Lprq3^NZB/BlNJ
QTL Variant Detail

Summary

• QTL variant: Lprq3^NZB/BlNJ
• Name: lipoprotein QTL 3; NZB/BlNJ
• MGI ID: MGI:3511884
• QTL: Lprq3 Location: Chr1:169038741-169038913 bp Genetic Position: Chr1, cM position of peak correlated region/allele: 76.73 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 and plasma Apoa2 levels on CHOW and atherogenic diets compared to SM/J. (J:29072)
• Inheritance: Other (see notes)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Lprq3 exhibits additive inheritance.

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

J:29072

Linkage analysis was performed on 184 (NZB/BlNJ x SM/J)F2 animals to identify QTLs associated with lipoprotein metabolism on CHOW and atherogenic diets. 125 polymorphic loci at an average spacing of 20 cM were used in the genome scan.

On a CHOW diet, parental strain NZB/BlNJ exhibits 2.5-fold greater total plasma cholesterol compared to parental strain SM/J. Triglycerides and free fatty acids were comparable between the 2 parental strains on the CHOW diet. On a 5-week atherogenic diet, parental strain SM/J exhibits decreased HDL cholesterol and significantly increased LDL and VLDL cholesterol compared to NZB/BlNJ. Triglycerides and free fatty acids were comparable between the 2 parental strains on the atherogenic diet.

A locus near D1Mit36 (92.3 cM) on mouse Chromosome 1 shows linkage to total cholesterol (LOD=5.9), HDL cholesterol (LOD=6.9), and plasma Apoa2 levels (LOD=14.8) on a CHOW diet. D1Mit36 also shows linkage to plasma Apoa2 levels on an atherogenic diet (LOD=7.9). This locus is named Lprq3 (lipoprotein QTL 3). The Apoa2 gene (92.6 cM) colocalizes with Lprq3 and shows significant linkage to total cholesterol on a CHOW diet (LOD=6.6) and HDL cholesterol on a CHOW (LOD=8.1) and atherogenic diet (LOD=3.6). NZB/BlNJ-derived alleles confer increased HDL cholesterol and plasma Apoa2 levels on CHOW and atherogenic diets. Lprq3 appears to exhibit additive inheritance. Sequence analysis of Apoa2 cDNA revealed 2 nonconservative polymorphisms between NZB/BlNJ and SM/J.

An interval on mouse Chromosome 5 between 61 cM (D5Mit25) and 72 cM (D5Mit30) shows linkage to total cholesterol (LOD=6.7) and HDL cholesterol (LOD=5.3) on a CHOW diet and HDL cholesterol (LOD=5.6) on an atherogenic diet. This locus is named Lprq4. Lprq4 shows a stronger effect in female animals compared to male animals. NZB/BlNJ-derived alleles confer increased total cholesterol (CHOW) and HDL cholesterol (CHOW and atherogenic) at Lprq4. This QTL appears to exhibit additive inheritance.

A locus on mouse Chromosome 7 near D7Mit55 (15 cM) shows linkage to total plasma triglycerides (LOD=5.1) and free fatty acids (LOD=5.6) on an atherogenic diet. This locus is named Lprq5. Candidate genes mapping near Lprq5 are Lipe (5.5 cM), Apoe (4 cM), Apoc2 (4 cM), and Apoc1 (4 cM).

J:4733

15 NXSM (N= NZB/BlNJ; SM=SM/J) recombinant in bred (RI) strains were examined for plasma lipid traits. Female animals were placed on CHOW or high fat diets and then sacrificed for lipid analysis. Parental strain NZB/BlNJ exhibits elevated HDL cholesterollevels compared to parental strain SM/J.

Marker Mtv27 (96.8 cM) on mouse Chromosome 1 shows linkage to HDL cholesterol (P^{0.0004) on a CHOW diet. This locus is named Lprq3 (lipoprotein QTL 3). NZB/BlNJ-derived alleles confer increased HDL cholesterol levels at Lprq3. A major candidate gene located directly under the area of peak linkage is Apoa2 (92.6 cM). Lprq3 was confirmed in a panel of BXD RI strains. Apoa2 gave peak linkage to HDL cholesterol levels (LOD=3.7) on a CHOW diet in the BXD RI population. Lprq3 explains 74% of the phenotypic variance.}

The Apoa2 locus map close to another HDL-related QTL named Tnfsf4 (90.1 cM). To determine if the Apoa2 locus and Tnfsf4 are the same QTL the congenic strain B6.C-H25/(HW65)ByJ was examined. This congenic carries BALB/cJ-derived alleles from Fcgr2b (92.3 cM) to Spna1 (95.4 cM). Apoa2 is contained within the congenic region while Tnfsf4 is outside of the congenic region. (Donor strain BALB/cJ exhibits high HDL cholesterol on a high fat diet compared to C57BL/6J.) The B6.C-H25^c/(HW65)ByJ congenic exhibits increased HDL cholesterol on a high fat diet compared to background strain C57BL/6J. Authors theorize that the observed increase in HDL cholesterol is most likely due to the Apoa2 locus. Since Tnfsf4 is outside the congenic region, Tnfsf4 and Apoa2 are most likely distinct and separate loci. Interestingly, the congenic exhibits increased aortic lesion development on a high fat diet compared to both donor strain BALB/cJ (atherosclerosis resistant) andbackground strain C57BL/6J (atherosclerosis susceptible).

References

• Original: J:29072 Purcell-Huynh DA, et al., Genetic factors in lipoprotein metabolism. Analysis of a genetic cross between inbred mouse strains NZB/BINJ and SM/J using a complete linkage map approach. J Clin Invest. 1995 Oct;96(4):1845-58
• All: 1 reference(s)