Experiment
In the current study quantitative trait analysis (QTL) was performed using a male cohort derived from C.129P2(B6)-Apoe<tm1Unc/J (BALB-Apoe-/-) and SM.129P2(B6)-Apoe<tm1Unc/J (SM-Apoe-/-) mice to find potential genetic connections between plasma glucose and lipid traits. BALB-Apoe -/- have much higher HDL and lower non-HDL cholesterol levels and are more resistant to development of type 2 diabetes compared to SM-Apoe-/- mice.
225 male (C.129P2(B6)-Apoetm1Unc/J x SM.129P2(B6)-Apoetm1Unc/J)F2 mice generated for analysis. F2 progeny were fed a western diet for 5 weeks. The mice were bled twice, once before the start of the western diet and once at the time of euthanasia. Mice were fasted overnight before blood was drawn. Plasma glucose, total cholesterol, HDL cholesterol and triglyceride were also measured. Non-HDL cholesterol was calculated as the difference between total and HDL cholesterol.
DNA samples from the parental strains, the F1 and F2 mice were genotyped. 144 SNPs across the genome were typed. QTL analysis was performed using J/qtl and Map Manager QTX. 1000 permutations of trait values were run to define LOD score thresholds; p values of <0.05 were considered significant, p values of <0.63 were considered suggestive.
Table 1:
A genome scan for main effect QTL revealed a highly significant QTL, Bglu19 (blood glucose level 19) mapping to Chromosome 9, peaking at 12.7 cM (rs3704408) with a LOD=6.463 for fasting glucose levels when mice were fed the chow diet.
Curator Note: The authors state that the Chromosome 9 QTL identified here overlaps in position with a previously identified QTL, Bglu16, that was identified in J:224437. Bglu16 was identified in a map population of exclusively female mice and achieved only a suggestive LOD score in the previous study. Since the locus identified here mapped with significance in male mice only we have assigned it unique nomenclature.
Two suggestive loci for fasting glucose on the chow diet were also detected mapping to Chromosomes 15 (3.658 cM, LOD=3.263) and 18 (15.91 cM, LOD=2.27).
A suggestive locus for fasting glucose was detected in the distal region of Chromosome X ( 68.38 cM, LOD=3.069) for F2 mice fed the western diet.
Inheritance of BALB alleles conferred an increased glucose level for the Bglu19 and the Chr 15 locus while inheritance of SM alleles conferred increased glucose levels for the Chr 18 and the Chr X loci.
Genome wide scans for main effect QTL detected multiple loci for HDL, non-HDL cholesterol and triglyceride levels:
For HDL, 3 suggestive QTL for the chow diet were detected on Chr 1, Chr 12 and Chr 20.
Five QTL were detected for HDL for the western diet mapping to Chromosomes 1, 9, 13, 15 and 17.
The Chromosome 9 QTL, Hdlq109 (HDL QTL 109) mapped with a highly significant LOD score of 6.31 peaking at 19.13 cM (rs3023205). The B6 allele was the high allele at this locus, inherited in an additive mode of inheritance.
Curator Note: The authors have equated the HDL locus mapped here on Chromosome 9 with the previously mapped Hdlq17 locus. However, Hdlq17 was mapped using a mapping population [J:88486] which differs from the mapping population used in the current study. We have assigned the Chromosome 9 HDL locus identified here with unique nomenclature.
For non-HDL cholesterol suggestive QTL were detected on Chr 1 (60.141 cM, LOD=3.94) and Chr 15 (41.658 cM, LOD=3.52) when mice were fed the Western diet.
For triglyceride, 3 suggestive QTL were detected for mice on the western diet, one on Chr 1 (41.77 cM, LOD=3.239) and another on Chr 1 (80.1 cM, LOD=2.74) and one on Chr X (66.386 cM, LOD=3.25). The Chr X locus was also detected in mice fed the chow diet (63.386 cM, LOD=3.063).
Significant correlations of fasting glucose with with non-HDL cholesterol and triglyceride were observed when mice were fed either chow or western diet. In contrast, HDL cholesterol levels were only marginally correlated with fasting glucose levels on either chow or western diet.
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