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

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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.

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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

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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).

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Authors and Affiliations

  1. Division of Genetic Information, Institute for Genome Research, The University of Tokushima, Tokushima, 770-8503, Japan

    Takao Suzuki, Maki Moritani & Mitsuo Itakura

  2. Molecular Medicine Research Labs, Astellas Pharma. Inc, Ibaraki, 305-8585, Japan

    Masayasu Yoshino, Mitsuhiro Kagami, Shoji Iwasaki, Kouichi Nishimura, Masahiko Akamatsu, Masato Kobori, Hitoshi Matsushime, Masao Kotoh & Kiyoshi Furuichi

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  1. Takao Suzuki
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  2. Maki Moritani
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Correspondence to Mitsuo Itakura.

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Suzuki, T., Moritani, M., Yoshino, M. et al. Diabetic modifier QTLs in F2 intercrosses carrying homozygous transgene of TGF-β . Mamm Genome 19, 15–25 (2008). https://doi.org/10.1007/s00335-007-9080-y

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  • DOI: https://doi.org/10.1007/s00335-007-9080-y

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