Hdlq20^NZB/BlNJ
QTL Variant Detail

Summary

• QTL variant: Hdlq20^NZB/BlNJ
• Name: HDL QTL 20; NZB/BlNJ
• MGI ID: MGI:3041307
• QTL: Hdlq20 Location: unknown Genetic Position: Chr1, cM position of peak correlated region/allele: 88.97 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NZB/BlNJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele confers increased HDL cholesterol concentrations on CHOW and atherogenic diets compared to SM/J. (J:89309)
• Inheritance: Dominant

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

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 identifiedas a 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/BlNJ and 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: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.

References

• Original: J:89309 Korstanje R, et al., Influence of sex and diet on quantitative trait loci for HDL cholesterol levels in an SM/J by NZB/BlNJ intercross population. J Lipid Res. 2004 May;45(5):881-8
• All: 1 reference(s)