A Polymorphism in the TCF7 Gene, C883A, Is Associated With Type 1 Diabetes
Author:
Noble Janelle A.1, White Amy M.2, Lazzeroni Laura C.3, Valdes Ana M.2, Mirel Daniel B.2, Reynolds Rebecca2, Grupe Andrew4, Aud Dee5, Peltz Gary5, Erlich Henry A.2
Affiliation:
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
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.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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