (RNAi) requires loading of a short guide RNA (small interfering RNA (siRNA) or microRNA (miRNA)) onto an Argonaute protein to form the functional center of an RNA-induced silencing complex (RISC). In humans, Argonaute2 (AGO2) assembles with the guide RNA-generating enzyme Dicer and the RNA-binding protein TRBP to form a RISC-loading complex (RLC), which is necessary for efficient transfer of nascent siRNAs and miRNAs from Dicer to AGO2. Here, using single-particle EM analysis, we show that human Dicer has an L-shaped structure. The RLC Dicer's N-terminal DExH/D domain, located in a short 'base branch', interacts with TRBP, whereas its C-terminal catalytic domains in the main body are proximal to AGO2. A model generated by docking the available atomic structures of Dicer and Argonaute homologs into the RLC reconstruction suggests a mechanism for siRNA transfer from Dicer to AGO2

    Diagnosis and management of adult coeliac disease: guidelines from the British Society of Gastroenterology

    Get PDF
    A multidisciplinary panel of 18 physicians and 3 non-physicians from eight countries (Sweden, UK, Argentina, Australia, Italy, Finland, Norway and the USA) reviewed the literature on diagnosis and management of adult coeliac disease (CD). This paper presents the recommendations of the British Society of Gastroenterology. Areas of controversies were explored through phone meetings and web surveys. Nine working groups examined the following areas of CD diagnosis and management: classification of CD; genetics and immunology; diagnostics; serology and endoscopy; follow-up; gluten-free diet; refractory CD and malignancies; quality of life; novel treatments; patient support; and screening for CD
    • …
    corecore