Biomedical subjects

Beverly Paigen

Publications and source records attributed to Beverly Paigen.

At least 19 recordsLinked to original sources

PubMed2006

Lipolytic and ligand-binding functions of hepatic lipase protect against atherosclerosis in LDL receptor-deficient mice.

To elucidate the separate contributions of the lipolytic versus ligand-binding functions of hepatic lipase (HL) to lipoprotein metabolism and atherosclerosis, and to investigate the role of the low density lipoprotein receptor (LDLr) in these processes, we compared mice expressing catalytically active HL (HL-WT) with mice expressing inactive HL (HL-S145G) in a background lacking endogenous HL and the LDLr (LDLr-KOxHL-KO). HL-WT and HL-S145G reduced (P < 0.05 for all) cholesterol (55% vs. 20%), non-HDL-cholesterol (63% vs. 22%), and apolipoprotein B (apoB; 34% vs. 16%) by enhancing the catabolism of autologous (125)I-apoB-intermediate density lipoprotein (IDL)/LDL (fractional catabolic rate in day(-1): 6.07 +/- 0.25, LDLr-KOxHL-WT; 4.76 +/- 0.30, LDLr-KOxHL-S145G; 3.70 +/- 0.13, LDLr-KOxHL-KO); HL-WT had a greater impact on the concentration, composition, particle size, and catabolism of apoB-containing lipoproteins (apoB-Lps) and HDL. Importantly, consistent with the changes in apoB-Lps, atherosclerosis in LDLr-KOxHL-KO mice fed a regular chow diet (RCD) was reduced by both HL-WT and HL-S145G (by 71% and 51% in cross-sectional analysis, and by 85% and 67% in en face analysis; P < 0.05 for all). These data identify physiologically relevant but distinct roles for the lipolytic versus ligand-binding functions of HL in apoB-Lp metabolism and atherosclerosis and demonstrate that their differential effects on these processes are mediated by changes in catabolism via non-LDLr pathways. These changes, evident even in the presence of apoE, establish an antiatherogenic role of the ligand-binding function of HL in LDLr-deficient mice.

Animals↗

PubMed2006

Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited.

We previously reported that liver-specific overexpression of ABCG5/G8 in mice is not atheroprotective, suggesting that increased biliary cholesterol secretion must be coupled with decreased intestinal cholesterol absorption to increase net sterol loss from the body and reduce atherosclerosis. To evaluate this hypothesis, we fed low density lipoprotein receptor-knockout (LDLr-KO) control and ABCG5/G8-transgenic (ABCG5/G8-Tg)xLDLr-KO mice, which overexpress ABCG5/G8 only in liver, a Western diet containing ezetimibe to reduce intestinal cholesterol absorption. On this dietary regimen, liver-specific ABCG5/G8 overexpression increased hepatobiliary cholesterol concentration and secretion rates (1.5-fold and 1.9-fold, respectively), resulting in 1.6-fold increased fecal cholesterol excretion, decreased hepatic cholesterol, and increased (4.4-fold) de novo hepatic cholesterol synthesis versus LDLr-KO mice. Plasma lipids decreased (total cholesterol, 32%; cholesteryl ester, 32%; free cholesterol, 30%), mostly as a result of reduced non-high density lipoprotein-cholesterol and apolipoprotein B (apoB; 36% and 25%, respectively). ApoB-containing lipoproteins were smaller and lipid-depleted in ABCG5/G8-TgxLDLr-KO mice. Kinetic studies revealed similar 125I-apoB intermediate density lipoprotein/LDL fractional catabolic rates, but apoB production rates were decreased 37% in ABCG5/G8-TgxLDLr-KO mice. Proximal aortic atherosclerosis decreased by 52% (male) and 59% (female) in ABCG5/G8-TgxLDLr-KO versus LDLr-KO mice fed the Western/ezetimibe diet. Thus, increased biliary secretion, resulting from hepatic ABCG5/G8 overexpression, reduces atherogenic risk in LDLr-KO mice fed a Western diet containing ezetimibe. These findings identify distinct roles for liver and intestinal ABCG5/G8 in modulating sterol metabolism and atherosclerosis.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Enhanced ABCG1 expression increases atherosclerosis in LDLr-KO mice on a western diet.

ABCG1 promotes cholesterol efflux from cells, but ABCG1(-/-) bone marrow transplant into ApoE(-/-) and LDLr(-/-) mice reduces atherosclerosis. To further investigate the role of ABCG1 in atherosclerosis, ABCG1 transgenic mice were crossed with LDLr-KO mice and placed on a high-fat western diet. Increased expression of ABCG1 mRNA was detected in liver (1.8-fold) and macrophages (2.7-fold), and cholesterol efflux from macrophages to HDL was also increased (1.4-fold) in ABCG1xLDLr-KO vs. LDLr-KO mice. No major differences were observed in total plasma lipids. However, cholesterol in the IDL-LDL size range was increased by approximately 50% in ABCG1xLDLr-KO mice compared to LDLr-KO mice. Atherosclerosis increased by 39% (10.1+/-0.8 vs 6.1+/-0.9% lesion area, p=0.02), as measured by en face analysis, and by 53% (221+/-98 vs 104+/-58x10(3)microm(2), p =0.01), as measured by cross-sectional analysis in ABCG1xLDLr-KO mice. Plasma levels for MCP-1 (1.5-fold) and TNF-alpha (1.2-fold) were also increased in ABCG1xLDLr-KO mice. In summary, these findings suggest that enhanced expression of ABCG1 increases atherosclerosis in LDLr-KO mice, despite its role in promoting cholesterol efflux from cells.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2006

Complex genetic architecture revealed by analysis of high-density lipoprotein cholesterol in chromosome substitution strains and F2 crosses.

Intercrosses between inbred lines provide a traditional approach to analysis of polygenic inheritance in model organisms. Chromosome substitution strains (CSSs) have been developed as an alternative to accelerate the pace of gene identification in quantitative trait mapping. We compared a classical intercross and three CSS intercrosses to examine the genetic architecture underlying plasma high-density lipoprotein cholesterol (HDL) levels in the C57BL/6J (B) and A/J (A) mouse strains. The B x A intercross revealed significant quantitative trait loci (QTL) for HDL on chromosomes 1, 4, 8, 15, 17, 18, and 19. A CSS survey revealed that many have significantly different HDL levels compared to the background strain B, including chromosomes with no significant QTL in the intercross and, in some cases (CSS-1, CSS-17), effects that are opposite to those observed in the B x A intercross population. Intercrosses between B and three CSSs (CSS-3, CSS-11, and CSS-8) revealed significant QTL but with some unexpected differences from the B x A intercross. Our inability to predict the results of CSS intercrosses suggests that additional complexity will be revealed by further crosses and that the CSS mapping strategy should be viewed as a complement to, rather than a replacement for, classical intercross mapping.

Animals↗

PubMed2006

ABCA1 overexpression in the liver of LDLr-KO mice leads to accumulation of pro-atherogenic lipoproteins and enhanced atherosclerosis.

The identification of ABCA1 as a key transporter responsible for cellular lipid efflux has led to considerable interest in defining its role in cholesterol metabolism and atherosclerosis. In this study, the effect of overexpressing ABCA1 in the liver of LDLr-KO mice was investigated. Compared with LDLr-KO mice, ABCA1-Tg x LDLr-KO (ABCA1-Tg) mice had significantly increased plasma cholesterol levels, mostly because of a 2.8-fold increase in cholesterol associated with a large pool of apoB-lipoproteins. ApoB synthesis was unchanged but the catabolism of (125)I-apoB-VLDL and -LDL were significantly delayed, accounting for the 1.35-fold increase in plasma apoB levels in ABCA1-Tg mice. We also found rapid in vivo transfer of free cholesterol from HDL to apoB-lipoproteins in ABCA1-Tg mice, associated with a significant 2.7-fold increase in the LCAT-derived cholesteryl linoleate content found primarily in apoB-lipoproteins. ABCA1-Tg mice had 1.4-fold increased hepatic cholesterol concentrations, leading to a compensatory 71% decrease in de novo hepatic cholesterol synthesis, as well as enhanced biliary cholesterol, and bile acid secretion. CAV-1, CYP2b10, and ABCG1 were significantly induced in ABCA1-overexpressing livers; however, no differences were observed in the hepatic expression of CYP7alpha1, CYP27alpha1, or ABCG5/G8 between ABCA1-Tg and control mice. As expected from the pro-atherogenic plasma lipid profile, aortic atherosclerosis was increased 10-fold in ABCA1-Tg mice. In summary, hepatic overexpression of ABCA1 in LDLr-KO mice leads to: 1) expansion of the pro-atherogenic apoB-lipoprotein cholesterol pool size via enhanced transfer of HDL-cholesterol to apoB-lipoproteins and delayed catabolism of cholesterol-enriched apoB-lipoproteins; 2) increased cholesterol concentration in the liver, resulting in up-regulated hepatobiliary sterol secretion; and 3) significantly enhanced aortic atherosclerotic lesions.

ATP Binding Cassette Transporter 1↗

PubMed2006

Structural model analysis of multiple quantitative traits.

We introduce a method for the analysis of multilocus, multitrait genetic data that provides an intuitive and precise characterization of genetic architecture. We show that it is possible to infer the magnitude and direction of causal relationships among multiple correlated phenotypes and illustrate the technique using body composition and bone density data from mouse intercross populations. Using these techniques we are able to distinguish genetic loci that affect adiposity from those that affect overall body size and thus reveal a shortcoming of standardized measures such as body mass index that are widely used in obesity research. The identification of causal networks sheds light on the nature of genetic heterogeneity and pleiotropy in complex genetic systems.

Adipose Tissue↗

PubMed2006

QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains.

To identify additional loci that influence lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) mapping in offspring of PERA/EiJxI/LnJ and PERA/EiJxDBA/2J intercrosses and in a combined data set from both crosses after 8 weeks of consumption of a high fat-diet. Most QTLs identified were concordant with homologous chromosomal regions that were associated with lipoprotein levels in human studies. We detected significant new loci for HDL cholesterol levels on chromosome (Chr) 5 (Hdlq34) and for non-HDL cholesterol levels on Chrs 15 (Nhdlq9) and 16 (Nhdlq10). In addition, the analysis of combined data sets identified a QTL for HDL cholesterol on Chr 17 that was shared between both crosses; lower HDL cholesterol levels were conferred by strain PERA. This QTL colocalized with a shared QTL for cholesterol gallstone formation detected in the same crosses. Haplotype analysis narrowed this QTL, and sequencing of the candidate genes Abcg5 and Abcg8 confirmed shared alleles in strains I/LnJ and DBA/2J that differed from the alleles in strain PERA/EiJ. In conclusion, our analysis furthers the knowledge of genetic determinants of lipoprotein cholesterol levels in inbred mice and substantiates the hypothesis that polymorphisms of Abcg5/Abcg8 contribute to individual variation in both plasma HDL cholesterol levels and susceptibility to cholesterol gallstone formation.

Alleles↗

PubMed2006

Quantitative trait locus analysis for obesity reveals multiple networks of interacting loci.

Obesity is a highly heritable and genetically complex trait with hundreds of potential loci identified. An intercross of 513 F2 progeny between the SM/J x NZB/BINJ inbred mouse strains was generated to identify quantitative trait loci (QTL) that are involved in the weight of four fat pads: mesenteric, inguinal, gonadal, and retroperitoneal. Sex and lean body weight were treated as covariates in the analysis of these fat pads. This analysis uncoupled genetic effects related to overall body size from those influencing the adiposity of a mouse. We identified multiple significant QTL. QTL alleles associated with increased lean body weight and individual fat pad weights are contributed by the NZB background. Adiposity loci are distinct from these body size QTLs and high-adiposity alleles are contributed by the SM background. An extended network of epistatic QTL is also observed. A QTL on Chr 19 is the center of a network of eight interacting QTL, Chr 4 is the center of six, and Chr 17 the center of four interacting QTL. We conclude that interacting networks of multiple genes characterize the regulation of fat pad depots and body weight. Haplotype patterns and a literature-driven approach were used to generate hypotheses regarding the identity of the genes and pathways underlying the QTL.

Animals↗

PubMed2006

In search of new targets for plasma high-density lipoprotein cholesterol levels: promise of human-mouse comparative genomics.

Many lines of evidence suggest that raising plasma high-density lipoprotein cholesterol (HDL-C) levels may inhibit, perhaps even reverse, atherosclerosis. Quantitative trait locus (QTL) analysis has been performed in both humans and mice. So far, approximately 40 high-density lipoprotein (HDL)-regulating QTLs have been identified in each species. To compare human and mouse HDL-C QTLs, we generate human-mouse comparative chromosome maps based on homologous genes in humans and mice. The comparative maps reveal that most human and mouse HDL-C QTLs are concordant, which suggests that identifying the underlying QTL genes in mice will facilitate identifying their homologs in humans. The maps also help to narrow QTLs by mouse-human homologous QTL comparison. By using a combination of classic genetic approaches and newer bioinformatics tools (including comparative genomics as highlighted in this study), identifying new drug targets for plasma HDL-C levels holds more promise than ever.

Animals↗

PubMed2006

Validation of high-throughput methods for measuring blood urea nitrogen and urinary albumin concentrations in mice.

Chronic kidney disease is a substantial medical and economic burden. Animal models, including mice, are a crucial component of kidney disease research; however, recent studies disprove the ability of autoanalyzer methods to accurately quantify plasma creatinine levels, an established marker of kidney disease, in mice. Therefore, we validated autoanalyzer methods for measuring blood urea nitrogen (BUN) and urinary albumin concentrations, 2 common markers of kidney disease, in samples from mice. We used high-performance liquid chromatography to validate BUN concentrations measured using an autoanalyzer, and we utilized mouse albumin standards to determine the accuracy of the autoanalyzer over a wide range of albumin concentrations. We observed a significant, linear correlation between BUN concentrations measured by autoanalyzer and high-performance liquid chromatography. We also found a linear relationship between known and measured albumin concentrations, although the autoanalyzer method underestimated the known amount of albumin by 3.5- to 4-fold. We confirmed that plasma and urine constituents do not interfere with the autoanalyzer methods for measuring BUN and urinary albumin concentrations. In addition, we verified BUN and albuminuria as useful markers to detect kidney disease in aged mice and mice with 5/6-nephrectomy. We conclude that autoanalyzer methods are suitable for high-throughput analysis of BUN and albumin concentrations in mice. The autoanalyzer accurately quantifies BUN concentrations in mouse plasma samples and is useful for measuring urinary albumin concentrations when used with mouse albumin standards.

Albumins↗

PubMed2005

Bioinformatics toolbox for narrowing rodent quantitative trait loci.

Quantitative trait locus (QTL) analysis is a powerful method for localizing disease genes, but identifying the causal gene remains difficult. Rodent models of disease facilitate QTL gene identification, and causal genes underlying rodent QTL are often associated with the corresponding human diseases. Recently developed bioinformatics methods, including comparative genomics, combined cross analysis, interval-specific and genome-wide haplotype analysis, followed by sequence and expression analysis, each facilitated by public databases, provide new tools for narrowing rodent QTLs. Here we discuss each tool, illustrate its application and generate a bioinformatics strategy for narrowing QTLs. Combining these bioinformatics tools with classical experimental methods should accelerate QTL gene identification.

Animals↗

PubMed2005

Quantitative trait loci that determine BMD in C57BL/6J and 129S1/SvImJ inbred mice.

UNLABELLED: BMD is highly heritable; however, little is known about the genes. To identify loci controlling BMD, we conducted a QTL analysis in a (B6 x 129) F2 population of mice. We report on additional QTLs and also narrow one QTL by combining the data from multiple crosses and through haplotype analysis. INTRODUCTION: Previous studies have identified quantitative trait loci (QTL) that determine BMD in mice; however, identification of genes underlying QTLs is impeded by the large size of QTL regions. MATERIALS AND METHODS: To identify loci controlling BMD, we performed a QTL analysis of 291 (B6 x 129) F2 females. Total body and vertebral areal BMD (aBMD) were determined by peripheral DXA when mice were 20 weeks old and had consumed a high-fat diet for 14 weeks. RESULTS AND CONCLUSIONS: Two QTLs were common for both total body and vertebral aBMD: Bmd20 on chromosome (Chr) 6 (total aBMD; peak cM 26, logarithm of odds [LOD] 3.8, and vertebral aBMD; cM 32, LOD 3.6) and Bmd22 on Chr 1 (total aBMD; cM 104, LOD 2.5, and vertebral aBMD; cM 98, LOD 2.6). A QTL on Chr 10 (Bmd21, cM 68, LOD 3.0) affected total body aBMD and a QTL on Chr 7 (Bmd9, cM 44, LOD 2.7) affected vertebral aBMD. A pairwise genome-wide search did not reveal significant gene-gene interactions. Collectively, the QTLs accounted for 21.6% of total aBMD and 17.3% of vertebral aBMD of the F(2) population variances. Bmd9 was previously identified in a cross between C57BL/6J and C3H/HeJ mice, and we narrowed this QTL from 34 to 22 cM by combining the data from these crosses. By examining the Bmd9 region for conservation of ancestral alleles among the low allele strains (129S1/SvImJ and C3H/HeJ) that differed from the high allele strain (C57BL/6J), we further narrowed the region to approximately 9.9 cM, where the low allele strains share a common haplotype. Identifying the genes for these QTLs will enhance our understanding of skeletal biology.

Animals↗

PubMed2005

Identifying novel genes for atherosclerosis through mouse-human comparative genetics.

Susceptibility to atherosclerosis is determined by both environmental and genetic factors. Its genetic determinants have been studied by use of quantitative-trait-locus (QTL) analysis. So far, 21 atherosclerosis QTLs have been identified in the mouse: 7 in a high-fat-diet model only, 9 in a sensitized model (apolipoprotein E- or LDL [low-density lipoprotein] receptor-deficient mice) only, and 5 in both models, suggesting that different gene sets operate in each model and that a subset operates in both. Among the 27 human atherosclerosis QTLs reported, 17 (63%) are located in regions homologous (concordant) to mouse QTLs, suggesting that these mouse and human atherosclerosis QTLs have the same underlying genes. Therefore, genes regulating human atherosclerosis will be found most efficiently by first finding their orthologs in concordant mouse QTLs. Novel mouse QTL genes will be found most efficiently by using a combination of the following strategies: identifying QTLs in new crosses performed with previously unused parental strains; inducing mutations in large-scale, high-throughput mutagenesis screens; and using new genomic and bioinformatics tools. Once QTL genes are identified in mice, they can be tested in human association studies for their relevance in human atherosclerotic disease.

Animals↗

PubMed2005

Positional identification of TNFSF4, encoding OX40 ligand, as a gene that influences atherosclerosis susceptibility.

Ath1 is a quantitative trait locus on mouse chromosome 1 that renders C57BL/6 mice susceptible and C3H/He mice resistant to diet-induced atherosclerosis. The quantitative trait locus region encompasses 11 known genes, including Tnfsf4 (also called Ox40l or Cd134l), which encodes OX40 ligand. Here we report that mice with targeted mutations of Tnfsf4 had significantly (P <or= 0.05) smaller atherosclerotic lesions than did control mice. In addition, mice overexpressing Tnfsf4 had significantly (P <or= 0.05) larger atherosclerotic lesions than did control mice. In two independent human populations, the less common allele of SNP rs3850641 in TNFSF4 was significantly more frequent (P <or= 0.05) in individuals with myocardial infarction than in controls. We therefore conclude that Tnfsf4 underlies Ath1 in mice and that polymorphisms in its human homolog TNFSF4 increase the risk of myocardial infarction in humans.

Aged↗

PubMed2005

Combining data from multiple inbred line crosses improves the power and resolution of quantitative trait loci mapping.

Rodent inbred line crosses are widely used to map genetic loci associated with complex traits. This approach has proven to be powerful for detecting quantitative trait loci (QTL); however, the resolution of QTL locations, typically approximately 20 cM, means that hundreds of genes are implicated as potential candidates. We describe analytical methods based on linear models to combine information available in two or more inbred line crosses. Our strategy is motivated by the hypothesis that common inbred strains of the laboratory mouse are derived from a limited ancestral gene pool and thus QTL detected in multiple crosses are likely to represent shared ancestral polymorphisms. We demonstrate that the combined-cross analysis can improve the power to detect weak QTL, can narrow support intervals for QTL regions, and can be used to separate multiple QTL that colocalize by chance. Moreover, combined-cross analysis can establish the allelic states of a QTL among a set of parental lines, thus providing critical information for narrowing QTL regions by haplotype analysis.

Cholesterol, HDL↗

PubMed2005

Genetics of variation in HDL cholesterol in humans and mice.

Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same. Strategies to more rapidly identify genes underlying mouse and human QTLs for HDL-C include focusing on the mouse and using mouse-human homologies, combining crosses, and haplotyping to narrow the region. Sequence analysis and expression studies can distinguish candidate genes consistent across multiple mouse crosses, and testing the candidate genes in human association studies can provide additional evidence for the candidacy of a gene. Together these strategies can accelerate the pace of finding genes that regulate HDL.

Animals↗

PubMed2005

Single and interacting QTLs for cholesterol gallstones revealed in an intercross between mouse strains NZB and SM.

Quantitative trait locus (QTL) mapping was employed to investigate the genetic determinants of cholesterol gallstone formation in a large intercross between mouse strains SM/J (resistant) and NZB/B1NJ (susceptible). Animals consumed a gallstone-promoting diet for 18 weeks. QTL analyses were performed using gallstone weight and gallstone absence/presence as phenotypes; various models were explored for genome scans. We detected seven single QTLs: three new, significant QTLs were named Lith17 [chromosome (Chr) 5, peak=60 cM, LOD=5.4], Lith18 (Chr 5, 76 cM, LOD=4.3), and Lith19 (Chr 8, 0 cM, LOD=5.3); two confirmed QTLs identified previously and were named Lith20 (Chr 9, 44 cM, LOD=2.7) and Lith21 (Chr 10, 24 cM, LOD=2.9); one new, suggestive QTL (Chr 17) remains unnamed. Upon searching for epistatic interactions that contributed to gallstone susceptibility, the final suggestive QTL on Chr 7 was determined to interact significantly with Lith18 and, therefore, was named Lith22 (65 cM). A second interaction was identified between Lith19 and a locus on Chr 11; this QTL was named Lith23 (13 cM). mRNA expression analyses and amino acid haplotype analyses likely eliminated Slc10a2 as a candidate gene for Lith19. The QTLs identified herein largely contributed to gallstone formation rather than gallstone severity. Cloning the genes underlying these murine QTLs should facilitate prediction and cloning of the orthologous human genes.

Animals↗

PubMed2005

Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice.

To examine further the genetic determinants of cholesterol gallstone susceptibility in inbred mice, we performed quantitative trait locus (QTL) analysis of an intercross of gallstone-susceptible PERA/EiJ and gallstone-resistant DBA/2J inbred mice. Three hundred twenty-four F2 offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers. Linkage analysis was performed by interval mapping. In addition, we analyzed the combined datasets from this cross and from an independent cross of strain PERA and gallstone-resistant I/Ln mice. QTL mapping detected one significant new gallstone susceptibility (Lith) locus on Chromosome 13 (Lith15). A second significant QTL on Chr 6 (Lith16) confirmed a previous QTL. Furthermore, suggestive QTLs confirmed Lith loci from previous crosses on Chromosomes 1, 2, 5, 16 and X. QTL analysis of the dataset derived from the combined crosses increased the detection power and narrowed confidence intervals of Lith loci on Chromosomes 2, 6, 13, and 16. Moreover, the analysis of combined datasets revealed a shared QTL between both crosses on Chromosome 17 (Lith9). Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9.

ATP Binding Cassette Transporter, Subfamily G, Mem↗