Scarb1^{Hdlq1-NZB/BlNJ}
QTL Variant Detail

Summary

• QTL variant: Scarb1^{Hdlq1-NZB/BlNJ}
• Name: scavenger receptor class B, member 1; NZB/BiNJ
• MGI ID: MGI:2387157
• QTL: Scarb1 Location: Chr5:125354151-125418082 bp, - strand Genetic Position: Chr5, 64.11 cM

Variant origin

• Strain of Specimen: NZB/BlNJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased HDL cholesterol concentrations on a CHOW diet compared to SM/J. (J:76707)
• Inheritance: Other (see notes)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Hdlq1 exhibits additive inheritance.

Candidate Genes

J:133501

SNP analysis, mRNA microarray analysis and protein expression difference analysis were used to narrow the QTL intervals of 9 previously identified QTLs for HDL cholesterol (Hdlq1, Hdlq20, Hdlq24), gallstone susceptibility (Lith17, Lith19, Lith21) and obesity (Obwq3, Obwq4, Obwq5). This methodology identified a manageable list of potential candidate genes for each QTL.

A panel of 130,000 SNPs for SM/J and NZB/BlNJ reduced the QTL intervals by 40%-72%. Liver mRNA analysis identified 10 genes differentially expressed between SM/J and NZB/BlNJ strains and this finding was confirmed using TaqMan RT-PCR assays. Mass spectrometry analysis of liver proteins identified 45 proteins displaying differential expression between SM/J andNZB/BlNJ.

On mouse Chromosome 1, Apoa2 (92.6 cM), Fh1, and Hsd11b1 were identified as potential candidate genes for Hdlq20 at 96 cM. Apoa2 was identified based on protein expression and SNP coding sequence differences. Apoa2 displays up-regulation in NZB/BlNJ liver proteins comparedto SM/J. Fh1 displays gene coding sequence differences and decreased protein expression in NZB/BlNJ livers compared to SM/J. Hsd11b1 was identified based on decreased protein expression in NZB/BlNJ.

On mouse Chromosome 5, Acads (65 cM) and Scarb1 (68 cM)were identified as potential candidate genes for Hdlq1 (70 cM) and Lith17 (60 cM). Acads was identified on the basis of decreased protein expression in NZB/BlNJ livers compared to SM/J, as well as coding sequence differences. Scarb1 displays coding regionsequence differences and decreased liver mRNA expression in NZB/BlNJ. Scarb1 is located more closely to Hdlq1 and decreased Scarb1 mRNA expression was observed for this QTL.

On mouse Chromosome 6, Pparg (52.7 cM), Rassf4 and Adipor2 (60.7 cM) were identified as potential candidate genes for Hdlq24 (66 cM) and Obwq3 (42 cM). Pparg displays coding sequences differences between NZB/BlNJ and SM/J while Rassf4 displays decreased liver mRNA expression in NZB/BlNJ animals. Adipor2 displays increased liver mRNAexpression in NZB/BlNJ and gene coding sequence differences. Ndufa9 was identified as a QTL for Hdlq24 on the basis of decreased liver protein expression in NZB/BlNJ and coding sequence differences.

On mouse Chromosome 8,Slc10a2 (2 cM) was identifiedasa potential candidate gene for Lith19 (0 cM) on the basis of increased liver mRNA expression in NZB/BlNJ animals compared to SM/J.

On mouse Chromosome 10, Ctgf (17 cM) was identified as a potential candidate gene for Lith21 (24 cM)on the basis of decreased liver mRNA expression in NZB/BlNJ animals compared to SM/J and gene coding sequences differences.

On mouse Chromosome 17, Pgc (30 cM) was identified as a potential candidate for Obwq4 (32 cM).Pgc displays coding sequence differences between NZB/BlNJand SM/J.

Atrnl1 was identified as a candidate for Obwq5 (52 cM) on chromosome 19. Atrnl1 displays increased liver mRNA expression in NZB/BlNJ animals compared to SM/J.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:66421

A (CAST/Ei x C57BL/6J)F2 intercross was typed for polymorphic markers on all mouse chromosomes except the Y Chromosome at an average marker density of 10 cM to identify loci associated with plasma HDL levels in response to either chow or atherogenic diet. Inbred parental strain CAST/Ei exhibits lower plasma HDL levels compared to inbred parental strain C57BL/6J, with (CAST/Ei x C57BL/6J)F1 hybrids displaying an intermediate phenotype. HDL-associated QTLs with a LOD>4.3 threshold were detected and are as follows. Hdl1, a QTL associated with HDL levels on an atherogenic diet, mapped to mouse Chromosome 2 at approximately 37 cM with a peak LOD = 5.6 at D2Mit9. Hdl1 co-localizes with loci mapped for body fat and insulin levels. Pltp, a possible candidate gene for Hdl1, did not appear to segregate with this locus. Hdl2, a QTL associated with HLD levels on an atherogenic, diet mapped to mouse Chromosome 5 from 35 cM - 60 cM with a peak LOD = 6.1 near D5Mit10. Previously mapped HDL QTLs using different inbred strains are located near Hdl2. A possible candidate gene for Hdl2 is Scarb1, but following investigation the authors conclude this QTL is unlikely due to the effect of Scarb1. Hdl3, a QTL associate with HDL levels on a chow diet, mapped to mouse chromosome16 from 9.61 cM - 38.0 cM with a peak LOD = 4.4 near D16Mit3. The LOD score peaks over the gene for ApoD but no difference in ApoD expression is apparent between CAST/Ei and C57BL/6J. Hdl4, a QTL associated with HDL levels on an atherogenic diet, mapped to mouse Chromosome 17 from 20 cM - 48 cM with a peak LOD = 6.5 near D17Mit7. Suggestive QTLs associated with HDL levels with LOD>2.8 (but less than 4.3) mapped to Chromosome 2 near D2Mit50, Chromosome 3 near D3Mit12, Chromosome 8 near D8Mit12 and D8Mit14, Chromosome 9 near D9Mit2, Chromosome 14 near D14Mit2, Chromosome 18 near D18Mit142, and Chromosome 19 near D19Mit5.

J:72737

Linkage analysis was performed on (DBA/2J x AKR/J)F1 x DBA/2J and (129P3/J x SJL/J)F1 x 129P3/J backcross populations and 21 AKXD (AK = AKR/J; D = DBA2/J) recombinant inbred (RI) strains to identify QTLs associated with intestinal cholesterol absorption.The AKR/J parental strain exhibits high cholesterol absorption whereas DBA/2J exhibits low cholesterol absorption. In the the (DBA/2J x AKR/J)F1 x DBA/2J backcross population, linkage was detected on mouse Chromosome 2 (Chab1; LOD = 4.0 at D2Mit305) and mouse Chromosome 10 (Chab2; LOD = 3.5 at D10Mit6) assuming an additive mode of inheritance. Nr1h3 (previously Lxra) is a possible candidate gene for Chab1. In the AKXD RI strains, three loci contributing to intestinal cholesterol absorption (Chab3, Chab4,and Chab5) were identified. Chab3 is linked to the rhodopsin gene (Rho) on mouse Chromosome 6 with a LOD score of 2.0 at 51.5 cM. Pparg was identified as a candidate gene for Chab3. Chab4 is linked to salivary protein 2 (Spt2) on mouse Chromsome 15 with aLOD score of 2.0 at 58.1 cM, and Acat2 was identified as a candidate gene. *Note-MGD currently places Acat2 at 7.55 cM on mouse Chromosome 17* Chab5 maps to 16 cM on mouse Chromosome 19 with a LOD score of 1.6 at D19Mit41 with Vldlr and Osbp identifiedascandidate genes. In the (129P3/J x SJL/J)F1 x 129P3/J backcross population two loci (Chab6 and Chab7) were detected. 129P3/J is a high-absorbing strain whereas SJL/J is a low-absorbing strain. Assuming an additive mode of inheritance, Chab6 maps to 63.1 cMon mouse Chromosome 1 with a LOD score of 2.9 at D1Mit90, and Chab7 maps to 61 cM on mouse Chromosome 5 with a LOD score of 4.3 at D5Mit317. Cyp27 and Hdlbp were identified as candidate genes for Chab6, and Scarb1 was identified as a candidate gene for Chab7.

J:76707

90 female animals from an (SM/J x NZB/BlNJ)F1 x NZB/BlNJ backcross population were screened for an initial set of 78 SSLP markers to identify QTLs associated with HDL cholesterol (HDL-C) concentrations. Parental strain NZB/BlNJ exhibits elevated HDL-C onboth a CHOW and atherogenic diet compared to parental SM/J and F1 hybrid animals. A QTL linked to HDL-C on a CHOW diet, Hdlq1, peaked at 65 cM on mouse Chromosome 5 near D5Mit370 (LOD=2.7). NZB-derived alleles confer increased HDL cholesterol concentrations at Hdlq1. Scarb1 was identified as a viable candidate gene, but expression analysis did not reveal a difference in protein or mRNA levels between SM/J and NZB/BlNJ on CHOW or atherogenic diets. Sequence analysis detected a single nucleotide polymorphism between the 2 strains that does not result in an amino acid change. Therefore, Scarb1 is not likely to be the gene underlying Hldq1. A QTL linked to HDL-C on an atherogenic diet, Hdlq2, also mapped to mouse Chromosome 5 and peaks at 45 cM near D5Mit239(LOD=3.6). NZB-derived alleles confer increased HDL-C concentrations at Hdlq2. Both Hdlq1 and Hdlq2 were detected in linkage to HDL-C in previous QTL studies of different crosses such as (NZB/BlNJ x SM/J)F2, (CAST/Ei x C57BL/6J)F2, and (C57BL/6J x C3H/HeJ)F2. Suggestive loci were also detected near D6Mit44 (48 cM) and D18Mit24 (18 cM) in linkage to inducible HDL-C, and on mouse Chromosome 11 at 14 cM and 44 cM in linkage to non-HDL-C on a CHOW diet and non-HDL-C on an atherogenic diet, respectively.

J:84430

Genome scan was performed on 104 female (C57BL/6J x NZB/BlNJ)F1 x C57BL/6J backcross animals to identify QTLs associated with CHOW- and atherogenic-fed HDL cholesterol levels. 97 polymorphic markers were typed and statistically significant loci were confirmed and resolved using (C57BL/6J x NZB/BlNJ)F11 advanced intercross lines (AIL). Parental strain C57BL/6J exhibits decreased HDL cholesterol levels and susceptibility to atherosclerosis compared to parental strain NZB/BlNJ. 6 weeks on an atherogenic diet results in increased HDL levels in NZB/BlNJ but not in C57BL/6J.

Significant linkage was detected at 96 cM on mouse Chromosome 1 near D1Mit206 (LOD=5.5) in the backcross population. This locus, named Hdlq5, is associated with CHOW- and atherogenic-fed HDL levels. Using AILs, the Hdlq5 locus was resolved to a 6 cM interval (87 cM - 93 cM) and a second QTL is named Hdlq6 was discovered. Hdlq6 maps to 102 cM near D1Mit291 (LOD=5.8) and is associated with atherogenic-fed HDL levels. The confidence intervalof Hdlq6 spans 87 cM - 110 cM. Homozygosity for C57BL/6J-derived alleles at Hdlq5 and Hdlq6 confers decreased HDL level whereas homozygosity for NZB/BlNJ-derived alleles confers increased HDL levels. Heterozygous animals exhibit an intermediate phenotype. Three candidate genes for Hdlq5 show differential expression between C57BL/6J and NZB/BlNJ: Nr1i3, Apoa2, and Apcs (Sap). Tgfb2 is a candidate gene for Hdlq6 exhibiting differential expression between the two parental strains.

Significant linkage was also detected at 38 cM on mouse Chromosome 5 near D5Mit200 (LOD=4.7 on the atherogenic diet). Using AILs this locus was resolved into 3 separate QTLs: Hdlq7, Hdlq8, and Hdlq1. Hdlq7 maps to 29 cM and is associated with HDL levels on both CHOW and atherogenic diets (LOD=12 at D5Mit233). The confidence interval of Hdlq7 spans 25 cM - 32 cM. Hdlq8 maps to 60 cM and is associated with HDL levels on an atherogenic diet (LOD=3.6 at D5Mit155). The confidence interval of Hdlq8 spans 58 cM - 63 cM. Hdlq1 (identified in a previous study) maps to 69 cM and is associated with HDL levels on both CHOW and atherogenic diets (LOD=7.1 at D5Mit242.) The confidence interval of Hdlq1 spans 66 cM - 77 cM. Homozygosity for C57BL/6J-derived alleles at Hdlq7, Hdlq8, and Hdlq1 confers decreased HDL level whereas homozygosity for NZB/BlNJ-derived alleles confers increased HDL levels. Heterozygous animals exhibit an intermediate phenotype. Several candidate genes exhibiting differential expression between C57BL/6J and NZB/BlNJ map to the region containing Hdlq7, Hdlq8, and Hdlq1: Fgfbp1, Prom1, Ppargc1a, Tcf1, Ncor2, Scarb1 (Srb1).

Hdlq9 mapped to 59 cM on mouse Chromosome 16 near D16Mit227 (LOD=1.3 on CHOW diet). The confidence interval of Hdlq9 spans 50 cM - 60 cM. This locus was found to interact with Hdlq7 on mouse Chromosome 5. Animals homozygous for C57BL/6J-derived alleles at both Hdlq7 and Hdlq9 exhibit the lowest HDL cholesterol levels on a CHOW diet. Candidate genes for Hdlq9 showing differential expression between the parental strains are App and Ifnar1.

J:89309

Linkage analysis was performed on 513 animals from a (SM/J x NZB/BlNJ)F2 intercross to map QTLs associated with HDL cholesterol levels on a CHOW or atherogenic diet. Genome scan was conducted using 157 polymorphic markers. Parental strain NZB/BlNJ exhibits elevated HDL cholesterol on both CHOW and atherogenic diets compared to parental strain SM/J. Male animals from both strains exhibit increased HDL cholesterol compared to females.

Hdlq20 mapped to 96 cM on mouse Chromosome 1 near D1Mit291 (LOD=11.0 on CHOW diet, LOD=4.1 on Ath diet). The QTL range of Hdlq20 spans 94 cM - 103 cM. NZB/BlNJ-derived alleles confer increased HDL cholesterol with dominant inheritance. Hdlq20 overlaps with previously identified QTL Hdlq5 at 85 cM and may represent the same locus. Apoa2 has been identified as a strong candidate gene for Hdlq20.

Hdlq21 mapped to 56 cM on mouse Chromosome 3 near D3Mit11 (LOD=4.0 on CHOW diet, LOD=3.8 on Ath diet). The QTL range of Hdlq21 spans 34 cM - 60 cM. NZB/BlNJ-derived alleles confer increased HDL cholesterol with additive inheritance.

Previously identified QTLs Hdlq1 (66 cM) and Hdlq2 (50 cM) on mouse Chromosome 5 were detected in this study. Hdlq1 is linked to D5Mit161 (LOD=10.1 on CHOW diet, LOD=12.1 on Ath diet) and Hdlq2 is linkedto D5Mit205 (LOD=7.6 on CHOW diet, LOD=10.8 on Ath diet). Scarb1 and Tcf1 map within the QTL interval of Hdlq1 and are potential candidate genes. A novel QTL named Hdlq22 mapped to 18 cM on mouse Chromosome 5 near D5Mit228 (LOD=5.2 on CHOW diet, LOD=7.6 on Ath diet.) Lrpap1 is proposed as a candidate gene for Hdlq22. NZB/BlNJ-derived alleles confer increased HDL cholesterol with additive inheritance at Hdlq1, Hdlq2, and Hdlq22.

A female-specific QTL named Hdlq23 mapped to 26 cM on mouse Chromosome 6 nearD6Mit74 (LOD=4.2 on CHOW diet). The QTL range of Hdlq23 spans 12 cM - 32 cM. A second QTL named Hdlq24 mapped to 66 cM near D6Mit259 (LOD=6.3 on CHOW diet). The QTL range of Hdlq24 spans 54 cM - 70 cM. Hdlq24 overlaps with previously identified QTLs Hdlq11 (46 cM) and Hdlq12 (71.2 cM). NZB/BlNJ-derived alleles confer increased HDL cholesterol with additive inheritance at both Hdlq23 and Hdlq24.

Hdlq25 maps to 0 cM on mouse Chromosome 8 near D8Mit58 (LOD=4.2 on Ath diet). The QTL range of Hdlq25 spans 0cM - 12 cM. NZB/BlNJ-derived alleles confer increased HDL cholesterol with dominant inheritance.

A female-specific locus named Hdlq26 mapped to 70 cM on mouse Chromosome 10 near D10Mit271 (LOD=4.1 on Ath diet). The QTL range of Hdlq26 spans 60 cM - 70 cM.NZB/BlNJ-derived alleles confer increased HDL cholesterol with recessive inheritance. A potential candidate gene for Hdlq26 is Apof.

A female-specific locus named Hdlq27 mapped to 48 cM on mouse Chromosome 15 near D15Mit70 (LOD=4.2 on CHOW diet). The QTL range of Hdlq27 spans 44 cM - 60 cM. NZB/BlNJ-derived alleles confer increased HDL cholesterol with recessive inheritance. Hdlq27 overlaps with a previously identified QTL named Pltpq4 (phospholipid transfer protein activity QTL 4). Candidate gene Pparamaps to this region and exhibits 4-fold greater expression in male SM/J on a CHOW diet compared to NZB/BlNJ.

Hdlq28 mapped to 26 cM on mouse Chromosome 16 near D16Mit57 (LOD=3.7 on CHOW diet). The QTL range of Hdlq28 spans 0 cM - 60 cM. NZB/BlNJ-derived alleles confer increased HDL cholesterol with dominant inheritance. Apod has been suggested as a candidate gene for Hdlq28.

A male-specific locus named Hdlq29 mapped to 36 cM on mouse Chromosome 17 near D17Mit20 (LOD=4.5 on Ath diet). NZB/BlNJ-derived alleles confer increased HDL cholesterol with additive inheritance. Potential candidate genes for Hdlq29 are Abcg5 and Abcg8.

Hdlq30 mapped to 48 cM (LOD=4.2 on CHOW diet at D18Mit9) and Hdlq31 mapped to 56 cM (LOD=5.2 cM on Ath diet at D18Mit4) on mouseChromosome 18. The QTL range of Hdlq31 spans 42 cM - 60 cM. A potential candidate gene for Hdlq31 is Lipg. NZB/BlNJ-derived alleles confer increased HDL cholesterol with additive inheritance at both Hdlq30 and Hdlq31.

A female-specific locus named Hdlq32 mapped to 26 cM on mouse Chromosome 19 near D19Mit11 (LOD=4.0 on Ath diet). The QTL range of Hdlq32 spans 10 cM - 70 cM. NZB/BlNJ-derived alleles confer increased HDL cholesterol with recessive inheritance. Hdlq32 overlaps with a previously identified QTL named Chab5 (cholesterol absorption 5) at 16 cM. Fas has been proposed as a candidate gene for both Hdlq32 and Chab5. Vldlr is also a potential candidate gene for Hdlq32.

J:53728

Genome scan using 105 polymorphic markers at an average spacing of 20 cM was performed on 189 (MRL/MpJ-Tnfrsf6^lpr x BALB/cJ)F2 animals to map QTLs associated with plasma lipid traits. Parental strain MRL/MpJ-Tnfrsf6^lpr exhibits increased HDL, VLDL, and triglycerides on both CHOW and high fat diets compared to parental strain BALB/cJ. Also, BALB/cJ is relatively resistant to atherosclerosis on a high fat diet whereas MRL/MpJ- Tnfrsf6^lpr is moderately susceptible. Animals were placed on a high fat diet for 8 weeks.

A locus on mouse Chromosome 5 near D5Mit10 (54 cM) showed linkage to unesterified cholesterol (LOD=4.1), total cholesterol (LOD=3.8), and VLDL (LOD=2.8) on a high fat diet. This QTL is named Lprq1 (lipoprotein QTL 1). Homozygosity for MRL/MpJ-derived alleles confer decreased lipid levels with a recessive mode of inheritance. Potential candidate genes mapping near Lprq1 are Scarb1 (Srb1, 68 cM) and Mvk (64 cM).

Hyplip2 mapped to 32 cM mouse Chromosome 15 near D15Mit17. Hyplip2 shows linkage to total cholesterol (LOD=11.1), VLDL (LOD=6.7), and unesterified cholesterol (LOD=4.6) on a high fat diet. Homozygosity for the MRL/MpJ-derived allele confers increased total cholesterol and VLDL. A potential candidate gene mapping near Hyplip2 is Srebf2 (48.5 cM).

A locus at 26 cM on mouse Chromosome 19 near D19Mit12 showed linkage to HDL (LOD=8.4) and total cholesterol (LOD=3.8) on the high fat diet. This locus is named Lprq2. Homozygosity for MRL/MpJ-derived alleles confer decreased HDL cholesterol on a high fat diet. An attractive candidate gene for Lprq2 is Fas (23 cM). Tnfrsf6 shows tight linkage to both anti-dsDNA antibody levels and HDL concentration.

A suggestive QTL for unesterified cholesterol (LOD=3.1) and total cholesterol (LOD=2.1)on aCHOW diet mapped to mouse Chromosome 8 near D8Mit242 (42 cM). Homozygosity for MRL/MpJ-derived alleles confer increased total cholesterol, VLDL, and unesterified cholesterol levels on a CHOW diet. A possible candidate gene mapping near this suggestive locus is Lcat (53 cM).

J:144089

Linkage analysis was performed on 528 animals from a (C57BL/6J x 129S1/SvImJ)F2 intercross to map QTL associated with plasma HDL levels on either a CHOW or atherogenic diet. F2 animals were fed a CHOW diet until 8 weeks of age and then placed on an atherogenic diet until 16 weeks of age. An array of 508 SNPs was used for genome scan. Plasma HDL is significantly higher in 129S1/SvImJ parental strain compared to C57BL/7J on CHOW and high fat diets, with a stronger effect observed in males compared to females. Several previously identified HDL QTL were detected in this study as well as several novel loci, some of which showed interactive effects.

Mouse Chromosome 5 showed evidence for multiple QTL. Hdlq1 (HDL QTL 1) is a previously identified QTL. In this study Hdlq1 mapped to 91.4 Mb (45 cM) near rs134778390 and is linked to increased plasma HDL on CHOW diet (LOD=3.3). The Hdlq1 95% confidence interval spans 79 Mb (44 cM) - 127 Mb (70 cM). 129S1/SvImJ-derived alleles at Hdlq1 confer increased plasma HDL on CHOW diet. Hdlq1 also interacts with Hdlq16 on chromosome 8. Homozygosity for 129S1/SvImJ-derived allele at both Hdlq1 and Hdlq16 significantly decreased plasma HDL concentration in male and female animals fed a CHOW diet. A novel QTL named Hdlq52 (HDL QTL 52) was identified at 23.4 Mb (8 cM) near rs13478142. This locus is associated with increased plasma HDL on an atherogenic diet (LOD=3.6) and the 95% confidence interval spans 7 Mb (1 cM) to 33 Mb (18 cM). 129S1/SvImJ-derived alleles at Hdlq52 confer increased plasma HDL on an atherogenic diet.

References

• Original: J:76707 Pitman WA, et al., Quantitative trait locus mapping of genes that regulate HDL cholesterol in SM/J and NZB/B1NJ inbred mice. Physiol Genomics. 2002;9(2):93-102
• All: 2 reference(s)