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Diabetes 52:1579-1582, 2003
© 2003 by the American Diabetes Association, Inc.

Brief Genetics Reports

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

1 Children’s Hospital Oakland Research Institute, Oakland, California
2 Roche Molecular Systems, Alameda, California
3 Department of Health Research and Policy, Stanford University, Palo Alto, California
4 Celera Diagnostics, Alameda, CA
5 Roche Bioscience, Palo Alto, California

Type 1 diabetes is an autoimmune disease with a Th1 phenotype in which insulin-producing ß-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.


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