Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gall stone disease

Schafmayer, Clemens; Tepel, Jürgen; Egberts, Jan Hendrik; Franke, Arthur E.; Buch, Sajad Ahmad; Seeger, Markus; Lammert, Frank; Kremer, Bernd; Fölsch, U.R.; Fändrich, F.; Schreiber, Stefanie; Hampe, Jochen

doi:10.1055/s-2006-950845

Cited by 12 publications

(15 citation statements)

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“…Despite increasing evidence from mouse studies for gallstone susceptibility genes, 15 none of the murine Lith loci have yet been confirmed in a human population. 41 Thus, our study represents a successful translational study that confirmed an association of a mouse Lith locus (Lith9 on chromosome 17) as a susceptibility factor for cholelithiasis in humans or a human LITH gene. Rosmorduc et al 12 provided evidence that rare loss-of-function mutations in the ABCB4 gene encoding the hepatocanalicular transporter required for biliary phosphatidylcholine secretion lead to gallstone formation.…”

Section: Discussionsupporting

confidence: 61%

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

et al. 2007

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Genomewide scans of inbred strains of mice have linked the genes encoding the hepatocanalicular cholesterol transporter ABCG5/G8 to gallstone formation. Five nonsynonymous coding single-nucleotide polymorphisms (SNPs) in the orthologous human genes are associated with differences in serum cholesterol and plant sterol levels. We now tested these ABCG5/G8 SNPs for linkage and association with gallstone susceptibility in humans. Prospectively, we collected data from 178 white individuals with gallbladder stones or history of cholecystectomy in 84 families and from 70 stone-free controls, as confirmed by abdominal ultrasound. We performed nonparametric linkage (NPL) analysis of affected sib pairs (ASPs) and association tests of cases and controls. In ASPs, gallstones were strongly linked to the D19H variant of the ABCG8 gene (NPL score ‫؍‬ 7.1; P ‫؍‬ 4.6 ؋ 10 ؊13 ). The risk of gallstones in carriers of the 19H allele was significantly increased in randomly selected cases from the ASP cohort compared to the stone-free controls (OR ‫؍‬ 3.018; P ‫؍‬ 0.017). Consistent with the mouse model, heterozygosity for the lithogenic ABCG8 allele was associated with gallstones in humans; 21.4% of gallstone patients carried the heterozygous D19H genotype, compared with 8.6% of controls (OR ‫؍‬ 2.954; P ‫؍‬ 0.026). Conclusion: The linkage and association studies identified the cholesterol transporter ABCG5/G8 as a genetic determinant of gallstone formation, or LITH gene, in humans. The function of this transporter and the results of the genetic study taken together indicate that in gallstone-susceptible carriers of the ABCG8 19H allele, cholesterol cholelithiasis is secondary to increased hepatobiliary cholesterol secretion. (HEPATOLOGY 2007;46:793-801.)

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Section: Discussionsupporting

confidence: 61%

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

et al. 2007

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“…More than 90% of gallstones consist mainly of cholesterol and are formed within the gallbladder [12]. Cholesterol stones form mainly if bile contains more cholesterol than can be solubilized by mixed micelles of bile salts and phosphatidylcholine (lecithin).…”

Section: Cholesterol Stonesmentioning

confidence: 99%

“…A very small proportion of gallbladder stones (2%) are black pigment stones [12]. They consist predominantly of polymerized calcium bilirubinate, which precipitates if the ion product of calcium and unconjugated bilirubin exceeds its solubility product and polymerizes slowly in biliary sludge.…”

Section: Black Pigment Stonesmentioning

confidence: 99%

Gallstone disease: From genes to evidence-based therapy

Lammert

Míquel

2008

Journal of Hepatology

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The number of gallstone patients is increasing in ageing populations with a high prevalence of metabolic syndrome and obesity. Recently variants of hepatic ATP binding cassette transporters have been identified as genetic susceptibility factors for gallstone disease, pointing to novel means for risk assessment and prevention. Although laparoscopic cholecystectomy is the mainstay of therapy for symptomatic gallbladder stones, the clinical management of gallstone disease is changing rapidly, with an increase in day case surgery and the advent of transluminal endoscopic surgery. Here, we summarize the molecular and genetic mechanisms of gallstone formation as well as the current evidence-based algorithms for diagnosis and therapy of gallbladder and bile duct stones.

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“…Defects of bile formation are likely to be important in the development of biliary calculi [138] , inspiring candidate gene studies of important transport proteins involved in this process [139] . Given this a priori knowledge, it was not surprising that the main disease locus in a German gallstone GWAS was ABCG8, encoding a component of the cholesterol transporter heterodimer ABCG5/G8 [140] .…”

Section: Gallstonesmentioning

confidence: 99%

Genome-wide association studies - A summary for theclinical gastroenterologist

Melum¹,

Franke²,

Karlsen³

2009

WJG

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Genome-wide association studies (GWAS) have been applied to various gastrointestinal and liver diseases in recent years. A large number of susceptibility genes and key biological pathways in disease development have been identified. So far, studies in inflammatory bowel diseases, and in particular Crohn's disease, have been especially successful in defining new susceptibility loci using the GWAS design. The identification of associations related to autophagy as well as several genes involved in immunological response will be important to future research on Crohn's disease. In this review, key methodological aspects of GWAS, the importance of proper cohort collection, genotyping issues and statistical methods are summarized. Ways of addressing the shortcomings of the GWAS design, when it comes to rare variants, are also discussed. For each of the relevant conditions, findings from the various GWAS are summarized with a focus on the affected biological systems.

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Investigation of the Lith1 candidate genes ABCB11 and LXRA in human gall stone disease

Cited by 12 publications

References 0 publications

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol

Gallstone disease: From genes to evidence-based therapy

Genome-wide association studies - A summary for theclinical gastroenterologist

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