Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms?

Acalovschi, Monica; Ciocan, Andra; Mostean, Ofelia; Tirziu, Simona; Chiorean, Erica; Keppeler, Hildegard; Schirin-Sokhan, Ramin; Lammert, Frank

doi:10.1016/j.ejim.2006.04.012

Cited by 58 publications

(77 citation statements)

References 24 publications

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“…22 Because serum plant sterol levels are lower in 19H carriers, the predicted change would be expected to increase transporter expression or function, although effects on ABCG5/G8 function can only be determined after reconstitution in in vitro sterol transfer assays. 44 Our previous study of siblings with gallstones 25 and other reports 23 have also observed significantly lower serum levels of total and LDL cholesterol in 19H carriers, indicating that D19H represents a gain-of-function variant that increases ABCG5/G8-mediated removal of plant sterols and cholesterol into bile and intestine. Hypersecretion of cholesterol from liver with cholesterol supersaturation of bile represents the common defect in patients with cholesterol gallstones.…”

Section: Discussionmentioning

confidence: 99%

“…This analysis resulted in highly significant NPL scores for the total range of 19H allele frequencies (f ϭ 0.03-0.13) previously reported. 23,25,[28][29][33][34][35] Figure 2A illustrates that an NPL score of 7.1, calculated using the marker allele frequency estimate in our sample (f ϭ 0.11), is a conservative estimate because the allele frequency is a result of selective sampling, higher than in other populations; lower frequencies would result in even higher NPL scores ( Fig. 2A; Table 4).…”

Section: Resultsmentioning

confidence: 99%

“…1): ABCG5 rs6720173 ϭ c.1810GϾC (p.E604Q); ABCG8 rs11887534 ϭ c.55GϾC (p.D19H), rs4148211 ϭ c.161AϾG (p.Y54C), rs4148217 ϭ c.1199CϾA (p.T400K), and rs6544718 ϭ c.1895CϾT (p.A632V). 22,23,25,28,29 All SNPs were genotyped using solution-phase hybridization reactions with 5Ј-nuclease and fluorescence detection (TaqMan assays) in a 7300 Real-Time polymerase chain reaction (PCR) system (Applera, Norwalk, CT). PCR reactions contained 20 ng of genomic DNA, 1ϫ TaqMan Universal Master Mix, 900 nM of each primer, and 200 nM of VIC-labeled and FAM-labeled probes in 25-L reactions.…”

Section: Methodsmentioning

confidence: 99%

“…All allele frequencies were within the ranges reported in the Entrez SNP database (www.ncbi.nih.gov) and in previous publications. 23,25,[28][29][33][34][35] In addition, we calculated allelesharing logarithm of the odds ratio (LOD) scores for exponential models according to Kong and Cox, 36 using GENEHUNTER-PLUS. 37 For the association (case-control) study, we randomly selected one affected sibling from each pedigree as a case.…”

Section: Methodsmentioning

confidence: 99%

“…17,21 On the other hand, we and others have shown that non-sitosterolemia-associated ABCG5/G8 polymorphisms are associated with decreased serum plant sterol and cholesterol levels. [22][23][24][25] Hence, the ABCG5/G8 transporter appears to be a key determinant of serum cholesterol level and cholesterol efflux into bile and intestine. We therefore hypothesized that the previously described 22 functionally relevant ABCG5/G8 polymorphisms confer an increased risk of gallstone formation and investigated their effects on gallstone susceptibility in affected sib pairs and stone-free controls, employing a combination of genetic linkage and association approaches.…”

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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: Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

et al. 2007

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Picky ABCG5/G8 and promiscuous ABCG2 ‐ a tale of fatty diets and drug toxicity

et al. 2020

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Structural data on ABCG5/G8 and ABCG2 reveal a unique molecular architecture for subfamily G ATP-binding cassette (ABCG) transporters and disclose putative substrate-binding sites. ABCG5/G8 and ABCG2 appear to use several unique structural motifs to execute transport, including the triple helical bundles, the membrane-embedded polar relay, the re-entry helices, and a hydrophobic valve. Interestingly, ABCG2 shows extreme substrate promiscuity, whereas ABCG5/G8 transports only sterol molecules. ABCG2 structures suggest a large internal cavity, serving as a binding region for substrates and inhibitors, while mutational and pharmacological analyses support the notion of multiple binding sites. By contrast, ABCG5/G8 shows a collapsed cavity of insufficient size to hold substrates. Indeed, mutational analyses indicate a sterol-binding site at the hydrophobic interface between the transporter and the lipid bilayer. In this review, we highlight key differences and similarities between ABCG2 and ABCG5/G8 structures. We further discuss the relevance of distinct and shared structural features in the context of their physiological functions. Finally, we elaborate on how ABCG2 and ABCG5/G8 could pave the way for studies on other ABCG transporters.

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Genetics of Gallstone Disease

Weber¹,

Lammert²

2019

Encyclopedia of Life Sciences

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Gallstone disease is one of the most frequent diseases, with up to 20% of adults developing gallstones and >20% of them symptoms. The treatment of symptomatic stones and their complications by endoscopy and surgery causes high costs in health care systems. Linkage studies in families and twins demonstrated that gallstones are, in part, genetically determined. Genome‐wide association studies have identified a panel of more than 30 ‘lithogenic genes’ that confer gallstone susceptibility in humans. The largest population attributable risk is conferred by variant p.D19H of the hepatobiliary and intestinal cholesterol transporter ABCG5/G8. Deficiency of a second hepatobiliary ABC transporter, the phosphatidylcholine translocase ABCB4, causes a peculiar type of gallstone disease and chronic cholangiopathy. Other lithogenic genes affect metabolic and inflammatory pathways along the gut–liver axis. Understanding the pathobiology of gallstones might help to overcome the current invasive treatment of gallstone disease by personalised effective prevention strategies for patients at risk. Key Concepts Gallstone disease is a complex disease affected by exogenous and genetic risk factors. The hepatobiliary cholesterol transporter ABCG5/G8 represents the major lithogenic gene in humans. ABCB4 deficiency causes low phospholipid‐associated cholelithiasis ( LPAC ). α 1 ‐Antitrypsin ( SERPINA1 ) and adiponutrin ( PNPLA3 ) mutations do not only cause chronic liver diseases but modify gallstone disease. In the future, polygenic risk scores for gallstone disease might guide prevention and non‐invasive treatment strategies.

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Are plasma lipid levels related to ABCG5/ABCG8 polymorphisms?

Cited by 58 publications

References 24 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

Picky ABCG5/G8 and promiscuous ABCG2 ‐ a tale of fatty diets and drug toxicity

Genetics of Gallstone Disease

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