FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice

Wittenburg, Henning; Lyons, Malcolm A.; Li, Renhua; Churchill, Gary A.; Carey, Martin C.; Paigen, Beverly

doi:10.1016/s0016-5085(03)01053-9

Cited by 120 publications

(105 citation statements)

References 49 publications

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“…Consistent with the results of our study, there is supporting evidence from animal and human genetic studies that the ABCG5/G8 transporter is a true lithogenic risk factor: (1) Wittenburg et al 16 mapped a susceptibility locus for gallstone formation to the murine orthologue of the ABCG5/G8 genes, using quantitative trait locus analysis in experimental crosses of inbred mouse strains, and (2) a recent linkage study of 715 individuals from 39 Mexican American families with gallstones provided suggestive evidence of linkage to gallbladder disease on chromosome 2p21, 40 the site of the ABCG5/G8 genes. 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.…”

Section: Discussionsupporting

confidence: 91%

“…Carriers of the 19H allele whether homozygous or heterozygous were significantly overrepresented in the cases compared with the controls (OR ϭ 3.118; P ϭ 0.019). Consistent with the mouse model, 16 heterozygosity for the lithogenic ABCG8 allele is associated with gallstones in humans: 21.4% (18 of 84) of all gallstone patients carried the heterozygous D19H genotype, as compared with 8.6% (6 of 70) of the controls (OR ϭ 2.954; P ϭ 0.026). However, no association was observed for the other 4 ABCG5/G8 SNPs under investigation.…”

Section: Resultssupporting

confidence: 59%

“…14,15 Interestingly, Wittenburg et al established Abcg5/g8 (ATP-binding cassette [ABC] transporters, subfamily G, members 5 and 8; also known as sterolins 1 and 2) as candidate genes in the mouse Lith9 locus. 16 ABC transporters use the energy of ATP-binding/hydrolysis to transport substrates across cell membranes. The ABCG5/G8 genes encode protein half-transporters that heterodimerize to form the functional transporter localized in the canalicular membrane of hepatocytes and facilitating cholesterol secretion into bile, 17 consistent with the candidacy of this gene pair in cholesterol gallstone susceptibility in mice.…”

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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: Discussionsupporting

confidence: 91%

Section: Resultssupporting

confidence: 59%

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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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“…We have shown that clumpy growth of yeast cells maps to the same locus as the expression of daughter-specific genes involved in mitosis and budding (6). In keeping with these observations, several groups have used expression profiling to choose among gene candidates when physiological traits map to large genetic regions (43)(44)(45).…”

Section: Discussionsupporting

confidence: 78%

The landscape of genetic complexity across 5,700 gene expression traits in yeast

Brem

Kruglyak

2005

Proc. Natl. Acad. Sci. U.S.A.

557

682

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Many studies have identified quantitative trait loci (QTLs) that contribute to continuous variation in heritable traits of interest. However, general principles regarding the distribution of QTL numbers, effect sizes, and combined effects of multiple QTLs remain to be elucidated. Here, we characterize complex genetics underlying inheritance of thousands of transcript levels in a cross between two strains of Saccharomyces cerevisiae. Most detected QTLs have weak effects, with a median variance explained of 27% for highly heritable transcripts. Despite the high statistical power of the study, no QTLs were detected for 40% of highly heritable transcripts, indicating extensive genetic complexity. Modeling of QTL detection showed that only 3% of highly heritable transcripts are consistent with single-locus inheritance, 17-18% are consistent with control by one or two loci, and half require more than five loci under additive models. Strikingly, analysis of parent and progeny trait distributions showed that a majority of transcripts exhibit transgressive segregation. Sixteen percent of highly heritable transcripts exhibit evidence of interacting loci. Our results will aid design of future QTL mapping studies and may shed light on the evolution of quantitative traits.Beavis effect ͉ epistasis ͉ transgressive segregation M ost heritable traits show continuous variation in a population. Such quantitative traits have been a subject of intensive study (see refs. 1-4 for reviews). Identification of genetic polymorphisms underlying quantitative traits, known as quantitative trait loci or QTLs, is of interest in medical genetics, where they can provide insights into disease mechanisms and lead to new diagnostics and therapeutics, and in agricultural genetics, where they can aid breeding programs. Genetic factors underlying quantitative traits also play a crucial role in evolutionary theory. Most quantitative traits appear to be genetically complex, i.e., controlled by multiple QTLs (2).Linkage mapping of QTLs has been reported for thousands of quantitative traits. In a handful of cases, the DNA sequence polymorphisms underlying a quantitative trait have been identified (4-8). However, it has proven difficult to comprehensively identify the multiple QTLs that combine to determine the complex genetic architecture of a trait, largely because of limitations in the statistical power of mapping experiments (9). As a result, the principles that govern genetic complexity remain an area of active research. Are traits more likely to be controlled by a few loci of large effect or many loci of small effect (10, 11)? Are most QTL effects additive, or do QTLs often act in a nonadditive (epistatic) manner (12)? Does inheritance of alleles from a given parent at multiple QTLs usually affect a trait in the same direction, as predicted by certain evolutionary models (13)? In addition to elegant theoretical advances (1, 10, 11, 13), several studies have surveyed large numbers of traits empirically to identify genetic trends (14-16). But many que...

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“…Total genetic deletion of ABCG5/ G8 produces sitosterolemia, a disease associated with hyperabsorption of cholesterol and plant sterols that is linked to accelerated atherosclerosis [1]. Interestingly, the ABCG5/G8 locus has also long been implicated in the formation of cholesterol gallstones [10]. Recently, specific coding variants have been identified in genome-wide association studies that likely result in a gain-of-function of ABCG5/G8, supposedly translating into increased biliary cholesterol secretion [11].…”

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confidence: 99%

The Neglected Cousin of the Hepatocyte: How Gallbladder Epithelial Cells Might Contribute to Cholesterol Gallstone Formation

Dikkers

Tietge

2013

Dig Dis Sci

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FXR and ABCG5/ABCG8 as determinants of cholesterol gallstone formation from quantitative trait locus mapping in mice

Cited by 120 publications

References 49 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

The landscape of genetic complexity across 5,700 gene expression traits in yeast

The Neglected Cousin of the Hepatocyte: How Gallbladder Epithelial Cells Might Contribute to Cholesterol Gallstone Formation

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