Hypn^C57BL/6
QTL Variant Detail

Summary

• QTL variant: Hypn^C57BL/6
• Name: hyperinsulinemia; C57BL/6
• MGI ID: MGI:2663486
• QTL: Hypn Location: Chr14:32160616-32160765 bp Genetic Position: Chr14, Syntenic

Variant origin

• Strain of Specimen: C57BL/6

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers increased insulin levels compared to 129S6/SvEvTac. (J:83539)

Expression

In Structures Affected by this Mutation:

1 anatomical structure(s)

Notes

Interaction between Hypn and Elpt reached statistical significance. Hyperinsulinemia is enhanced when animals are homozygous for C57BL/6-derived alleles at both Hypn and Elpt.

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

J:83539

Linkage analysis was performed on a population of male (C57BL/6-Insr^tm1DacIrs1^tm1Jos X 129S6/SvEvTac)F2 animals to identify QTLs associated with insulin, glucose, and leptin traits. 80 polymorphic markers at an average spacing of 20 cM were screened.Parental strain C57BL/6-Insr^tm1DacIrs1^tm1Jos exhibits a smaller body size, reduced weight and elevated glucose and insulin levels compared to parental strain 129S6/SvEvTac.

A QTL contributing to hyperinsulinemia, Hypn, mapped to 10.5 cM on mouse Chromosome 14 with a peak LOD score of 5.6 between D14Mit11 and D14Mit55.(This locus also shows linkage to diabetes with a LOD score of 3.0 at D14Mit55.) C57BL/6-derived alleles confer increased insulin levels with an additive effect at Hypn. Candidate genes mapping near Hypn are Ucp2 and Ucp3.

A QTL contributing to elevated leptin levels, Elpt, mapped to 50 cM on mouse Chromosome 7 with a LOD score of 3.7 at D12Mit38. (*D12Mit38 has been mapped to mouse Chromosome 7 in the Celera Database.) C57BL/6-derived alleles confer increased leptin levels with dominant inheritance at Elpt. Candidate genes mapping near Elpt include Prkcd, Arf4, and Dusp13.

Interaction between Hypn and Elpt reached statistical significance. Hyperinsulinemia is enhanced when animalsare homozygous for C57BL/6-derived alleles at both Hypn and Elpt.

Suggestive QTLs for glucose level at 6 months of age mapped to 48 cM on mouse Chromosome 12 with a LOD score of 2.7 at D12Mit231, and to approximately 50 cM on mouse Chromosome 14 with a LOD score of 2.3 between D14Mit75 and D14Mit228. C57BL/6-derived alleles confer hyperglycemia at these loci. An interaction between Elpt and the locus at D12Mit231 reached statistical significance. Homozygosity for C57BL/6-derived alleles at both loci enhances elevated leptin levels.

J:142949

Quantitative trait loci (QTL) associated with diet-induced energy expenditure and insulin resistance were mapped using 50 animals from a (C57BL/6J x 129S6/SvEvTac)F2 intercross. Parental strain C57BL/6J displays increased obesity (despite lower food intake), increased insulin resistance and decreased energy expenditure on low- and high-fat diets compared to parental strain 129S6/SvEvTac. Male F2 animals aged 6 weeks were placed on a low-fat or high-fat diet for a period of 18 weeks. A panel of 114 polymorphic markers spaced approximately 20 cM apart was used for linkage analysis.

Significant linkage to plasma insulin levels mapped to 33.7 cM on mouse Chromosome 3 near D3Mit278 (LOD=3.2). This locus explains 29% of the phenotypic variance and is named Hypn2 (hyperinsulinemia 2). Homozygosity for C57BL/6J-derived alleles at Hypn2 confer increased plasma insulin concentration after 12 weeks on a low-fat diet. Significant linkage to plasma leptin concentration mapped to 70.3 cM near D3Mit127 (LOD=2.7). Thislocus explains 78% of the plasma leptin variance and is named Elpt2 (elevated leptin 2). Homozygosity for C57BL/6J-derived alleles at Elpt2 confers increased plasma leptin concentration after 12 weeks on a low-fat diet.

Significant linkage to plasma leptin concentration after 2 weeks on a high fat diet mapped to 59 cM on mouse Chromosome 10 near D10Mit162 (LOD=2.9). This locus is named Elpt3 (elevated leptin 3). Homozygosity for 129S6/SvEvTac-derived alleles at Elpt3 confer increased plasma leptin concentration after a 2 week high fat diet. Elpt3 explains 28% of the phenotypic variance.

A locus at 62 cM on mouse Chromosome 11 displayed significant linkage to plasma insulin concentration near D11Mit199 (LOD=3.0) after 6 weeks on high fat diet. This QTL is named Hypn3 (hyperinsulinemia 3). Homozygosity for C57BL/6J-derived alleles at Hypn3 increases plasma insulin levels after 6 weeks of high fat diet. Hypn3 explains 30% of the plasma insulin variance.

Significant linkage to hyperglycemia after 2weeks on a high-fatdiet mapped to 48 cM on mouse Chromosome 12 near D12Mit231 (LOD=3.2). This locus was detected in a previous study in suggestive linkage to blood glucose concentration at age 6 months and is named Dibg1 (diet-induced blood glucose concentration1). Dibg1 explains 25% of the phenotypic variance with homozygosity for 129S6/SvEvTac-derived alleles conferring 1.9-fold increased blood glucose concentration compared to homozygosity for C57BL/6J-derived alleles. Dbsty3 (48 cM) is a previously identified obesity QTL overlapping with Dibg1.

A locus on mouse Chromosome 14 colocalizing with Hypn (hyperinsulinemia) displayed significantly linkage to insulin level on a low-fat diet at 11.5 cM at D14Mit52 (LOD=3.0). This locus explains 25% of the variance for plasma insulinlevels. F2 animals homozygous for C57BL/6J-derived alleles displayed 8.9-fold higher plasma insulin after 18 weeks on a low-fat diet compared to F2 animals homozygous for 129S6/SvEvTac-derived alleles. Potential candidate genes for Hypn include Prkcd (11cM), Wnt5a (7.8 cM), Ncoa4, Cacna2d3 and Tkt. A distal locus at 40 cM near D14Mit192 displayed significant linkage to weight gain on a low-fat diet (LOD=3) and hyperglycemia (LOD=3.3) on a high-fat diet. This locus is named Diwg1 (diet-induced weight gain 1) and explains 52% of the weight gain variance and 33% of the blood glucose concentration variance. Homozygosity for C57BL/6J alleles at Diwg1 confers a 22.5% increase in body weight after 18 weeks on a low fat diet compared to homozygosity for 129S6/SvEvTac alleles. Homozygosity for C57BL/6J alleles at Diwg1 also confers increased blood glucose concentration after 12 weeks on a high fat diet. Potential candidate genes for Diwg1 based on mRNA expression differences between parental strains B6 and 129 include Esd (41.5 cM), Bmp1 (32.5 cM), Epb4.9 (38 cM), and Ppp3cc.

Suggestive linkage to fasting plasma glucose concentration after 19 weeks on low-fat diet mapped to 6.7 cM on mouse Chromosome 15 near D15Mit13 (LOD=3.3).

References

• Original: J:83539 Almind K, et al., Identification of interactive Loci linked to insulin and leptin in mice with genetic insulin resistance. Diabetes. 2003 Jun;52(6):1535-43
• All: 2 reference(s)