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Association of a polymorphism in the betacellulin gene with type 1 diabetes mellitus in two populations

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Abstract

Betacellulin, a member of the epidermal growth factor family, is expressed in fetal and adult pancreas. In vitro and in vivo studies suggest a role for betacellulin in islet neogenesis and regeneration. Therefore, a mutation in the betacellulin gene might lead to fewer beta cells. With reduced beta cell reserve, beta cells may not be able to compensate for an autoimmune attack, and in turn, susceptibility to type 1 diabetes mellitus (T1DM) would increase. Previous mutational analysis identified seven polymorphisms in the betacellulin gene [5′ UT (−233G>C, −226A>G), exon 1 (TGC19GGC, Cys7Gly), exon 2 (CTC130TTC, Leu44Phe), exon 4 (TTG370ATG, Leu124Met), intron 2 (-31T>C), and intron 4 (-4C>T)]. An association study of these variants with T1DM was first carried out in 100 Caucasian subjects with T1DM and 282 Caucasian subjects without diabetes recruited at the University of Maryland. The frequency of the intron 4 T-4 allele was significantly higher among nondiabetic controls than that among diabetic cases (0.29 vs 0.21, p=0.04). Allele frequencies for the other polymorphisms did not differ significantly between cases and controls. The intron 4 T-4 association was then replicated by transmission disequilibrium testing in a separate population of Caucasian parent/offspring with T1DM trios (n=168 trios, 113 informative) recruited at the Medical College of Wisconsin (p=0.024). An interaction of the intron 4 T-4 allele and human leukocyte antigen (HLA) was also detected with undertransmission of the T allele in those T1DM subjects with susceptible HLA types as compared to those T1DM subjects without susceptible HLA types (p=0.018). RNA studies of the intron T-4 variant showed similar RNA levels for intron 4 T-4 and intron 4 C-4 alleles. Additionally, there was no evidence for an effect of this variant on exon–intron splicing. We conclude that the intron 4 T-4 allele in the betacellulin gene is associated with lower risk of T1DM and may interact with HLA. Further studies will be necessary to establish the significance of this association.

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Abbreviations

bp:

Base pair

EGF:

Epidermal growth factor

RFLP:

Restriction fragment length polymorphism

SSCP:

Single-stranded conformational polymorphism

T1DM:

Type 1 diabetes mellitus

T2DM:

Type 2 diabetes mellitus

5′UT:

5′ Untranslated region

3′UT:

3′ Untranslated region

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Acknowledgements

We thank Xiao Chun Wang, Deana Trowbridge, and Kerry Nolan for excellent technical assistance; Amy Nathanson and Susan Kopunek for assistance in obtaining DNA samples; and Drs. Alan Farney and Lioubov Poliakova for providing adult human pancreatic tissue samples.

This work was supported by NIH grants 1K23DK02945-01 (K.S.) and 1R03DK062923-01 (K.S.) and JDRF grant 9-2001-1012 (V.M.). Funding and support were also provided by the Medical College of Wisconsin General Clinical Research Center Grant M01-RR00058, General Clinical Research Centers Program, National Center for Research Resources, National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD, USA

    Kristi D. Silver, Jian Wang & Braxton D. Mitchell

  2. Department of Pediatrics, Max McGee National Research Center for Juvenile Diabetes, Medical College of Wisconsin and Children’s Research Institute, Milwaukee, WI, USA

    Victoria L. Magnuson

  3. Department of Epidemiology and Preventive Medicine, University of Maryland School of Medicine, Baltimore, MD, USA

    Magdalena Tolea & Braxton D. Mitchell

  4. Diabetes Department, Pacific Northwest Research Institute, Seattle, WA, USA

    William A. Hagopian

  5. University of Maryland School of Medicine, 660 West Redwood Street, Room 498, Baltimore, MD, 21201, USA

    Kristi D. Silver

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  1. Kristi D. Silver
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  2. Victoria L. Magnuson
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Correspondence to Kristi D. Silver.

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Silver, K.D., Magnuson, V.L., Tolea, M. et al. Association of a polymorphism in the betacellulin gene with type 1 diabetes mellitus in two populations. J Mol Med 84, 616–623 (2006). https://doi.org/10.1007/s00109-006-0052-6

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  • DOI: https://doi.org/10.1007/s00109-006-0052-6

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