ABCB4 gene mutation—associated cholelithiasis in adults

Rosmorduc, Olivier; Hermelin, B.; Boëlle, Pierre‐Yves; Parc, R; Taboury, Jean; Poupon, Raoul

doi:10.1016/s0016-5085(03)00898-9

Cited by 263 publications

(206 citation statements)

References 31 publications

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“…An additional application of the chip is as an investigative tool to study the role of synonymous and non-synonymous polymorphisms of individual genes, or of heterozygous polymorphisms in functionally related genes, in phenotype determination of children and adults with chronic cholestasis, intrahepatic cholestasis of pregnancy, and gallstone formation associated with mutations in ABCB4. 43,44 One specific disease that may benefit from such investigative approach is biliary atresia, in which the systematic analysis of all five genes may provide insight into the potential role of genetic variations in long-term survival with the native liver. For all of these settings, the current version of the Jaundice Chip offers a real opportunity to translate laboratory discoveries into a tool that may simplify the diagnostic algorithm at the bedside, and facilitate the design of treatment protocols that take into account the genetic makeup of the patient.…”

Section: Discussionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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Background and Aims-Inherited syndromes of intrahepatic cholestasis commonly result from mutations in the genes SERPINA1 (α1-antitrypsin deficiency), JAG1 (Alagille syndrome), ATP8B1 (Progressive Familial Intrahepatic Cholestasis type 1/PFIC1), ABCB11 (PFIC2), and ABCB4 (PFIC3). However, the large gene sizes and lack of mutational hotspots make it difficult to survey for disease-causing mutations in clinical practice. Here, we aimed to develop a technological tool that reads out the nucleotide sequence of these genes rapidly and accurately.

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Section: Discussionmentioning

confidence: 99%

Novel Resequencing Chip Customized to Diagnose Mutations in Patients With Inherited Syndromes of Intrahepatic Cholestasis

et al. 2007

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“…As estimated in our previous large twin study 10 and a recent family study, 11 environmental factors account for up to 75% of the phenotypic variation in gallstone disease, but 25% to 29% is determined by genes. Notwithstanding, except for apparently rare gene variants, 8,12,13 genetic risk factors for most patients with cholesterol gallbladder stones have yet to be identified. Studies of common polymorphisms in the genes encoding apolipoproteins A, B, and E and cholesterol 7␣-hydroxylase, as well as cholesteryl ester transfer protein, did not find any associations that have been replicated.…”

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confidence: 99%

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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“…The term "LPAC (Low Phospholipid Associated Cholelithiasis) Syndrome" was derived from this study 28 . Post-cholecystectomy biliary symptoms may be due to intrahepatic cholesterol deposits and bile duct inflammation, rather than detectable stones 29 . Homozygous and heterozygous mutations of ABCB4 were found in 56% of LPAC syndrome patients.…”

Section: Clinical Presentationmentioning

confidence: 99%