A Polymorphism in the TCF7 Gene, C883A, Is Associated With Type 1 Diabetes
- Janelle A. Noble1,
- Amy M. White2,
- Laura C. Lazzeroni3,
- Ana M. Valdes2,
- Daniel B. Mirel2,
- Rebecca Reynolds2,
- Andrew Grupe4,
- Dee Aud5,
- Gary Peltz5 and
- Henry A. Erlich2
- 1Children’s Hospital Oakland Research Institute, Oakland, California
- 2Roche Molecular Systems, Alameda, California
- 3Department of Health Research and Policy, Stanford University, Palo Alto, California
- 4Celera Diagnostics, Alameda, CA
- 5Roche Bioscience, Palo Alto, California
Abstract
Type 1 diabetes is an autoimmune disease with a Th1 phenotype in which insulin-producing β-cells in the pancreas are destroyed. The T-cell–specific transcription factor TCF7 activates genes involved in immune regulation and is a candidate locus for genetic susceptibility to type 1 diabetes. A nonsynonymous single nucleotide polymorphism (SNP) (Pro to Thr) in the TCF7 gene, C883A, was examined in samples from 282 Caucasian multiplex type 1 diabetic families. HLA-DRB1 and -DQB1 genotypes were previously determined for these samples, allowing data stratification based on HLA-associated risk. The transmission disequilibrium test showed significant overtransmission of the A allele from fathers (64.1%, P < 0.007) and nonsignificant overtransmission (57.4%, P < 0.06) of the A allele to patients who do not carry the highest-risk HLA-DR3/DR4 genotype. Elliptical sib pair analysis showed significant associations of the A allele with type 1 diabetes in paternal transmissions (P < 0.03), transmissions to male children (P < 0.04), and in the non-DR3/DR4 group (P < 0.04). These data also suggest that TCF7 C883A may affect age of disease onset. Analysis of genotype data from surrounding SNPs suggests that this TCF7 polymorphism may itself represent a risk factor for type 1 diabetes.
Footnotes
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Address correspondence and reprint requests to Dr. Janelle Noble, Children’s Hospital Oakland Research Institute, 5700 Martin Luther King, Jr. Way, Oakland, CA 94609. E-mail: jnoble{at}chori.org.
Received for publication 24 October 2002 and accepted in revised form 10 March 2003.
A.G. was employed by Roche Bioscience during the course of this study.
ESP, elliptical sib pair; IBD, identity by descent; IL, interleukin; LD, linkage disequilibrium; SNP, single nucleotide polymorphism; TDT, transmission disequilibrium test.
- DIABETES
