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Mammalian Genome

, Volume 19, Issue 1, pp 15–25 | Cite as

Diabetic modifier QTLs in F2 intercrosses carrying homozygous transgene of TGF-β

  • Takao Suzuki
  • Maki Moritani
  • Masayasu Yoshino
  • Mitsuhiro Kagami
  • Shoji Iwasaki
  • Kouichi Nishimura
  • Masahiko Akamatsu
  • Masato Kobori
  • Hitoshi Matsushime
  • Masao Kotoh
  • Kiyoshi Furuichi
  • Mitsuo ItakuraEmail author
Article

Abstract

When the homozygous active form of porcine TGF-β1 transgene (Tgf/Tgf) (under control of the rat glucagon promoter) is introduced into the nonobese diabetic mouse (NOD) genetic background, the mice develop endocrine and exocrine pancreatic hypoplasia, low serum insulin concentrations, and impaired glucose tolerance. To identify genetic modifiers of the diabetic phenotypes, we crossed hemizygous NOD-Tgf with DBA/2J mice (D2) or C3H/HeJ mice (C3H) and used the “transgenic mice” for quantitative trait loci (QTL) analysis. Genome-wide scans of F2-D Tgf/Tgf (D2 × NOD) and F2-C Tgf/Tgf (C3H × NOD), homozygous for the TGF-β1 transgene, identified six statistically significant modifier QTLs: one QTL (Tdn1) in F2-D Tgf/Tgf, and five QTLs (Tcn1 to Tcn5) in F2-C Tgf/Tgf. Tdn1 (Chr 13, LOD = 4.39), and Tcn3 (Chr 2, LOD = 4.94) showed linkage to body weight at 8 weeks of age. Tcn2 (Chr 7, LOD = 4.38) and Tcn4 (Chr 14, LOD = 3.99 and 3.78) showed linkage to blood glucose (BG) concentrations in ipGTT at 30, 0, and 120 min, respectively. Tcn1 (Chr 1, LOD = 4.41) and Tcn5 (Chr 18, LOD = 4.99) showed linkage to serum insulin concentrations in ipGTT at 30 min. Tcn2 includes the candidate gene, uncoupling protein 2 (Ucp2), and shows linkage to Ucp2 mRNA levels in the soleus muscle (LOD = 4.90). Identification of six QTLs for diabetes-related traits in F2-D Tgf/Tgf and F2-C Tgf/Tgf raises the possibility of identifying candidate susceptibility genes and new targets for drug development for human type 2 diabetes.

Keywords

Quantitative Trait Locus Genetic Modifier Blood Glucose Concentration Serum Insulin Concentration Significant QTLs 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

BW

Body weight

BG

Blood glucose

C3H

C3H/HeJ mice

D2

DBA/2J mice

eQTL

Expression quantitative trait loci

NOD-Tgf

Hemizygous transgenic NOD mice with TGF-β1

F1-Tgf

Hemizygous transgenic F1 mice with TGF-β1

NOD-Tgf/Tgf

Homozygous transgenic NOD mice with TGF-β1

F2-D Tgf/Tgf

Homozygous transgenic F2 intercross progeny with TGF-β1 between the D2 mice and NOD

F2-C Tgf/Tgf

Homozygous transgenic F2 intercross progeny with TGF-β1 between the C3H/HeJ mice and NOD

F2-Tgf/Tgf

Homozygous transgenic F2 intercross progeny with TGF-β1

Idd

Insulin-dependent diabetes

ipGTT

Intraperitoneal glucose tolerance test

NOD

Nonobese diabetic mice

QTL

Quantitative trait loci

T1D

Type 1 diabetes

T2D

Type 2 diabetes

Notes

Acknowledgments

The authors sincerely thank Sato A for technical assistance. This study was supported by a grant from the Cooperative Link of Unique Science and Technology for Economy Revitalization (CLUSTER).

Supplementary material

335_2007_9080_MOESM1_ESM.pdf (92 kb)
(PDF 92 kb)

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Takao Suzuki
    • 1
  • Maki Moritani
    • 1
  • Masayasu Yoshino
    • 2
  • Mitsuhiro Kagami
    • 2
  • Shoji Iwasaki
    • 2
  • Kouichi Nishimura
    • 2
  • Masahiko Akamatsu
    • 2
  • Masato Kobori
    • 2
  • Hitoshi Matsushime
    • 2
  • Masao Kotoh
    • 2
  • Kiyoshi Furuichi
    • 2
  • Mitsuo Itakura
    • 1
    Email author
  1. 1.Division of Genetic InformationInstitute for Genome Research, The University of TokushimaTokushimaJapan
  2. 2.Molecular Medicine Research LabsAstellas Pharma. IncIbarakiJapan

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